Antibiotic Therapy for Musculoskeletal Infections (2001)

Antibiotics are grouped into categories on the basis of their mechanisms of action. These categories include cell-wall active antibiotics, ribosomal active antibiotics, RNA active antibiotics, DNA active antibiotics, antimetabolites, and the reducing compounds. Cell-Wall Active Antibiotics The cell-wall active antibiotics include penicillins, β-lactamase inhibitors, cephalosporins, other β-lactam antibiotics, and vancomycin. β-lactamase inhibitors are combined with the penicillins to enhance the antibiotic activity against β-lactamase-producing organisms. Penicillins The penicillin class of antibiotics is frequently used for the treatment of musculoskeletal infections. The penicillins can be divided into general groups on the basis of their antibacterial activity. The major penicillin groups of interest to an orthopaedic surgeon are natural penicillins, aminopenicillins, penicillinase-resistant penicillins, antipseudomonal penicillins (carboxypenicillins), and extended spectrum penicillins (ureidopenicillins). There is overlap among these groups; the differences are usually pharmacological in nature. The major side effects of all of the penicillins are hypersensitivity reactions that range in severity from a rash to anaphylaxis1. Immediate hypersensitivity reactions have been reported to occur in 0.0004% to 0.15% of patients2. Of those patients, urticaria occurs in 1% to 5% and a rash occurs in 2% to 9%. Hemolytic anemia and central nervous system toxicities can also occur with penicillin administration. Serum sickness rarely occurs with penicillins. Additionally, exfoliative dermatitis and erythema multiforme are rare forms of allergic reactions to penicillin. Penicillin G is the major natural penicillin. Although penicillin G has a half-life of thirty to sixty minutes, it can be combined with procaine or benzathine to produce a repository penicillin. Penicillin is the drug of choice for the treatment of Streptococcus pyogenes, Streptococcus agalactiae, and Clostridium perfringens. In addition, penicillin has a good anaerobic spectrum of activity except for the Bacteroides fragilis group. Streptococcus pneumoniae continues to become more resistant to penicillin. Currently, Streptococcus pneumoniae has an intermediate resistance to penicillin in 15% of cases and a high-level resistance to penicillin in 15%. The major side effects of the natural penicillins are immediate hypersensitivity reactions, including anaphylaxis, bronchospasm, and hives, as well as delayed reactions, including skin rashes3. Other potential side effects are renal failure, Coombs-positive hemolytic anemia, and seizure activity, which usually occurs with aqueous penicillin doses of >20 ¥ 106 U/day. The parenteral penicillinase-resistant penicillins are methicillin, nafcillin, and the isoxazolyl penicillins (including oxacillin, cloxacillin, dicloxacillin, and flucloxacillin). The most active parenteral semisynthetic penicillins are nafcillin and oxacillin. These drugs are resistant to Staphylococcal β-lactamase and are used when methicillin-sensitive Staphylococcus aureus is present or suspected. The semisynthetic penicillins are also active against Streptococcus pyogenes and Streptococcus pneumoniae. However, they have no activity against Enterococcus species or gram-negative bacilli. Methicillin is associated with the greatest potential for producing interstitial nephritis4. Nafcillin and oxacillin may cause interstitial nephritis, leukopenia, and reversible hepatic dysfunction5,6. Cloxacillin and dicloxacillin are the oral semisynthetic penicillins of choice in the United States, and they have fewer side effects than the parenteral semisynthetic penicillins. The major aminopenicillins include ampicillin and amoxicillin. Ampicillin may be given parenterally or orally, whereas amoxicillin may be given only orally. The antibacterial activities of the aminopenicillins are similar. They are the antibiotics of choice for the treatment of sensitive Enterococcus species(Enterococcus faecalis andEnterococcus faecium)7. The aminopenicillins are also active against many highly susceptible gram-negative rods, such as Escherichia coli and Proteus mirabilis. They are not stable to β-lactamase and are less active than penicillin G against Streptococcus pyogenes and Streptococcus agalactiae. While the aminopenicillins may cause skin rashes, an idiosyncratic rubella-form rash occurs in 99% of patients who have mononucleosis and are given the aminopenicillins. Ticarcillin (carboxypenicillin) is an antipseudomonal