Temple W. Williams

Bone Concentrations of Antimicrobial Agents After Parenteral Administration

Bone concentrations of seven antimicrobial agents were determined after parenteral administration. Antibiotics were administered in large doses at customary intervals for 12 to 20 h before total hip or knee replacement; anticipated levels of each drug were achieved in the serum. Methicillin, carbenicillin, and clindamycin were detected in bone with greatest frequency. Cefazolin and gentamicin were each detected in bone specimens from only one of four patients. Neither penicillin G nor cephalothin was present in bone in sufficient quantity to be measurable. These data suggest that a number of factors, in addition to serum concentration, affect concentration of antimicrobial agents in bone. The clinical significance of the relationship between bone concentrations of antibiotics and therapeutic outcome is not certain.

Study of the Effects of Ticarcillin on Blood Coagulation and Platelet Function

Ticarcillin is a new semisynthetic penicillin similar to carbenicillin. Since carbenicillin has been shown to inhibit platelet function to such an extent that bleeding may accompany its use, an investigation of the effects of ticarcillin on hemostasis was made. The drug was administered to 17 human volunteers for periods of 3 to 10 days in intravenous doses of 100, 200, or 300 mg/kg per day (7 to 21 g/day). Serial studies of blood coagulation and platelet function indicated that coagulation was unaffected by ticarcillin but that platelet function became defective in all subjects. Abnormal platelet function was evidenced by lengthening of bleeding time (17 of 17 volunteers), depressed adenosine diphosphate-induced platelet aggregation (17 of 17), defective collagen-induced aggregation (15 of 17), and abnormal epinephrine-induced aggregation (10 of 17). Prothrombin consumption, due to reduced platelet procoagulant activity, was significantly decreased with a dose of 300 mg/kg per day. Comparison of results from this study with those from an earlier carbenicillin study revealed that ticarcillin at 300 mg/kg per day produces the same defects in hemostasis as does carbenicillin at 300 mg/kg per day, but that lower doses (100 or 200 mg/kg per day) of ticarcillin result in only a mild defect in platelet function. If the effective dose of ticarcillin is proven to be lower than the doses of carbenicillin currently employed for treatment of certain gram-negative infections, bleeding should not be a frequent complication of ticarcillin administration, when the drug is given to patients with normal renal function.

Susceptibility and Synergy Studies of Methicillin-Resistant Staphylococcus epidermidis

Methicillin-resistant Staphylococcus epidermidis is an important cause of cerebrospinal fluid shunt infections and prosthetic valve endocarditis. Agar dilution minimum inhibitory concentrations were determined for 100 strains of methicillin-resistant S. epidermidis which were isolated from clinical specimens. Vancomycin inhibited all 100 strains at ≤3.12 μg/ml, whereas clindamycin inhibited only 46 strains at ≤12.5 μg/ml. Methicillin-resistant S. epidermidis strains were resistant to achievable levels of erythromycin, with 90 strains having a minimum inhibitory concentration of ≥3.12 μg/ml. Of the five cephalosporins and one cephamycin tested, cefamandole was the most active in vitro, inhibiting 97 strains at ≤25 μg/ml. Antibiotic synergism was examined by a quantitative bacterial time-kill method. Synergism (≥102 kill by the combination over the most effective single antibiotic at 24 h) was demonstrated with vancomycin (1.56 μg/ml) plus cefamandole (6.25 μg/ml) in 14 of 14 strains, vancomycin plus cephalothin (6.25 μg/ml) in 14 of 14 strains, vancomycin plus rifampin (0.008 to 0.012 μg/ml) in 6 of 12 strains, rifampin plus cefamandole in 9 of 12 strains, and rifampin plus cephalothin in 10 of 12 strains. The emergence of populations of bacteria resistant to 0.2 μg of rifampin per ml developed in three of five methicillin-resistant S. epidermidis strains tested. The addition of either vancomycin, cephalothin, or cefamandole to the rifampin prevented the emergence of resistance in these three strains. Clinical trials of synergistic antibiotic combination therapy for serious methicillin-resistant S. epidermidis infections are indicated.

