bluuebunny/crossref_metadata_2025 huggingface dataset:
Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease
Authors: Thompson M I , Russo M E , Saxon B J , Atkin-Thor E , Matsen J M
Published: June 2012

Possible antibiotic inactivation was studied in 12 subjects with end-stage renal disease who were undergoing thrice-weekly hemodialysis. The study was a randomized three-way crossover. Subjects received (i) gentamicin as a single intravenous dose of 2 mg/kg, (ii) 4 g of piperacillin intravenously every 12 h for four doses or 2 g of carbenicillin intravenously every 8 h for six doses, and (iii) gentamicin as described in (i) plus piperacillin or carbenicillin as described in (ii). Subjects were studied on their off-dialysis days, and each treatment phase was separated by a 3-week wash-out period. Gentamicin was inactivated to a greater extent by carbenicillin than by piperacillin (P less than 0.05). In the six subjects in the carbenicillin group, the terminal elimination-phase half-life (t 1/2 beta) of gentamicin was 61.6 h when gentamicin was administered alone, and it was 19.4 h when gentamicin was administered with carbenicillin. In six subjects in the piperacillin group, the mean t 1/2 beta of gentamicin when gentamicin was given alone was 53.9 h, and it was 37.7 h when gentamicin was given with piperacillin. The inactivation rate constant (ki) of gentamicin was 0.0251/h for the carbenicillin group and 0.0064/h for the piperacillin group, demonstrating that carbenicillin inactivated gentamicin for time faster than did piperacillin. No inactivation of either beta-lactam could be measured. Control samples verified that no in vitro inactivation occurred.
Chemical and chromatographic analysis of lipopolysaccharide from an antibiotic-supersusceptible mutant of Pseudomonas aeruginosa
Authors: Kropinski A M , Kuzio J , Angus B L , Hancock R E
Published: June 2012

Lipopolysaccharides extracted from Pseudomonas aeruginosa strain K799 and its antibiotic-supersusceptible derivative Z61 were analyzed chemically and chromatographically. The side-chain polysaccharides purified by gel exclusion chromatography were compositionally identical, being composed of fucosamine (2-amino-2,6-dideoxygalactose), quinovosamine (2-amino-2,6-dideoxyglucose), and an unidentified amino sugar. In addition, low amounts of the core-specific components (glucose, rhamnose, alanine, and galactosamine) were found associated with the side chains from both strains. An average molecular weight of 38,000 to 50,000 was calculated for this fraction based on the glucose and rhamnose levels. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the lipopolysaccharides from these two strains were microheterogeneous. Qualitative analysis of the lipopolysaccharide neutral sugars, using a series of single-step revertants of mutant Z61, demonstrated that full revertants showed patterns indistinguishable from those of the wild-type strain K799, whereas partial revertants had intermediate levels and mutant Z61 low levels of neutral sugars. Quantitative analysis revealed that the core oligosaccharide fraction from the wild-type strain had a glucose/rhamnose/galactosamine ratio of 4:1:1, whereas the core from Z61 exhibited major deficiencies in both glucose and rhamnose. The lipid A from both strains contained five fatty acids, namely, 3-hydroxydecanoate, dodecanoate, 2- and 3-hydroxydodecanoate, and hexadecanoate. Whereas the overall fatty acid content was equal, the mutant strain showed markedly lower levels of dodecanoate and hexadecanoate and increased levels of 2-hydroxydodecanoate. Results of whole-cell fatty acid analyses were consistent with this observation. Evidence for an additional alteration of the lipid A of strain Z61 was obtained from acid hydrolysis studies and infrared spectra of isolated lipid A, although the actual chemical basis could not be determined by a variety of techniques. It is suggested that the state of the lipopolysaccharide is able to influence the number of open functional protein F pores in the outer membrane of P. aeruginosa.
Clinical evaluation of cefotaxime for therapy of lower respiratory tract infections
Authors: Schleupner C J , Engle J C
Published: June 2012

A clinical trial was designed to evaluate the efficacy and safety of cefotaxime, a new semisynthetic, broad-spectrum cephalosporin, in the therapy of community-and hospital-acquired pneumonias. Thirty-nine males (mean age, 65 years) were treated for 41 episodes of pneumonia. Only five patient did not have a serious underlying disease; 15 had two or more significant disorders. Sixty-six percent of these pneumonias were due to Streptococcus pneumoniae or Haemophilus influenzae. The minimal inhibitory concentrations for all bacterial isolates ranged from 0.008 to 4 micrograms/ml. Peak serum cefotaxime levels during therapy ranged from 12 to 124 micrograms/ml 1 h after a 1-g dose. Satisfactory bacteriological and clinical responses were observed in 85% of the cases. Four episodes of pulmonary superinfections due to cefotaxime-resistant gram-negative bacilli were noted, each in a patient being mechanically ventilated. Pseudomonas was involved in each of these superinfections, and three were fatal. No serious toxicity or adverse reaction to cefotaxime was seen. The results of this study suggest that cefotaxime is an affective and well-tolerated new cephalosporin antimicrobial agent for the therapy of pneumonia due to susceptible organisms.
Rapid acyclovir radioimmunoassay, using charcoal adsorption
Authors: Skubitz K M , Quinn R P , Lietman P S
Published: June 2012