penicillin. Ticarcillin has a β-lactam ring and is susceptible to β-lactamase of both gram-positive and gram-negative organisms. Ticarcillin has a gram-negative spectrum of activity similar to ampicillin but is more active than ampicillin against Pseudomonas species, Enterobacter species, Serratia species, and certain strains of the Bacteroides fragilis group. Ticarcillin has poor activity against Klebsiella species8. The side effects of this class of penicillins include sodium-loading and bleeding problems secondary to platelet dysfunction9. The extended spectrum penicillins (ureidopenicillins) include mezlocillin and piperacillin. They have an antibacterial spectrum similar to that of ticarcillin. In vitro, these antibiotics are active against Enterococcus species and Streptococcus species, and they inhibit the majority of Klebsiella species. They are also more active than ticarcillin against Haemophilus influenzae and the Bacteroides fragilis group10,11. These drugs act in synergy with the aminoglycosides against Pseudomonas aeruginosa and most of the Enterobacteriaceae. They have the same side effects as ticarcillin, except they cause less sodium-loading and bleeding dysfunction. Penicillins as a group have a number of drug interactions. However, these interactions are generally uncommon. The carboxypenicillins and ureidopenicillins inactivate the aminoglycosides12,13. This drug interaction is seen in patients who have underlying renal dysfunction14,15. Probenecid inhibits tubular secretion of the penicillins and increases the drug half-life of these agents16. b-lactamase Inhibitors β-lactamase of gram-positive species is an exoenzyme. Clavulanic acid, sulbactam, and tazobactam are potent inhibitors of β-lactamase produced by gram-positive and gram-negative organisms17. Clavulanic acid, sulbactam, and tazobactam have been shown to inhibit β-lactamase for a number of clinically important gram-positive organisms, including Staphylococcus aureus and Staphylococcus epidermidis18.β-lactamase of both gram-negative and most anaerobic organisms is situated in the periplasmic space and is chromosome and plasmid-induced19. Clavulanic acid, sulbactam, and tazobactam inhibit β-lactamase of many gram-negative organisms, including Escherichia coli, and most Klebsiella and Bacteroides species. Currently, clavulanic acid is commercially available with amoxicillin (Augmentin; SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania) and ticarcillin (Timentin; SmithKline Beecham Pharmaceuticals). Sulbactam is available with ampicillin (Unasyn; Pfizer, New York, NY). Tazobactam is combined with piperacillin (Zosyn; Lederle, Pearl River, New York). The β-lactam inhibitors enhance the gram-positive coverage and, to a lesser extent, the gram-negative spectrum of these antibiotics. The side effects are the same as those of the penicillin class of antibiotics. Cephalosporins The cephalosporins have been divided into first, second, third, and fourth-generation agents. The first-generation cephalosporins include cephalothin, cephapirin, cephradine, and cefazolin and are active against Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus species. They have limited gram-negative activity but are active against Escherichia coli, Klebsiella species, and Proteus mirabilis. The first-generation cephalosporins are safe antibiotics but are occasionally associated with allergic reactions, drug eruptions, phlebitis, and diarrhea. Cefazolin is the first-generation cephalosporin used by the orthopaedic community for the treatment of staphylococcal infections, including osteomyelitis. The large amounts of β-lactamase produced by Staphylococcus aureus (109 organisms per gram of tissue) inactivate cefazolin20. However, high numbers of Staphylococcus aureus are not the norm in staphylococcal osteomyelitis; £105 organisms per gram of bone are usually found. Cefazolin has a longer half-life and higher serum concentration than the other first-generation cephalosporins21. The remainder of the first-generation cephalosporins are comparable. They are all more stable to β-lactamase than cefazolin is. There are many second-generation cephalosporins, but the major parenteral ones are cefamandole, cefoxitin, cefotetan, and cefuroxime. The major oral cephalosporins are cefuroxime, cefprozil, and loracarbef. The second-generation cephalosporins are somewhat more active against gram-negative organisms than are the first-generation agents, but they are less active than the third-generation agents. Cefoxitin and cefotetan are more active against the anaerobes, especially the Bacteroides