|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Pharmacy UpdateJanuary/February 1997                                                            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|Pharmacy Update Archives
                Drug Information
         Service

         Pharmacy Department
         Warren G. Magnuson Clinical Center
         National Institutes of Health
         Bethesda, Maryland 20892-1196

         Charles E. Daniels,
         Ph.D.
         Chief, Pharmacy Department

         Editor-in-Chief

         Karim Anton Calis, Pharm.D., M.P.H.
         Coordinator, Drug Information Service, and Endocrinology
         Clinical Pharmacy Specialist[email protected]

         Associate
         Editor

         Iris Masucci, Pharm.D.
         Specialized Resident in Drug Information Practice and
         Pharmacotherapy | Evaluation and Management of Antimicrobial Resistance

         Introduction
         Antibiotic-resistant bacteria, such as vancomycin-resistant enterococci (VRE) 
         and organisms with extended spectrum beta-lactamases (ESBL), have become an 
         ever-increasing problem, particularly among hospitalized patients. Resistance 
         to antibacterials has been observed since their introduction, but recently 
         "super-resistant" bacteria have been reported that leave only one antibacterial 
         choice for treatment.
         
         The prevalence of the different types of resistant bacteria has increased 
         at varying rates. Oxacillin-resistant Staphylococcus aureus (ORSA), a clinically 
         isolated pathogen since the early 1960s, has increased among U.S. hospitals from 
         2.4% in 1975 to 29% in 1991. Penicillin-resistant pneumococci, First reported 
         in 1967, have increased worldwide, with some areas of the U.S. reporting very 
         high rates of resistance among clinical isolates. Gram-negative bacilli, primarily 
         Klebsiella pneumoniae and Escherichia coli, that carry transferable resistance 
         to extended-spectrum beta-lactams, have also become more common, with one U.S. 
         study reporting up to 8.6% of clinical isolates having at least intermediate 
         resistance to ceftazidime. Although vancomycin has been used for more than 30 
         years, resistance to this drug has only recently emerged. The prevalence of VRE 
         in the U.S. has increased among nosocomial isolates from less than 0.5% in 
         1989 to more than 10% in 1995, a 20-fold increase. A variety of patient 
         factors have been associated with the development of resistance (Table 1).
         

                The increasing prevalence of resistant bacteria reported nationally has also been 
                observed at the Clinical Center in the past few years, although the presence of 
                these organisms is relatively rare compared to most community hospitals (see Table 
                2 for a list of resistant bacteria commonly encountered at U.S. hospitals). The 
                most common clinically relevant resistant organism cultured at this institution 
                has been ORSA. Since 1984 there have been a total of 94 patients who have had at 
                least one ORSA-positive culture. The number of patients with this organism has 
                remained fairly constant between 1984 and 1996, with the identification of an average 
                of six new patients each year. There have been only eight patients with VRE identified 
                at the Clinical Center since 1994. There have also been five patients who have had an 
                ESBL-producing organism cultured from a clinical specimen, all in 1996.


         Table 1. Factors Associated with the Development of Bacterial ResistanceSite of InfectionBone
                                                Lower respiratory tract
                                                Central nervous system
                                                
                                                Inappropriate use of antimicrobialsSuboptimal dosing or duration
                                                Chronic or repeated administration
                                                Improper antibiotic selection (e.g., overuse of 
                                                broad-spectrum agents)Underlying condition of hostImmune system compromise
                                                Cystic fibrosis
                                                Central nervous system
                                                
                                                OtherIntensive care unit setting
                                                Mechanical ventilation
                                                Presence of mechanical or other foreign materialFish DN, Piscitelli SC, Danziger LH. Development of resistance during antimicrobial 
                therapy: a review of antibiotic classes and patient characteristics in 173 studies. 
                Pharmacotherapy 1995;15:279-91.French GL, Phillips I. Antimicrobial resistance in hospital flora and nosocomial 
                        infections. In: Hospital epidemiology and infection control. Mayhall CG, ed. Baltimore: 
                        Wiliams and Wilkins; 1996:980-99.
                Beta-Lactamase-Producing Gram-Negative Bacilli
        Beta-lactamases are the most common single cause of bacterial resistance 
        to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types 
        are known. These enzymes can hydrolyze the beta-lactam ring of penicillins, 
        cephalosporins, and related antimicrobial drugs, rendering them inactive.
         