Charcoal adsorption of unbound acyclovir rather than ammonium sulfate precipitation of bound acyclovir to facilitate the separation of bound antigen from free antigen gave rise to a radioimmunoassay which was quicker yet still as sensitive and accurate as that previously used.
Antibiotic entry into human polymorphonuclear leukocytes
Authors: Prokesch R C , Hand W L
Published: June 2012

Since bacteria which survive within phagocytes may produce serious infection, antibiotics which inactivate these intracellular organisms are needed. To establish those factors which mediate entry of antimicrobial agents into human phagocytes, we studied the uptake of 13 radiolabeled antibiotics by peripheral blood polymorphonuclear leukocytes (PMN). At intervals during a 2-h incubation period, antibiotic uptake by PMN was determined by means of velocity gradient centrifugation, which separates the cell-associated antibiotic from the extracellular antibiotic. Penicillin G and three cephalosporin antibiotics penetrated PMN poorly. The ratio of cellular concentration to extracellular concentration (C/E) of these drugs was less than 0.01 to 0.5. For gentamicin and isoniazid, the C/E values were approximately 0.8 to 1.0. Chloramphenicol, rifampin, and lincomycin, antibiotics with good lipid solubility, were concentrated twofold (C/E = 2) in PMN. Ethambutol (C/E = 5), clindamycin (C/E = 11), and two erythromycin preparations (C/E = 10 to 13) were markedly concentrated within PMN. Clindamycin uptake was rapid: greater than 70% of the total drug entry occurred within the first minute. Accumulation of clindamycin and erythromycin was an active, energy-requiring process, dependent at least in part upon glycolysis. Clindamycin entered PMN by means of an active membrane transport system which was saturable and had a high binding affinity (Km = 2 mM) and maximum velocity of uptake (Vmax = 5 nmol/45 s per 10(6) cells). These observations, together with studies of the biological consequences of intracellular antibiotics, should lead to more effective therapy for infection due to intracellular pathogens..
Pharmacokinetics and bacteriological efficacy of N-formimidoyl thienamycin in experimental Escherichia coli meningitis
Authors: Patamasucon P , McCracken G H
Published: June 2012

The pharmacokinetics and bacteriological efficacy of N-formimidoyl thienamycin were determined in rabbits infected with Escherichia coli K1. After a single intravenous dose of 25 mg/kg, a peak N-formimidoyl thienamycin concentration in cerebrospinal fluid (CSF) of 2.5 micrograms/ml was attained at 45 min. The penetration into CSF was calculated to be 31%. In animals that received continuous intravenous infusions of the drug for 9 h, the mean CSF concentration was 8.2 microgram/ml, and the CSF bactericidal titers against the E. coli K1 strain were from 1:16 to 1:32. This infusion produced a reduction in the numbers of E. coli in the CSF of 4 log10 colony-forming units per ml. N-Formimidoyl thienamycin might prove to be useful for therapy of meningitis caused by E. coli and other susceptible bacteria.
Efficacy of ceftriaxone in serious bacterial infections
Authors: Epstein J S , Hasselquist S M , Simon G L
Published: June 2012

Ceftriaxone is a new semisynthetic cephalosporin with broad-spectrum in vitro activity and an unusually long serum half-life. The clinical efficacy of ceftriaxone was evaluated in 35 infections in 34 patients; 12 of these patients had skin and soft tissue infections, 10 had infections of the urinary tract, 8 had pneumonia, 2 had biliary tract infections, 1 had sinusitis, 1 had diverticulitis, and 1 had a retroperitoneal abscess. Of the 35 infections, 9 were bacteremic. The bacteria isolated included Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus faecalis, other streptococcal species, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Haemophilus influenzae, Pseudomonas aeruginosa, Bacteroides fragilis, other Bacteroides species, and anaerobic cocci. Improvement or cure occurred in 32 episodes, for a response rate of 91%. There were three treatment failures in patients with soft tissue infections. No serious drug toxicities were observed. At a dosage regimen of 1 g every 12 h the peak and trough serum antibiotic concentrations were well above the minimal inhibitory concentrations of most pathogens. Our findings suggest that ceftriaxone is a safe and effective antibiotic for therapy of serious bacterial infections.
Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations
Authors: Zaske D E , Cipolle R J , Rotschafer J C , Solem L D , Mosier N R , Strate R G
Published: June 2012

The pharmacokinetics and dosage requirements of gentamicin were studied in 1,640 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine or normal creatinine clearance. The half-life ranged from 0.4 to 32.7 h in 331 patients who had normal creatinine clearance. The factors related to the elimination rate constant were creatinine clearance, age, distribution volume, weight, gender, and hematocrit. The daily dose necessary to obtain therapeutic serum concentrations ranged from 0.5 to 25.8 mg/kg in patients with normal serum creatinine and from 0.7 to 25.8 mg/kg in patients with normal creatinine clearance. In 13 patients (0.9%), a significant change in base-line serum creatinine (greater than or equal to 0.5 mg/dl) occurred during or after treatment, which may have been gentamicin-associated toxicity. Overt cochlear or vestibular toxicity did not occur in these patients. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.
Dose-dependent pharmacokinetics of mezlocillin in relation to renal impairment
Authors: Mangione A , Boudinot F D , Schultz R M , Jusko W J
Published: June 2012