fragilis group, than are the first-generation or the other second-generation cephalosporins22. The second-generation cephalosporins have the same toxicity potential as the first-generation cephalosporins with the exception of those that have a methylthiotetrazole side chain. The major third-generation cephalosporins are cefotaxime, ceftriaxone, ceftizoxime, cefoperazone, and ceftazidime. Compared with the first-generation cephalosporins, the third-generation cephalosporins are generally less active against gram-positive organisms but are more active against the Enterobacteriaceae23. Cefotaxime, ceftriaxone, and ceftizoxime are third-generation cephalosporins with similar antibacterial activity. They are highly resistant to β-lactamase, and they have activity against gram-positive organisms with the exception of the Enterococcus species. They have good activity against most gram-negative organisms except for Pseudomonas aeruginosa. Cefotaxime, ceftizoxime, and ceftriaxone have half-lives of 1.1, 1.7, and 8.0 hours, respectively. Ceftazidime is similar to cefotaxime, ceftizoxime, and ceftriaxone with regard to activity against the Enterobacteriaceae, but it has superior activity against Pseudomonas aeruginosa24. For serious Pseudomonas aeruginosa infections, it should be combined with an aminoglycoside25. The activity of ceftazidime against gram-positive organisms is half that of cefotaxime, ceftizoxime, and ceftriaxone. The fourth-generation cephalosporins are represented by cefepime. Cefepime has excellent activity against aerobic gram-positive organisms, including methicillin-sensitive Staphylococcus aureus, and gram-negative organisms, including Pseudomonas aeruginosa. In vitro data have suggested increased activity of cefepime against multiresistant Enterobacter species. Like other cephalosporins, cefepime has no activity against Enterococcus species. In general, the cephalosporins have a low prevalence of adverse reactions. A cross-reactivity occurs in 3% to 7% of patients with an allergy to penicillin. This may be a true cross-reactivity (allergy) or those patients may be more allergic. The allergic reactions to the cephalosporins include a type-I immediate hypersensitivity reaction, including bronchospasm, hives, and skin rashes, occurring three to five days after the initiation of therapy. Fever, lymphadenopathy, eosinophilia, and serum-sickness reactions may also occur. The cephalosporins cause a Coombs-positive anemia in approximately 3% of patients. Neutropenia occurs in approximately 1% of patients, usually after three weeks of the therapy. Liver function abnormalities, with elevation of liver enzyme levels, occur in 1% to 7% of patients. Antibiotic-associated colitis is associated with cephalosporin administration as well. Some second and third-generation cephalosporins, including cefotetan and cefamandole (second generation) as well as moxalactam and cefoperazone (third generation), have the methylthiotetrazole side chain. Antibiotics with the methylthiotetrazole side chain can cause a disulfiram reaction when a patient drinks alcohol26-30, and they are also associated with hypoprothrombinemia31-35. The cephalosporins have very few reported drug-drug and drug-food interactions. Other b-lactam Antibiotics Aztreonam is a monocyclic β-lactam antibiotic, which is active against most Enterobacteriaceae and Pseudomonas aeruginosa36. Aztreonam has no appreciable antibacterial activity against aerobic gram-positive or anaerobic bacteria. The drug must be given parenterally. No major adverse reactions have been reported with this antibiotic37,38. Minor reactions to aztreonam include nausea, vomiting, and diarrhea. On occasion, the drug may cause elevated levels of liver transaminases. Aztreonam has a low probability of cross-reactivity (allergy) in patients allergic to penicillin or cephalosporin. Imipenem is an antimicrobial agent belonging to the β-lactam class of antibiotics. Biochemically, it is a carbapenem. Imipenem also has excellent in vitro activity against aerobic gram-positive organisms, including Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcal species. Imipenem also has excellent activity against gram-negative organisms, including the Enterobacteriaceae and Pseudomonas aeruginosa. In addition, imipenem inhibits most anaerobic species, including the Bacteroides fragilis group39. Some patients have nausea, vomiting, and diarrhea with imipenem therapy. Penicillin cross-reactivity occurs with imipenem. Grand mal seizures occur in 1% to 4% of patients receiving this antibiotic. The prevalence of seizures