         Various cephalosporins are susceptible to cleavage by a variety of beta-lactamases 
         commonly found in gram-negative bacilli, including the chromosomal beta-lactamases 
         of Entero-bacter and Pseudomonas as well as the common plasmid-borne enzymes of the 
         Enterobacteriaceae. The plasmid-mediated enzymes have become common in staphylococci, 
         enteric gram-negative bacilli, Haemophilus influenzae, and Neisseria gonorrheae. 
         The most common beta-lactamase in enterobacteria is the plasmid-mediated TEM-1 
         enzyme, which is responsible for most of the ampicillin resistance seen in E. 
         coli isolates. Other common types are TEM-2 and SHV enzymes. Unlike the chromosomal 
         types, the plasmid-mediated types are usually inactivated by beta-lactamase 
         inhibitors such as clavulanic acid.
         

                Enteric gram-negative bacilli producing extended-spectrum beta-lactamases were 
                first described in Germany in 1983. They are transferable plasmid-mediated enzymes. 
                The most notable feature of these enzymes is their ability to attack extended spectrum 
                cephalosporins (e.g., ceftazidime, cefotaxime, and ceftriaxone) as well as monobactams 
                such as aztreonam. They also attack narrow spectrum cephalosporins (e.g., cephalothin) 
                and anti-gram-negative penicillins (e.g., piperacillin). Cephamycins such as cefoxitin 
                and carbapenems such as imipenem are stable. The majority of the ESBL enzymes reflect 
                the above pattern of activity, but individual enzymes vary in the level of resistance 
                they cause to different compounds. Resistance to ceftazidime and aztreonam, and 
                susceptibility to cephamycins are useful markers of ESBL production in gram-negative 
                bacilli. The most common ESBL-producing strains are Klebsiella pneumoniae, other 
                Klebsiella species, and E. coli.      
      
      Oxacillin-Resistant Staphylococcus Aureus (ORSA)
        Oxacillin-resistant Staphylococcus aureus (also known as methicillin-resistant 
        Staphylococcus aureus) has become a major noscomial pathogen in community, 
        long-term care, and tertiary care hospitals. This pathogen can cause serious 
        infection, and contributes signi�cantly to mortality and morbidity in hospitals 
        worldwide.
         
         Resistance to oxacillin and methicillin in staphylococci is mediated by alterations 
         in membrane-bound enzymes called penicillin binding proteins (PBPs). PBPs perform 
         important functions for cell survival and are the targets for beta-lactam antibiotics. 
         There must be a high af�nity between the drug and the bacterial PBPs for the antibiotic 
         to be effective. In the typical oxacilllin-resistant strain of S. aureus, the drug 
         resistant target termed PBP2a (or PBP2') mediates clinically relevant resistance to 
         all beta-lactam antibiotics. PBP2a is a unique cell wall-synthesizing enzyme that 
         confers resistance ranging from a few organisms to a majority of organisms in a 
         population. The low af�nity of PBP2a for beta-lactams enables the organism to survive 
         in the presence of otherwise lethal concentrations of beta-lactam antibiotics. PBP2a 
         is encoded by the chromosomal gene mecA which is highly conserved in clinical isolates 
         of oxacillin-resistant staphylococci.
         

                ORSA isolates are frequently resistant to a wide range of antibiotics by a variety 
                of different resistance mechanisms (e.g., many isolates are resistant to aminoglycosides 
                due to the presence of aminoglycoside modifying enzymes).      
      
      
      Vancomycin-Resistant Enterococci (VRE) and Aminoglycoside-Resistant Enterococci
        Enterococci are currently a major cause of nosocomial infection, 
        and antibiotic resistance in these organims has become a particular 
        problem in hospitals.
         
         Enterococci have intrinsic resistance to a wide variety of antimicrobial agents. 
         They also have the ability to acquire resistance by mutation or by receipt of 
         foreign genetic material through the transfer of plasmids and transposons. Until 
         recently, vancomycin was the only drug that could be consistently relied upon 
         to treat multidrug resistant enterococci.
         

                Vancomycin-resistant enterococci were �rst reported in Europe in the mid 
                1980s and later in the U.S. The most frequent enterococcal species demonstrating 
                acquired resistance to glycopeptides are E. faecium and E. faecalis. Acquired 
                vancomycin resistance in enterococci is mediated by complex mechanisms encoding 
                an alternative pathway for the production of a modi�ed cell wall component with 
                markedly reduced af�nity for vancomycin. Glycopeptide-resistant enterococci are 
                divided into different phenotypes primarily on the basis of their resistance to 
                vancomycin and teicoplanin. Four phenotypes have been described, namely Van A, 
                Van B, Van C, and Van D. VanA is the most common phenotype, and is manifested 
                by high-level resistance to vancomycin, and moderate or high level resistance 
                to teicoplanin.    
           