The dose dependence of mezlocillin pharmacokinetics was examined in relation to renal function after intravenous doses of 1 and 5 g in 16 subjects with various degrees of renal impairment. Dose and time-average model-independent physiological parameters were calculated from plasma concentration and urinary excretion data. Lack of superimposition of plasma concentration profiles occurred between dosage levels with a twofold exaggeration of areas under the curve produced between doses of 1 and 5 g. Decreased plasma clearances at the higher dose were caused partly by nonlinear renal clearance, but more markedly by dose dependence in nonrenal clearances. At each dosage level, these parameters were examined in relation to creatinine clearances. Plasma and renal clearances exhibited a typical linear correlation with creatinine clearance for each dose level. However, nonrenal clearances demonstrated a linear relationship with creatinine clearance at the 1-g dose, but apparent saturation of this pathway produced lower and relatively constant nonrenal clearance values at the 5-g dose. Mezlocillin pharmacokinetics are thus influenced by both dose and renal function over the dosage range of 1 to 5 g. Saturation in renal clearance and probably in biliary clearance explains the unusual disposition characteristics of mezlocillin observed in this and previously reported studies.
Intravenous metronidazole for treatment of infections involving anaerobic bacteria
Authors: George W L , Kirby B D , Sutter V L , Wheeler L A , Mulligan M E , Finegold S M
Published: June 2012

Intravenous metronidazole was administered, either by continuous or intermittent infusion, to 20 patients with infections involving anaerobic bacteria; 14 of the 20 patients were changed to oral administration of metronidazole for completion of therapy. Six of eight patients with infections derived from oropharyngeal bacterial flora were cured; the addition of ampicillin was required in one patient, however, because of an incomplete response to metronidazole. Eight of eleven evaluable patients with infections derived from bowel flora were also cured by metronidazole or metronidazole plus an aminoglycoside. Of 93 anaerobic bacteria isolated before therapy, 89 were susceptible to 16 micrograms or less of metronidazole per ml. Mean plasma levels of metronidazole were 27.6 +/- 11.4 micrograms/ml in patients receiving continuous infusions of drug and 19.9 +/- 10.7 micrograms/ml (trough) in patients receiving intermittent infusions. Two patients developed peripheral neuropathy during therapy. Metronidazole is an effective agent for the treatment of anaerobic infections. Because metronidazole is not active against facultative and aerobic bacteria, the addition of a second antimicrobial agent may be required for the treatment of mixed anaerobic-aerobic infections.
Rate of methicillin penetration into normal heart valve and experimental endocarditis lesions
Authors: Gengo F M , Schentag J J
Published: June 2012

Methicillin concentrations were measured in serum, normal heart valves, damaged heart valves, myocardium, and extravascular fluid from 12 New Zealand white rabbits to assess the influence of valvular damage on methicillin penetrations. Fibrin scarring of the aortic valve was induced by the placement of a polyethylene catheter through the aortic leaflet for 4 days. Each rabbit was then given a 40-mg/kg intravenous bolus dose of methicillin. Serum concentrations were collected, and animals were sacrificed 5, 15, 30, and 60 min after the dose. Normal and damaged heart valves from six different rabbits were desiccated to evaluate the fluid content of each. The time course of methicillin in damaged aortic valves was similar to that in serum and followed a bioexponential decline. The pharmacokinetic profile of methicillin in normal heart muscle and normal heart valves was clearly different from that of serum and damaged heart valves. Damaged valves showed a rapid and complete equilibrium with serum, whereas normal heart valve and muscle methicillin concentrations were consistently lower than serum concentrations at all times after the rapid bolus dose. The greater extravascular fluid content in damaged heart valves (P less than 0.001) compared with that in normal heart valves may be associated with the greater extent of penetration into damaged heart valves. Equilibrium between serum and damaged valves may be achieved more rapidly because the damaged area is composed of platelet and fibrin matrix and lacks the membrane integrity of normal heart valve tissue.
Topical polyriboinosinic-polyribocytidylic acid complex in the treatment of recurrent genital herpes
Authors: Crane L R , Levy H B , Lerner A M
Published: June 2012

Polyriboinosinic-polyribocytidylic acid complexed with poly-l-lysine and carboxymethylcellulose [poly(ICLC)] is a potent interferon inducer when given parenterally to humans. Topical application in animal models has shown beneficial antiviral and clinical effects. In a randomized, double-blinded, placebo-controlled trial of topical poly(ICLC) in recurrent genital herpes simplex virus infection, five clinical and two virological parameters were followed. Fifty-seven men and women, with 78 recurrences of genital herpes, were stratified by sex. No clinical or antiviral differences between poly(ICLC) and placebo groups in either stratum were found. Further analysis of male subgroups by age and size of lesions showed no changes in the rapidity of healing or viral shedding.
In vitro activity of cefotetan, a new cephamycin derivative, compared with that of other beta-lactam compounds
Authors: Wise R , Andrews J M , Hancox J
Published: June 2012