is increased in patients with renal dysfunction40,41 and/or a history of seizure activity. Finally, resistance to Pseudomonas aeruginosa and fungal superinfection may develop during therapy. Vancomycin Vancomycin has excellent activity against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus species. is the antibiotic of choice for who are to the penicillins or the Vancomycin is also the antibiotic of choice for the treatment of Staphylococcus and Staphylococcus on Enterococcus species have increased and used as the toxicity of is The may be with therapy. This of the and and is associated with occurs in 5% to of patients, especially when the is given less than reactions rarely occur with therapy. Vancomycin may be associated with or especially when given with an Vancomycin may also cause and Active Antibiotics The ribosomal active antibiotics include and is of the antibiotics most active against clinically important anaerobic the Bacteroides fragilis group. However, is against species, other than Clostridium in to of In to anaerobic activity, is also against Staphylococcus aureus, Staphylococcus species, and the Streptococcus species. has a half-life of and is given good into most including and well into is but diarrhea and colitis in approximately of In of patients who have colitis secondary to produced by the of Clostridium reactions, including rashes, and erythema may occur with administration. drug interactions are but may the of is the of the class of These the ribosomal and are has in vitro activity against Streptococcus species, and pneumoniae. The and can inhibit species, and pneumoniae They are also more active against Haemophilus and other The are active against the agent of of high is more active against and and is very active against The are for the treatment of and and skin infections. The are the of choice for infections. The are generally to be very safe They cause reactions, including nausea, vomiting, and in approximately of patients. These problems are less with such as and The have a number of drug interactions. They hepatic activity with This increased levels of and has the potential of the New is a of in a of This antibiotic in vitro and activity against most gram-positive organisms, including Enterococcus also has a in the treatment of Staphylococcus aureus and Staphylococcus species in patients who therapy. to to be and include reactions such as and as well as and side effects are phlebitis, especially in the The antibiotic should be given a central In a the drug in approximately 15% to of patients who The are divided into three the and an intermediate group and the more group and The are They are drugs for the treatment of including and are also active against and In addition, they also are in the treatment of including and is the most active drug of the class against Staphylococcus is used in with for the oral treatment of Staphylococcus aureus and Staphylococcus species. The have excellent of their high is the most The high and it for the treatment of organisms. in The have major side including nausea, vomiting, and diarrhea. also cause especially in They should not be given to less than of as they cause of and may bone in this are and renal They have a to cause major reactions. Other side effects include and hypersensitivity reactions. toxicity in patients. antibiotics have a number of drug interactions. including and when given to of the A number of drugs hepatic of the which a half-life of this class of antibiotics. The are a class of These have activity against a number of important organisms, including Staphylococcus aureus, Streptococcus and Enterococcus They have when parenterally or orally. effects include a of nausea, vomiting, and diarrhea. The which include and are the against which other antibiotics are for the treatment of aerobic gram-negative infections. The aminoglycosides generally have poor activity against gram-positive organisms. they may be used for the treatment of Staphylococcus aureus, but resistance may develop They have no against the Streptococcus species or anaerobes, but they have excellent activity against the Enterobacteriaceae and Pseudomonas aeruginosa. The aminoglycosides may be by has fewer available than the other aminoglycosides for the of strains susceptible to is than that susceptible to or There is no that has or lesser activity than the other The aminoglycosides can cause and reactions include and problems such as nausea, vomiting, and with Other toxicities include and hypersensitivity reactions. The aminoglycosides have drug interactions. There is increased