Keith H. Burch

Polymicrobial infective endocarditis: An increasing clinical entity

Polymicrobial endocarditis was very uncommon until ten years ago. However, since that time, at least 21 cases were reported, and 10 patients with this mixed infection were seen at our hospital. All, except one of these infections, occurred in patients who had undergone heart surgery or abused intravenous drugs. Although, generally clinically indistinguishable from mono-microbial endocarditis, these mixed infections carried a very high mortality rate (greater than 30 per cent), and an unusually large number of the patients (greater than 50 per cent) needed heart surgery either to control the infection or to repair cardiac defects resulting from the infection. The prognosis depended on the species rather than the number of organisms isolated and on aggressive antimicrobial and surgical therapy.

Effect of Renal Failure and Dialysis on the Serum Concentration of the Aminoglycoside Amikacin

Serum and dialysate levels of amikacin were determined at appropriate intervals after a 300-mg intravenous dose as a continuous infusion in six patients with end-stage renal failure undergoing hemodialysis and in three patients on peritoneal dialysis. The mean serum half-life of amikacin was 3.75 h during (or after) hemodialysis and 29 h during (or after) peritoneal dialysis. Although not on hemodialysis in the same six patients, the serum half-life was 28 h. The results indicate that the maintenance dose of amikacin should be markedly decreased in patients with severe renal failure even if they are treated with peritoneal dialysis, and that serial serum antibiotic concentrations are essential to prevent cumulative toxicity of the drug.

Clinical Studies of Cefazolin and Comparison with Other Cephalosporins

Cefazolin, a new cephalosporin derivative, was studied in the treatment of 105 hospitalized patients with a variety of infections including endocarditis, pneumonia, and urinary and soft tissue infections, and was found to be effective in 104 patients. Cefazolin was also tested in vitro and shown to be effective against staphylococci, pneumococci, Escherichia coli, Klebsiella sp., and Proteus mirabilis by agar dilution method. It was shown to produce high serum levels when administered in a 250- to 1,000-mg intramuscular dose and was well tolerated and free from renal toxicity. Comparison of the results of this study with those from our prior studies on cephaloridine revealed equivalent antibiotic potency, good tolerance to both the agents when given intramuscularly, superior, average blood levels with cefazolin, equal clinical efficacy, and absence of renal toxicity with cefazolin (unlike cephaloridine). Similarly, the results of treatment of pneumococcal pneumonia with intramuscular cefazolin were found to be superior to those for oral cephalexin.

Effects of Renal Failure and Dialysis on Cefazolin Pharmacokinetics

Serum and urinary levels of cefazolin were determined after a 500-mg parenteral dose in eight azotemic volunteers. The mean peak serum concentration was 1.5 to 5 times the levels obtained in nonazotemic patients. The serum half-life of cefazolin was increased significantly. In patients on dialysis, the mean serum half-life of cefazolin was 4.05 h during (or after) hemodialysis, and 32.1 h during (or after) peritoneal dialysis. There was a significant decrease in cefazolin removal when dialysate flow or membrane surface area of the dialyzer were decreased. It was also shown that one circuit through the dialysis unit caused measurable decrease in cefazolin concentration. These data and previously published reports suggest: (i) the maintenance dose of cefazolin can be decreased in azotemic patients; (ii) patients on hemodialysis will require an additional half dose after dialysis because of efficient removal during hemodialysis; and (iii) patients on peritoneal dialysis do not require an extra dose.