The in vitro activity of cefotetan, a new cephamycin, was compared with the activities of cefoxitin, cefuroxime, moxalactam, ceftazidime, and piperacillin against 273 recent clinical isolates. The minimum inhibitory concentrations of cefotetan for 90% of Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae were between 0.12 and 2 micrograms/ml; for 90% of Staphylococcus aureus, the minimum inhibitory concentration was 8 micrograms/ml, and for 90% of Bacteroides fragilis, Pseudomonas aeruginosa, and Lancefield group D streptococci it was 128 micrograms/ml or more. The activity of cefotetan against Enterobacteriaceae is comparable to the activities of ceftazidime and moxalactam and four to eight times greater than the activities of cefoxitin and cefuroxime. Cefotetan was approximately one-half as active as cefoxitin and cefuroxime against S. aureus. Although cefotetan was 87% bound to serum protein, serum had little effect on the in vitro antimicrobial activity of this agent.
beta-Lactamases of Branhamella catarrhalis and their inhibition by clavulanic acid
Authors: Farmer T , Reading C
Published: June 2012

Three of four clinical isolates of Branhamella catarrhalis from Belgium produced a beta-lactamase identical to enzymes previously reported to occur in French and British isolates of this organism. One strain, however, produced a new type of beta-lactamase. Both beta-lactamase types were readily inhibited by low concentrations of clavulanic acid.
Activity of N-formimidoyl thienamycin and cephalosporins against isolates from nosocomially acquired bacteremia
Authors: Gutiérrez-Núñez J , Harrington P T , Ramirez-Ronda C H
Published: June 2012

The in vitro activity of N-formimidoyl thienamycin was compared with that of seven beta-lactam agents against bacteremic clinical isolates, including gentamicin-resistant, gram-negative bacilli, Staphylococcus aureus, Staphylococcus epidermidis, streptococci, and enterococci. N-formimidoyl thienamycin was the most active antibiotic against all of the gram-positive cocci studied, with the exception of Staphylococcus epidermidis, and the only agent active against the enterococci. N-formimidoyl thienamycin was less active than some of the other agents against Enterobacteriaceae, except for the strains of Serratia and Citrobacter studied. For Pseudomonas aeruginosa, N-formimidoyl thienamycin was the most active agent (4 micrograms/ml was the lowest concentration that inhibited 90% of the strains tested).
Lack of efficacy of 2-deoxy-D-glucose in the treatment of experimental herpes genitalis in guinea pigs
Authors: Shannon W M , Arnett G , Drennen D J
Published: June 2012

Topical treatment of herpes genitalis in female guinea pigs with 2-deoxy-D-glucose in either agarose gels or miconazole nitrate ointments failed to prevent the development of genital lesions or to reduce the mean titers of recoverable virus in vaginal swabs from infected animals. In contrast, phosphonoacetic acid was therapeutically effective.
Antimicrobial susceptibility of Moraxella bovis determined by agar disk diffusion and broth microdilution
Authors: Webber J J , Fales W H , Selby L A
Published: June 2012

The antimicrobial susceptibility of 84 isolates of Moraxella bovis was evaluated by the standard agar disk diffusion and broth microdilution procedures. All isolates were resistant to cloxacillin by disk diffusion, with 97% of isolates having a minimal inhibitory concentration of greater than or equal to 2 micrograms/ml. Of the hemolytic isolates, 68% were resistant to streptomycin. A high frequency of susceptibility was recorded for all other antimicrobial agents tested. Quantitative data supported the use of sulfonamides, but not tylosin, for parenteral infectious bovine keratoconjunctivitis therapy.
Evidence for a chromosomal site specifying amikacin resistance in multiresistant Serratia marcescens
Authors: John J F , McNeill W F , Price K E , Kresel P A
Published: June 2012

We studied 21 strains of amikacin-resistant Serratia marcescens from three different U.S. cities, Twenty of the 21 strains contained conjugative R plasmids mediating gentamicin and tobramycin resistance. Amikacin-resistant S. marcescens from two cities predominated in protracted outbreaks. Conversely, the amikacin-resistant Charleston strain (serotype 02/03:nonmotile) was isolated from only four patients during an outbreak of gentamicin- and tobramycin resistant, amikacin-susceptible S. marcescens (serotype O19:O17). Five different representative amikacin-resistant S. marcescens, each containing a single conjugative plasmid, elaborated a nontransferable aminoglycoside (6')-N-acetyltransferase [AAC(6')] with similar substrate profiles in addition to other transferable aminoglycoside-modifying enzymes. One amikacin-resistant S. marcescens cured of its plasmid and another naturally occurring plasmid-free amikacin-resistant S. marcescens elaborated only AAC(6')-1. These data support the concept of a chromosomal locus in S. marcescens for AAC(6')-1 which commonly coexists with plasmid-mediated genes for aminoglycoside-modifying enzymes.
Minimal nephrotoxicity with cephalosporin-aminoglycoside combinations in patients with neoplastic disease
Authors: Brown A E , Quesada O , Armstrong D
Published: June 2012

Patients with cancer and suspected sepsis were treated in a prospective, randomized trial with one of four cephalosporin-aminoglycoside combinations: cephalothin and tobramycin; cephalothin and gentamicin; cefamandole and tobramycin; or cefamandole and gentamicin. Carbenicillin was added if the absolute granulocyte count was less than 1,000/mm3. Of 199 patients receiving 20 to more doses of an aminoglycoside and having serial determination of serum creatinines, nephrotoxicity developed in seven (3.5%) given any of the four combinations. There were no significant differences between patients receiving either cephalosporin or either aminoglycoside. Nephrotoxicity developed less frequently among children (2 or 125; 1.6%) than adults (5 of 74; 6.8%).
pH-dependent penicillin tolerance may protect intraleukocytic Staphylococcus aureus from killing by cloxacillin
Authors: Craven N , Anderson J C
Published: June 2012