and when acid, agents, or are given with the RNA Active Antibiotics activity against a of gram-positive and gram-negative organisms. is the most active agent However, it is less active against most gram-negative than are the is used for the treatment of infections, a of resistance can be by the of a second antibiotic. in with a semisynthetic penicillin has been used to by methicillin-sensitive Staphylococcus species. or and have been used to by Staphylococcus species. effects of include of and There are a number of drug The of with to a higher of of with can in a of with the of and this antibiotic must be on an hepatic and can the of certain drugs these must be and their drug doses must be when by hepatic and can the of these DNA Active Antibiotics There are of The acid, is used to infections. The second, third, and fourth-generation may be used to musculoskeletal infections, including The second-generation include and which and and have against most gram-negative organisms. strains and anaerobic organisms are resistant to and of resistance by Staphylococcus aureus and Staphylococcus strains is in the treatment of gram-negative bone infections, which parenteral antibiotic The third-generation include and which higher serum levels than or These have excellent activity against Streptococcus species, including strains and resistant Streptococcus pneumoniae. They are also active against species, and They have against most gram-negative organisms as well. The fourth-generation have aerobic gram-positive and gram-negative coverage similar to that of the third-generation the third-generation the fourth-generation have excellent anaerobic In a number of patients, has been associated with serious liver to liver and/or While this has been reported with both and treatment for more than weeks is associated with an increased of liver Currently, may be used only for serious or in a or of the have Enterococcus species The have Staphylococcus aureus and Staphylococcus and resistance to the second and third-generation is Although second, third, and fourth-generation are for parenteral oral administration excellent serum and is associated with a of and treatment In most treatment with is parenterally and, after to is to oral that is who have not should not be with the class of antibiotics bone has been in on the toxicity of the is of nausea, vomiting, and/or occur in 2% to 5% of patients. nervous system reactions, including and occur in 1% to 2% of patients. The may cause hypersensitivity reactions, including skin may be by of the especially and The may also cause and a to of the and, this class of antibiotic may cause interstitial While all cause have the for certain side for of the The also have drug-drug including and the and the of most have drug-drug interactions and and toxicity increased levels of or levels by nervous system with The include the and is a of a and In vitro, these are more active than agent is gram-negative including Escherichia coli, Proteus Haemophilus and are In addition, Klebsiella Enterobacter and Pseudomonas are frequently The of are aerobic gram-negative organisms, but gram-positive such as Staphylococcus aureus, Streptococcus and Streptococcus pyogenes are In the of and may be for the oral treatment of Staphylococcus aureus and Staphylococcus may be given parenterally or orally. The is as for osteomyelitis. of the including have side including Other side effects include such as hemolytic anemia, anemia, and reactions include erythema and erythema The may cause a or and of and A can occur with the and a drug occurs in 3% of patients these The have also been reported to cause and a should not be during the of The have a number of drug which include increased effects of and increased levels of They also the effects of the Finally, the the by is a and antibiotic for the treatment of anaerobic organisms. This antibiotic is a reducing that to the of are for anaerobic organisms, they the and is active against all anaerobic organisms except for and The drug is well and into and effects are rare but can include disulfiram reaction with and may also have side including nausea, vomiting, and In antibiotics for the treatment of musculoskeletal infections, the of and of adverse reactions must be the or organisms are and the are the antibiotic should be The of antibiotics for and anaerobic organisms are shown in and The antibiotic is on the basis of and of Antibiotics for of Antibiotics Bacteroides fragilis group or acid species or cefotetan species Penicillin G 106 or Clostridium species or penicillin G ¥ 106 of Antibiotics for of