Ceforanide: In Vitro and Clinical Evaluation

Ceforanide, a new cephalosporin antibiotic with a long half-life (3 h), can be administered twice daily. We evaluated its antimicrobial activity, pharmacology, and clinical efficacy. Twenty-seven patients with infections due to susceptible organisms received ceforanide, 0.5, 1, or 2 g, intramuscularly or intravenously every 12 h for 6 to 28 days. In vitro studies with the clinical isolates from 27 patients treated plus 263 additional isolates showed that ceforanide was active against cephalothin-susceptible gram-positive and gram-negative microorganisms. In addition, ceforanide inhibited 65% of cephalothin-resistant Escherichia coli and 65% of Enterobacter spp. at ≤12.5 μg/ml. After a single 1-g intramuscular dose, the mean peak plasma concentration at 1 h was 48.9 μg/ml and that at 12 h was 4.7 μg/ml. Plasma accumulation occurred in some patients. The infections included 10 pneumonias, 3 with bacteremia and 1 with empyema; 11 soft tissue infections, 4 with abscesses and 3 with sepsis; and 3 urinary tract infections. One case each of endocarditis, osteomyelitis, and septic thrombophlebitis, all due to Staphylococcus aureus, were treated. Clinical response was satisfactory in all patients; bacteriological response was satisfactory in 26 of 27 patients. Ceforanide was well tolerated. Three patients developed mild increases in liver enzymes, and one developed slight eosinophilia. In another case, the antibiotic was discontinued because of a fivefold rise in serum glutamic-oxalacetic transaminase (aspartate aminotransferase) and serum glutamic-pyruvic transaminase (alanine aminotransferase) and a twofold rise in lactic acid dehydrogenase and alkaline phosphatase.

Rifampin in the Management of Early Prosthetic Staphylococcus epidermidis Endocarditis

Staphylococcus epidermidis endocarditis occurred four days following aortic valve replacement with a Björk-Shiley prosthesis. Antimicrobial therapy, shown to be effective by in vitro and in vivo studies, failed to eradicate the infection. When rifampin was added to the existing antibiotic regimen, peak serum bactericidal activity increased, the patient defervesced, and blood cultures became negative.

Failure of probenecid to alter the pharmacokinetics of ceforanide.

This investigation evaluated the effect of probenecid on ceforanide concentrations in eight healthy volunteers. Each volunteer was given 1 or 2 g of ceforanide either alone or with 1 g of probenecid. Concentrations of ceforanide in plasma, urine, and saliva were then measured. Probenecid did not alter the plasma concentrations of ceforanide, nor did it affect the urinary excretion of this agent. Ceforanide was not secreted into saliva in any detectable amount either when administered alone or with probenecid. It is not clear why probenecid has a negligible effect on ceforanide concentrations in plasma. It may be that tubular secretion plays less of a role in the excretion of ceforanide than expected, or that the physical properties of ceforanide prevent probenecid from affecting its excretion.

In Vitro and Clinical Studies of Cefatrizine, a New Semisynthetic Cephalosporin

Cefatrizine, a new oral semisynthetic cephalosporin, was evaluated in vitro and in the treatment of 18 patients with acute urinary tract infection, pneumonia, and soft tissue infection. In vitro, it was more active than cephalexin for gram-positive and gram-negative bacteria. It was also more active than cephalothin, cefazolin, and cephapirin against most of the gram-negative bacteria but less active against the gram-positive bacteria. Of the patients treated with cefatrizine, only one failed to respond. This patient had pneumococcal conjunctivitis and hypogammaglobulinemia and neutropenia. The mean peak serum level after multiple 6-hourly doses of 500 mg was 6.2 μg/ml. The serum levels of cefatrizine necessary for inhibition of most susceptible organisms were well within the achievable range. The drug was well tolerated, and no renal, hepatic, or hematological toxicity was detected.

Parenteral Cephalothin Therapy for Pelvic Gonococcal Infections

The efficacy of intravenous cephalothin was studied prospectively in 20 patients with acute pelvic inflammatory disease, all of whom presented with lower abdominal pain, cervical and adnexal tenderness, fever, and leukocytosis. Blood, cervical, and cul-de-sac cultures were obtained on admission. The latter was transported anaerobically and inoculated in routine and prereduced medium. Transgrow medium with trimethoprim was used for endocervical cultures. Neisseria gonorrhoeae was isolated from the endocervix in 15 patients and from the cul-de-sac in four patients. All received intravenous cephalothin, 2 gm every four hours for seven days. Clinical improvement was observed in 48 to 78 hours. The cervical cultures were negative for N. gonorrhoeae after 48 hours, at the completion of treatment, and two weeks post-treatment. The drug was well tolerated. It was concluded that cephalothin intravenously is an acceptable alternative antibiotic for the treatment of gonococcal pelvic infection.

Comparative biliary concentrations of cephazolin and cephalothin in patients with biliary tract disease.

The concentration of cephazolin in the serum, gall bladder bile, common duct bile, and gall bladder wall were considerably higher than cephalothin especially with IV administration and indicate that cephazolin should be a useful antibiotic in the surgical treatment of acute cholecystitis.