Exposure of Staphylococcus aureus to cloxacillin at neutral pH rendered the bacteria more susceptible to subsequent lysis by lysostaphin. This sensitization effect also occurred at lower pH levels which were nonpermissive for the bactericidal action of cloxacillin, but the effect disappeared at pH 5.0. These findings elucidate previous observations on the protection of intraleukocytic S. aureus from killing by cloxacillin and indicate that low pH in the phagolysosomes may be involved.
Moxalactam in the therapy of serious infections
Authors: Marier R L , Faro S , Sanders C V , Williams W , Derks F , Janney A , Aldridge K
Published: June 2012

Sixty-seven patients were treated with moxalactam in a noncomparative trial of hospitalized patients; 32 had endometritis or chorioamnionitis, 12 had skin and soft tissue infections, 5 had osteomyelitis, 5 had pneumonia, 5 had urinary tract infections, 4 had arthritis, 2 had sepsis from an unknown source, 1 had endocarditis, and 1 had peritonitis. Bacteremia was present in 12 of these patients. Patients were given 3 to 12 g of moxalactam per day (mean, 6.24 g/day) in divided doses every 6 to 8 h. Seven patients were given intramuscular treatment for 3 to 20 days for part or all of their therapy. The rest were given intravenous treatment exclusively. Treatment was continued for 2 to 42 days (mean, 10 days). The dose and the duration of therapy were determined by the type of infection and the response of each patient. There were four treatment failures and one enterococcal-clostridial superinfection. Moxalactam was well tolerated. Allergic reactions led to the discontinuation of the antibiotic in three patients. Prolonged prothrombin and partial thromboplastin times were observed in 2 of 11 patients tested; in both instances in patients had severe underlying diseases, including malnutrition and alcoholism. Pain on intramuscular injection was noted in two patients receiving 1,500 mg, but not in five receiving a lower dose; in one case the pain forced the use of intravenous therapy after one dose, and in the other case the pain was mild and the patient was treated for 20 days. We concluded that moxalactam was effective in the treatment of the types of infections included in this study and produced few adverse reactions.
High-performance liquid chromatographic determination of piperacillin in plasma
Authors: Brisson A M , Fourtillan J B
Published: June 2012

A high-performance liquid chromatographic method has been developed for the quantitative determination of piperacillin in plasma. The compound is first extracted from acid-treated plasma into chloroform: 1-pentanol (3:1) and reextracted into a small volume of an aqueous phase at pH 7, which is injected in the chromatographic column (microgram-Bondapack C18; 10 micrometers). The mobile phase is a mixture of 0.01 M acetate buffer (pH 4.8) and methanol. The method is accurate and reproducible with a sensitivity of about 50 ng of piperacillin per ml of serum.
Activities of eight new beta-lactam antibiotics and seven antibiotic combinations against Neisseria meningitidis
Authors: Scribner R K , Wedro B C , Weber A H , Marks M I
Published: June 2012

Each of eight new beta-lactam antibiotics was highly active in vitro against Neisseria meningitidis, and activity was not reduced by combining some of these drugs with penicillin, ampicillin, or tobramycin. Antibacterial activity and lack of antagonism between moxalactam and ampicillin was confirmed in a model of lethal meningococcal infection in mice.
Pharmacokinetics of cefotaxime in newborn infants
Authors: McCracken G H , Threlkeld N E , Thomas M L
Published: June 2012

The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.
Characterization of ampicillin-resistant Haemophilus parainfluenzae
Authors: Scheifele D W , Fussell S J , Roberts M C
Published: June 2012

Carriage of ampicillin-resistant (Ampr) Haemophilus parainfluenzae has become frequent among children in our community, although carriage of Ampr Haemophilus influenzae remains uncommon. In this study we characterized the mechanism of ampicillin resistance in 27 representative isolates of H. parainfluenzae. As determined by isoelectric focusing, each isolate had a TEM-1 beta-lactamase; substrate profiles assessed for enzymes from 10 strains were also consistent with TEM-1 enzyme. Agarose gel electrophoresis revealed a plasmid of 23 to 34 megadaltons in each isolate and a small plasmid (less than or equal to 4 megadaltons) in 14 isolates. Transfer of ampicillin resistance to H. influenzae Rd was achieved during membrane mating with 14 of 15 donors. The transconjugants exhibited high-level ampicillin resistance (greater than or equal to 50 micrograms/ml), which was stable despite serial passage of isolates on antibiotic-free media. The transconjugants tested retained fertility. Cryptic plasmids were discovered in 7 of 25 antibiotic-susceptible H. parainfluenzae isolates. Our data suggest that H. parainfluenzae may play an important role in the exchange of Ampr genes among throat bacteria.
Development of clinical resistance to acyclovir in herpes simplex virus-infected mice receiving oral therapy
Authors: Field H J
Published: June 2012