Antibiotics Antibiotics species Ceftazidime and or imipenem Enterobacter species or imipenem or Escherichia coli or Haemophilus influenzae or or Klebsiella species or or Proteus Ampicillin or or Proteus Proteus or or imipenem or or of and of and species given or or imipenem Pseudomonas aeruginosa or or imipenem or Serratia or imipenem be used for strains of Haemophilus a serious cefepime or piperacillin should be used with an or resistance to the including of Antibiotics for of Antibiotics Antibiotics Staphylococcus aureus Nafcillin or Cefazolin or Staphylococcus species Nafcillin or Cefazolin or Staphylococcus aureus Vancomycin or or with or Staphylococcus species Vancomycin or or with or Streptococcus or Streptococcus pyogenes Penicillin G ¥ 106 or ampicillin or or Streptococcus Penicillin G ¥ 106 or ampicillin or Streptococcus pneumoniae Penicillin G ¥ 106 or Streptococcus pneumoniae or Streptococcus pneumoniae Vancomycin or or Enterococcus species Ampicillin or Enterococcus or and is sensitive to and an are used for a serious Enterococcus species the or organisms are the antibacterial activity of a of antibiotics can be by The is used for for and organisms. The of a of an approximately to the are as intermediate or resistance to antimicrobial agent to data are by that of antibiotics in or by or is a for the of the concentration of the antibiotic to inhibit and the or of an antibiotic or antibiotic with a low concentration to serum only and serum and levels, as by and are to the and of the treatment antibiotic or antibiotics. serum are from the patient after administration of a of the antibiotic in to the and serum The serum are and the are against an of the species. of this can the antibiotic to serum and antibiotic These are as and serum The and of the data among for a serum of an or higher of a serum has a on the species or In with serum have been to the of oral antibiotic In a patient with for antibiotics are by concentration the of is by the of than by the of Antibiotics in antibiotics must be used with in Antibiotics that have the include penicillins, cephalosporins, and Other antibiotics can cause the for can cause The when given in the from to The bone in the and can cause and liver in the is in The in and are in or cause adverse in Antibiotics in antibiotics, such as and in when to and can have adverse effects on is for the to during antibiotic by of a is a antibiotic, or should be of The of antibiotic to the of musculoskeletal or in a bone or a and the musculoskeletal infections, and the of antibiotic to can be to oral when the patient is clinically has a higher and a longer of parenteral is usually for this is with parenteral antibiotic usually for to three weeks after or or A can be given when the is by organisms that are very susceptible to antibiotic including Haemophilus Streptococcus species, and For the more resistant organisms, including Staphylococcus aureus and gram-negative three weeks of parenteral antibiotic is usually is with parenteral antibiotic usually for to weeks after the major but few have the of The data on this from of an Staphylococcus aureus and groups of with for or The longer that the with the the treatment The used in that is not to antibiotics must the antibiotic has been in The associated with to weeks of parenteral antibiotic in those from to The of antibiotic has not been from parenteral to oral may be an for the treatment of osteomyelitis. In a by patients with five to days of parenteral by weeks of oral therapy. in of the who to be In a of the treatment of weeks of parenteral antibiotic with weeks of parenteral by weeks of oral antibiotic therapy. The in the group that parenteral antibiotic and in the group with parenteral antibiotic by oral antibiotic therapy. The for the of antibiotic in the treatment of is to are given weeks of parenteral by weeks of oral therapy. The treatment for is to weeks of parenteral therapy. However, many weeks of parenteral by to weeks of oral therapy. in the The of antibiotic treatment of in the is usually on the of is not or is the patient can be with oral antibiotic therapy. is in a bone that is to the may be and to weeks of antibiotic should be after the patient is with and the bone the is antibiotics are given for weeks in to the bone is the patient is given to weeks of antibiotic therapy. Finally, when is to the of the patient is with a of antibiotic which is usually less than three a patient with of the is with oral antibiotic for of the This is only for the treatment of of the of the of with antibiotic is not The and the for their in the and of this