      
                Enterococci are also intrinsically resistant to amino-glycosides, but the 
                addition of a beta-lactam antibiotic (e.g., ampicillin) allows entry of the 
                aminoglycoside into the bacterial cell, producing a synergistic combination 
                that results in cell death. Enterococci that are highly resistant to 
                aminoglycosides pose an important clinical problem as these organisms 
                are resistant to synergistic killing by beta-lactam/ aminoglycoside combinations. 
                The resistance is due to the production of plasmid-mediated aminoglycoside-modifying 
                enzymes.  
      
      
      Table 2. Resistant Bacteria Commonly Encountered at U.S. HospitalsOrganism
                                        
                                        Mechanism of Resistance
                                                
                                        Treatment OptionsESBL1-producing gram-negative bacilli
                                        
                                        Production of beta-lactamase enzymes which 
                                        inactivate beta-lactam antibacterial agents
                                                
                                        Carbapenems
                                        Beta-lactam/beta-lactamase inhibitor combination 
                                        Fluoroquinolones, aminoglycosides, trimethoprim-sulfamethoxazoleORSA
                                        
                                        Alterations in the penicillin-binding proteins
                                                
                                        Vancomycin 
                                        Teicoplanin
                                        Mupirocin (topical)VRE3
                                        
                                        Modified cell wall precursors with decreased affinity for vancomycin
                                                
                                        Teicoplanin
                                        Quinupristin-dalfopristin
                                        Combinations of beta-lactam or 
                                        beta-lactams and a glycopeptideAdopted from Gold HS, Moellering RC. Antimicrobial-drug resistance. N Engl 
                J Med 1996; 335: 1445-53.
                1Extended-spectrum beta-lactamase;2Oxacillin-resistant S. aureus; 3Vancomycin-resistant enterococci
                Management of Patients with Resistant Bacteria at the Clinical Center
        Clinical Center patients with a positive culture for a strain of resistant 
        bacteria are immediately placed on isolation precautions that are specific for 
        this situation. These precautions are used to minimize the risk of nosocomial 
        transmission and are based on studies that suggest that spread of these organisms 
        can be limited when a diligent effort is made by healthcare providers. There have 
        been a number of reports of clusters and outbreaks caused by resistant bacteria 
        that have been related to the transient carriage of organisms on healthcare providers' 
        hands as they move from one patient to another. Therefore, glove use and proper 
        handwashing are important mechanisms for decreasing the spread of organisms. 
        Fomites, such as stethoscopes, blood pressure cuffs, and electric thermometers 
        have also been demonstrated to play a role in some outbreaks. Therefore, dedicated 
        equipment is required for patients with positive cultures for resistant bacteria. 
        The environment has also been suggested as a factor in the transmission of resistant 
        organisms, making good housekeeping procedures a necessity.
         
         The precautions currently used at the Clinical Center, called Resistant Bacteria 
                  Precautions, include: the use of a private room, the use of gloves for all 
                  patient contact (masks and gowns may also be needed in special situations), 
                  the use of dedicated patient equipment (stethoscope, blood pressure cuff, 
                  thermometer, etc.), scrupulous environmental cleaning, the restriction of 
                  the patient to his/her assigned room [except for patient-care procedures 
                  in ancillary departments and activities approved by Hospital Epidemiology 
                  Service (HES)], the restriction of the patient from contact with other 
                  patients, and most importantly, the practice of proper handwashing with 
                  an antiseptic cleaning agent. These precautions should be initiated as 
                  soon as a patient is identi�ed with a resistant organism, and HES should 
                  be contacted (496-2209).
         

                Unfortunately, most patients who have been found to be colonized or infected 
                with resistant bacteria will continue to be culture positive as long as they are 
                hospitalized. Attempts at eliminating a resistant organism by treating individuals 
                with different regimens are often unsuccessful, especially when the site that is 
                positive involves an implanted device, is an unhealed wound, or involves an area 
                that contains large amounts of body secretions (e.g., sputum). Occasionally, 
                patients may be cleared of a resistant organism and can have the special 
                restrictions discontinued. These patients must meet the following criteria: 
                the documentation of two sets of negative cultures obtained 48 hours apart; 
                these cultures must have been collected only after all relevant antibiotics have 
                been discontinued for 24 hours, and must be sent from all previously positive sites.    
           