Mice inoculated in the ear pinna with herpes simplex virus were treated effectively by including 1 mg of acyclovir per ml in the drinking water. During a 5-day course of treatment the development of resistance was not readily apparent. However, when a suboptimal therapeutic dose was used and virus was repeatedly inoculated into further mice undergoing therapy, the infection became completely refractory to treatment by passage 4. Some of the viruses isolated exhibited reduced ability to induce thymidine kinase, and this appeared to account at least in part for the development of resistance. However, the viruses isolated from the tissues of such mice comprised complex mixtures of strains with widely differing in vitro susceptibilities to acyclovir. The properties of these virus yields gave an indication of the likely nature of resistance to nucleoside analogs in humans and suggested some difficulties which may be encountered when clinical specimens are analyzed.
Determination of norfloxacin, a new nalidixic acid analog, in human serum and urine by high-performance liquid chromatography
Authors: Boppana V K , Swanson B N
Published: June 2012

A high-performance liquid chromatographic method for the analysis of norfloxacin (MK-366) [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)3-quinolinecarboxylic acid], a new nalidixic acid analog, in human serum and urine is described. A statistical evaluation of the assay data showed acceptable accuracy and precision for 0.1 to 10.0 micrograms of MK-366 per ml of serum and for 1.0 to 500 micrograms of MK-366 per ml of urine. MK-366 was extracted from serum and urine at pH 7.5 with methylene chloride and back-extracted with sodium hydroxide solution. Chromatography was performed on an anion-exchange column with acetonitrile-phosphate buffer as the mobile phase; UV absorbance was monitored at 273 nm. The method was used to measure MK-366 in clinical specimens.
Capillary agar diffusion assay for measuring metronidazole in human gingival crevice fluid
Authors: Notten F , Koek-Van Oosten A , Mikx F
Published: June 2012

An agar diffusion assay in capillaries, with Fusobacterium nucleatum M2 as the indicator strain, has been developed to measure metronidazole concentrations in gingival crevice fluid. The assay allows the measurement of 1.9 micrograms of metronidazole per ml in sample amounts of 0.6 microliters.
Placental transfer of disodium sulbenicillin
Authors: Miyakawa I , Taniyama K , Inoue H , Lee H C , Mori N
Published: June 2012

The concentrations of sulbenicillin in maternal and fetal blood and in the amniotic fluid compartment were measured in 27 women at parturition. With an intramuscular injection of 2,000 mg of sulbenicillin, the highest concentration of sulbenicillin in maternal blood (109.0 micrograms/ml) was attained at 55 min. The highest concentrations in umbilical cord blood (approximately 25 micrograms/ml) were attained between 1 and 3 h after dosage. The peak concentration in amniotic fluid (27.1 micrograms/ml) was attained approximately 7.5 h after sulbenicillin administration.
Effect of dihydrostreptomycin on active transport in isolated bacterial membrane vesicles
Authors: Eagon R G , Hartle R J , Rake J B , Abdel-Sayed S
Published: June 2012

Membrane vesicles prepared from bacterial cells grown in the absence of dihydrostreptomycin but subsequently incubated in the presence of dihydrostreptomycin transported proline normally, but vesicles prepared from cells grown in media to which dihydrostreptomycin was added 30 min before harvesting had a greatly impaired ability to accumulate proline. The latter cells extruded protons normally but were unable to maintain a proton gradient as effectively as normal cells. These data indicated that metabolism was required for dihydrostreptomycin to exert an effect on the bacterial cell membrane.
Comparative in vitro activities of beta-lactam-tobramycin combinations against Pseudomonas aeruginosa and multidrug-resistant gram-negative enteric bacilli
Authors: Fass R J
Published: June 2012

Piperacillin was more consistently active than tobramycin, carbenicillin, moxalactam, or ceftriaxone against strains of Pseudomonas aeruginosa isolated from blood cultures and against multidrug-resistant strains. Moxalactam and ceftriaxone were more consistently active than tobramycin, carbenicillin, or piperacillin against multidrug-resistant Enterobacteriaceae. Synergy between beta-lactam antibiotics and tobramycin was frequently observed against strains of P. aeruginosa isolated from blood cultures but not against multidrug-resistant organisms. Piperacillin plus tobramycin was the most active antibiotic combination against P. aeruginosa. Moxalactam plus tobramycin and ceftriaxone plus tobramycin were the most active antibiotic combinations against Enterobacteriaceae.
Clinical Impact of Rapid Antimicrobial Susceptibility Testing of Blood Culture Isolates
Authors: Doern Gary V. , Scott David R. , Rashad Abdel L.
Published: June 2012

The results of a rapid, direct blood culture disk susceptibility test indicated that antimicrobial chemotherapy should be changed in 48 of 173 patients with bacteremia. In 32 patients (66.6%), the indicated change was made approximately 24 h sooner than if conventional, nonrapid susceptibility tests had been used to guide therapy.
Effect of method of administration on extravascular penetration of four antibiotics
Authors: Van Etta L L , Kravitz G R , Russ T E , Fasching C E , Gerding D N , Peterson L R
Published: June 2012