Anaerobic bacterial meningitis

Anaerobic meningitis occurred in four patients in whom anaerobic bacteria had not been suspected as a possible cause. The predisposing conditions were typical of those seen in patients previously reported to have this infection and included chronic otitis media with mastoiditis, chronic sinusitis, recent craniotomy and abdominal trauma. Two of the patients had undergone immunosuppression (immunosuppressed patients); a compromised immune system may facilitate the development of anaerobic meningitis in patients with the appropritate underlying conditions. Head and neck neoplasms, head trauma, suppurative pharyngitis and laminectomy wounds are additional situations in which anaerobic meningitis occurs. Anaerobic bacterial meningitis probably occurs more often than is recognized. The cerebrospinal fluid should be transported and cultured anaerobically when meningitis develops in a patient with a predisposing condition.

Influence of Cephalosporin Antibiotics on Blood Coagulation and Platelet Function

Administration of cephalothin to normal volunteers in maximal doses of 300 mg/kg per day resulted in a combined defect of platelet function and blood coagulation. No such abnormalities were evident after infusion of cefazolin or cephapirin at a maximal dosage of 200 mg/kg per day. The observed thrombocytopathy was similar to but less severe than that induced by carbenicillin or ticarcillin and was not reflected by a prolonged bleeding time test or impaired prothrombin consumption. Moreover, it was not a consistent finding in those persons receiving cephalothin. A separate defect involving blood coagulation appeared to result from delayed fibrinogen-fibrin polymerization and was evidenced by extended values of the activated partial thromboplastin and thrombin time tests. It remains uncertain whether the abnormalities described may constitute clinically important hemostatic disorders in patients with normal renal function receiving large doses of cephalosporin antibiotics.

In Vitro Activity of Josamycin Against Aerobic Gram-Positive Cocci and Anaerobes

Josamycin, a new macrolide antibiotic, was compared with ampicillin, erythromycin, and clindamycin in vitro against 25 isolates each of pneumococci, enterococci, Staphylococcus aureus, S. epidermidis, and nonenterococcal hemolytic streptococci and against 25 anaerobes including 10 Bacteroides fragilis. Minimal inhibitory concentration and minimal bactericidal concentration data were obtained for the aerobic organisms, using serial twofold tube dilutions in Mueller-Hinton broth. Minimal inhibitory concentrations were determined for the anaerobes by the agar dilution technique. Josamycin was comparable to erythromycin and clindamycin in activity against the pneumococci, streptococci, and staphylococci and was more active than clindamycin against enterococci. It was somewhat less active than ampicillin against enterococci and S. epidermidis and showed its greatest in vitro activity against anaerobes, being comparable to clindamycin.

Successful management of Histoplasma capsulatum infection of an abdominal aortic aneurysm

A 65-year-old woman with disseminated histoplasmosis underwent resection of an atherosclerotic abdominal aortic aneurysm. Yeast forms of Histoplasma capsulatum were present in the aneurysm. Surgical resection and revascularization with a Dacron graft followed by systemic amphotericin B therapy and chronic ketoconazole suppressive therapy have resulted in a patient without symptoms 15 months postoperatively. It is important to be aware of the potential for artherosclerotic aortic aneurysm involvement by H. capsulatum.

Clavulanic acid and penicillin treatment of Staphylococcus aureus renal infection in mice.

Clavulanic acid, an inhibitor of beta-lactamase, was used together with penicillin to treat infection caused by a penicillinase-producing Staphylococcus aureus. Clavulanic acid + penicillin administered to mice, prophylactically or in treatment of established infection, reduced morbidity, bacterial counts in the kidneys, and/or mortality; these differences were statistically significant when compared with those obtained by using penicillin or clavulanic acid alone.