      Bibliography
        Berger-Bachi B.  Expression of resistance to methicillin. Trends in 
        Microbiology 1994;2:389-93.
         
         French GL, Phillips I. Antimicrobial resistance in hospital flora and nosocomial 
         infections. In: Hospital epidemiology and infection control. Mayhall CG, ed. 
         Baltimore: Wiliams and Wilkins; 1996:980-99.
         

                Gold HS and Moellering RC.  Antimicrobial-drug resistance.  
                N Engl J Med 1996;335:1445-53.
                
                Jacoby GA, Archer GL.  New mechanisms of bacterial resistance to antimicrobial 
                agents.  N Engl J Med 1991;324:601-12.
                
                Jones JS, Hoerle D, Riekses R.  Stethoscopes: a potential vector of infection?  
                Ann Emerg Med 1995;26:296-9.
                
                Layton MC, Perez M, Heald P, et al.  An outbreak of mupirocin-resistant 
                Staphylococcus aureus on a dermatology ward associated with an environmental 
                reservoir.  Infect Control Hosp Epidemiol 1993;14:369-75.
                
                Livermore DM. Beta-lactamases in laboratory and clinical resistance. Clin 
                Microbiol Rev 1995;8:557-84.
                
                Livornese LL, Dias S, Jamel C, et al.  Hospital-acquired infection with 
                vancomycin-resistant Enterococcus facecium transmitted by electronic 
                thermometers.  Ann Intern Med 1992;117: 112-6.
                
                Maple PAC, Hamilton-Miller JMT, Brumfitt W. World-wide antibiotic resistance 
                in methicillin resistance in Staphylococcus aureus. Lancet 1989;1:537-40.
                
                Mulligan ME, Murray-Leisure KA, Ribner BS, et al. Methicillin-resistant 
                Staphyloccocus aureus: a consensus review of the microbiology, pathogenesis, 
                and epidemiology with implications for prevention and management. Am J Med
                1993;94:313-28.
                
                Panlilio AL, Culver DH, Gaynew RP, et al.  Methicillin-resistant Staphyloccocus aureus
                 in U.S. hospitals, 1975-1991.  Infect Control Hosp Epidemiol 1992;13:582-6.
                 
                 
                 Editor's Note
                We wish to acknowledge Elizabeth O'Shaughnessy, M.D., Gary A. Fahle, 
                Mary Willy, M.P.H., Ph.D., and Steve Piscitelli, Pharm.D. for their 
                contributions and thank Michael Polis, M.D., M.P.H., Thomas Walsh, M.D., 
                Henry Masur, M.D., and John Bennett, M.D. for reviewing this special issue 
                of Pharmacy Update. | Site of InfectionBone
                                                Lower respiratory tract
                                                Central nervous system                                                         
|Site of InfectionBone
                                                Lower respiratory tract
                                                Central nervous system                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Inappropriate use of antimicrobialsSuboptimal dosing or duration
                                                Chronic or repeated administration
                                                Improper antibiotic selection (e.g., overuse of 
                                                broad-spectrum agents)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
|Underlying condition of hostImmune system compromise
                                                Cystic fibrosis
                                                Central nervous system                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | OtherIntensive care unit setting
                                                Mechanical ventilation
                                                Presence of mechanical or other foreign material                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
|Organism                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Mechanism of Resistance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Treatment Options                                                                                                                                                                                                            
|ESBL1-producing gram-negative bacilli                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Production of beta-lactamase enzymes which 
                                        inactivate beta-lactam antibacterial agents                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Carbapenems
                                        Beta-lactam/beta-lactamase inhibitor combination 
                                        Fluoroquinolones, aminoglycosides, trimethoprim-sulfamethoxazole               
|ORSA                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Alterations in the penicillin-binding proteins                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Vancomycin 
                                        Teicoplanin
                                        Mupirocin (topical)                                                                                                  
|VRE3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Modified cell wall precursors with decreased affinity for vancomycin                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Teicoplanin
                                        Quinupristin-dalfopristin
                                        Combinations of beta-lactam or 
                                        beta-lactams and a glycopeptide



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