The effect of both method of drug administration and serum protein binding on antibiotic penetration into subcutaneous Visking chambers was studied in rabbits. Ampicillin and oxacillin were administered by either repeated intramuscular injection of 30 mg/kg every 4 h or by constant infusion of 7.5 mg/kg per h for 24 h. Gentamicin was given by intramuscular injection of 4 mg/kg every 4 h for 28 h and by constant infusion of 1 mg/kg per h for 24 h. Amikacin was given by intramuscular injection of 8 mg/kg every 4 h for 12 h and by constant intravenous infusion of 2 mg/kg per h for 12 h. Protein binding to rabbit serum was 73% for oxacillin, 9% for ampicillin, 19% for gentamicin, and 0% for amikacin. Chamber concentrations achieved for oxacillin, gentamicin, and amikacin were not significantly different for constant infusion versus intermittent administration. For ampicillin, chamber concentration was slightly higher by constant infusion than by intermittent administration (P less than 0.02). Fluctuations in drug concentration from peak to trough values in the chambers during the intermittent administration studies were markedly dampened when compared with serum fluctuations. This study demonstrates that whereas steady state is reached more rapidly by intermittent administration, the mean steady-state concentration of an antibiotic achieved at an extravascular site is the same or greater by constant infusion than by intermittent dosing. This is true for highly protein bound antibiotics as well as those with low serum protein binding.
In vitro activity of U-57930E, a new clindamycin analog, against aerobic gram-positive bacteria
Authors: Ahonkhai V I , Cherubin C E , Shulman M A , Jhagroo M , Bancroft U
Published: June 2012

The in vitro activity of U-57930E, a new clindamycin analog, against aerobic gram-positive cocci was studied by microdilution broth susceptibility tests and compared with the activities of clindamycin, vancomycin, oxacillin, and ampicillin. U-57930E inhibited methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus viridans at concentrations of less than or equal to 1 microgram/ml. This degree of activity was generally slightly less than that of the other antimicrobial agents tested. Methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, penicillin-resistant Streptococcus pneumoniae, and enterococci were resistant to U-57930E. At the concentrations used, U-57930E exhibited bactericidal activity against most susceptible organisms, and a minimal effect of inoculum size was noted.
Primary site of action of ketoconazole on Candida albicans
Authors: Uno J , Shigematsu M L , Arai T
Published: June 2012

Ketoconazole, an antifungal drug, completely inhibited the growth of Candida albicans 7N at concentrations of greater than or equal to 50 microgram/ml (94 microM). However, ketoconazole incompletely inhibited the growth of this opportunistic yeast at concentrations of 25 to 0.2 microgram/ml (47 to 0.4 microM). At these lower concentrations, 2,3,5-triphenyl tetrazolium chloride, an electron acceptor, was reduced by several strains of C. albicans. This effect resulted in red coloration of colonies. Concomitantly, this phenomenon was not antagonized in the presence of ergosterol. Furthermore, neither ketoconazole nor antimycin A inhibited the growth of C. albicans under anaerobic conditions, as revealed by a paper disk method. Ketoconazole at the concentrations stated above inhibited endogenous and exogenous respiration immediately after it was added to a system containing log phase C. albicans cells, as determined polarographically. At the same time, ketoconazole inhibited the activity of NADH oxidase at the mitochondrial level. In contrast, higher concentrations of ketoconazole (greater than 100 microM) were required to inhibit the activity of succinate oxidase from rat liver mitochondria. In addition, concentrations of ketoconazole greater than 100 microM were required to impair the uptake of labeled leucine and adenine and, subsequently, the incorporation of the former into protein and the latter into DNA and RNA in intact cells. On the other hand, ketoconazole at concentrations of 10, 1.0, and 0.4 microM had no effect on either membrane permeability or macromolecular synthesis.
Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin
Authors: Barriere S L , Hatheway G J , Gambertoglio J G , Lin E T , Conte J E
Published: June 2012

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.
Activities of various beta-lactams and aminoglycosides, alone and in combination, against isolates of Pseudomonas aeruginosa from patients with cystic fibrosis
Authors: Scribner R K , Marks M I , Weber A H , Tarpay M M , Welch D F
Published: June 2012

The inhibitory and bactericidal activities of carbenicillin, ticarcillin, moxalactam, cefoperazone, azlocillin, piperacillin, ceftazidime, and three aminoglycosides, alone and in various combinations, were determined against 60 isolates of Pseudomonas aeruginosa from the sputum of patients with cystic fibrosis. Ceftazidime was the most active beta-lactam, with minimum inhibitory and bactericidal concentrations for 90% of isolates of 4 micrograms/ml. Moxalactam was the least active of the new beta-lactams, with activity equivalent to that of carbenicillin; each had a minimum inhibitory concentration for 90% of isolates of 64 micrograms/ml and a minimum bactericidal concentration for 90% of isolates of 128 microgram/ml. All combinations of an aminoglycoside plus a beta-lactam showed favorable inhibitory effects. Combinations of beta-lactams showed mostly addition or indifference. Although little antagonism was seen with combinations of beta-lactams or with aminoglycoside-beta-lactam combinations, no consistent advantage of beta-lactam combinations was demonstrated in vitro. These results suggest several single drugs and combinations that merit clinical evaluation in cystic fibrosis patients with Pseudomonas pulmonary infections.
Mode of action of azthreonam
Authors: Georgopapadakou N H , Smith S A , Sykes R B
Published: June 2012

Azthreonam (SQ 26,776) is a member of a new class of monocyclic beta-lactam antibiotics. In Escherichia coli, azthreonam caused filamentation at its lowest effective concentration (0.2 microgram/ml), a morphological effect identical to that observed with cephalothin. The penicillin-binding protein (PBP) profile indicated a very high affinity for PBP3 (complete binding at 0.1 microgram/ml), a moderate affinity for PBP1a (complete binding at 10 micrograms/ml), and poor affinities for PBP1b, PBP2, PBP4, and PBP5/6 (complete binding at greater than or equal to 100 micrograms/ml). Accordingly, azthreonam had poor activity against Streptomyces R61 DD-carboxypeptidase (50% inhibition, greater than 100 micrograms/ml) and E. coli peptidoglycan transpeptidase (50% inhibition, 100 micrograms/ml). Azthreonam also showed very high affinity for PBP3 (complete binding at 0.1 microgram/ml) in Proteus vulgaris, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In all four organisms, its PBP profile was similar to that observed in E. coli. It is concluded that azthreonam, although of novel structure, has a mode of action similar to that of cephalosporins, affecting specifically septation in E. coli and most likely other gram-negative bacteria.
Antagonism of carbenicillin and cefamandole by cefoxitin in treatment of experimental infections in mice
Authors: Goering R V , Sanders C C , Sanders W E
Published: June 2012

The ability of cefoxitin to antagonize the in vivo efficacy of cefamandole and carbenicillin as predicted by in vitro assays was analyzed in experimental infections in mice. Cefoxitin was administered in a nonprotective dose either at the time of challenge or simultaneously with the protective drug, 1 and 3.5 h postchallenge. In mice infected with Enterobacter cloacae, median 50% protective doses of cefamandole and carbenicillin were markedly increased by cefoxitin, especially when the latter was given at the time of challenge. The antagonistic effect was also associated with increased numbers of challenge bacteria present in animal heart blood within a 6.5-h period after infection. In infections with Pseudomonas aeruginosa, cefoxitin antagonized carbenicillin; however, the effect was less dramatic than that seen with E. cloacae. Antagonism in this model was pronounced with simultaneous administration of antagonizing and protective drugs. The antagonistic effects observed in all in vivo tests were not due to the selection of stable resistance to the protective drugs, but appeared to be due to a reversible induction of beta-lactamases by cefoxitin.
Comparison of the activities of ceftriaxone and penicillin G against experimentally induced syphilis in rabbits
Authors: Johnson R C , Bey R F , Wolgamot S J
Published: June 2012

The activity of ceftriaxone, a newly developed cephalosporin, against early cutaneous infections with Treponema pallidum in rabbits was compared with that of equimolar doses of penicillin G. Activity was related to the time required for cutaneous lesions to become dark-field negative, serological response, and the disappearance of T. pallidum from the popliteal lymph nodes. Both antibiotics were very effective in the treatment of syphilis in this animal model. The 50% curative dose for penicillin G was 0.8 mumol/kg (0.29 mg or 480 U/kg) and for ceftriaxone, it was 1.45 mumol/kg (0.96 mg/kg). Overall, ceftriaxone was slightly less effective than penicillin G was. Transmission and scanning electron microscopy studies of testicular aspirates obtained from rabbits treated with ceftriaxone revealed alterations in the treponeme surface which apparently resulted in changes in cell permeability and morphology.
Clinical evaluation of the therapeutic efficacy and tolerability of piperacillin
Authors: Lutz B , Mogabgab W , Holmes B , Pollock B , Beville R
Published: June 2012

The efficacy and tolerance of parenterally administered piperacillin were evaluated in 50 adult patients hospitalized with systemic and urinary tract infections. Dosage for 46 patients was 4 to 12 g daily and for 4 patients, 16 to 24 g daily; in each case divided doses were given every 4 to 6 h. The duration of treatment for most patients was 5 to 10 days. Of the 50 patients, 45 (90%) were considered cured, and 57 (89%) of the 64 pathogens isolated were eradicated by piperacillin treatment. Side effects, reported by 12 patients, were mild to moderate in degree and consisted of vein irritation, thrombophlebitis, pain at the injection site, and diarrhea, Piperacillin appears to be a highly effective antibiotic for treating infections caused by susceptible gram-positive and gram-negative microorganisms.
Efficacy of a twelve-hourly ceftriaxone regimen in the treatment of serious bacterial infections
Authors: Maslow M J , Levine J F , Pollock A A , Simberkoff M S , Rahal J J
Published: June 2012

Eighteen patients with 21 serious infections were treated with ceftriaxone, 1 g intravenously every 12 h, for a mean duration of 8 days. Eighteen gram-negative and two gram-positive organisms were isolated. Sites of infection included blood (three patients), urinary tract (six patients), respiratory tract (seven patients), biliary tract (three patients), ascitic fluid (one patient), and skin (one patient). Serum, bile, and ascitic fluid concentrations of ceftriaxone were in excess of the minimal bactericidal concentration required for the infecting organism in all cases. A bacteriological response was demonstrated in 94% of the infections. A clinical response occurred in four infections from which no pathogens were recovered. In one patient, ceftriaxone failed to eradicate a peritoneal infection due to Bacteroides fragilis. In two patients, superinfection with enterococci developed both during and after therapy. Systemic tolerance to ceftriaxone was excellent.