Edward L. Quinn

Trimethoprim-Sulfamethoxazole Compared with Vancomycin for the Treatment of Staphylococcus aureus Infection

OBJECTIVE To compare trimethoprim-sulfamethoxazole (TMP-SMZ) and vancomycin regarding efficacy and safety in the therapy of serious Staphylococcus aureus infections. DESIGN Randomized, double-blind comparative trial. SETTING A tertiary-care hospital. PATIENTS One hundred and one intravenous drug users hospitalized with S. aureus infection. MEASUREMENTS Cure and failure rates; blood and wound cultures; minimum inhibitory and bactericidal concentrations; serum inhibitory and bactericidal titers; temperature; leukocyte count; durations of treatment and hospitalization; and toxicity. RESULTS Of 228 intravenous drug users, 101 had S. aureus infection and were included in the efficacy analysis (43 received TMP-SMZ and 58 received vancomycin). Methicillin-resistant S. aureus (MRSA) accounted for 47% of S. aureus isolates, and 65% of patients were bacteremic. Infections were cured in 57 of 58 vancomycin recipients and in 37 of 43 TMP-SMZ recipients (P less than 0.02). Failure occurred mostly in patients with tricuspid valve endocarditis and only in those with infection caused by methicillin-sensitive S. aureus (MSSA). The mean duration of bacteremia was 6.7 days in TMP-SMZ recipients and 4.3 days in vancomycin recipients. Among 222 subjects hospitalized for at least 24 hours, toxicity rates were similar for TMP-SMZ (23%) and vancomycin (20%) recipients; nausea and vomiting were associated with TMP-SMZ and inflammation at the intravenous site was associated with vancomycin. Forty-four percent of TMP-SMZ recipients and 29% of vancomycin recipients experienced side effects in the efficacy cohort (P greater than 0.05). CONCLUSIONS Vancomycin is superior to TMP-SMZ in efficacy and safety when treating intravenous drug users who have staphylococcal infections. However, all treatment failures occurred in patients with MSSA infection at any site. Therefore, TMP-SMZ may be considered as an alternative to vancomycin in selected cases of MRSA infection.

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.

Bacteremia, endocarditis, and the Hancock valve.

Among 373 patients with porcine xenografts, there were 27 instances of exposure of the xenograft to bloodstream or endocardial infection in 22 patients. Nine patients underwent 10 separate insertions of xenografts for active infective endocarditis. There were no early infections or valve failures. Three patients returned with a late prosthetic valve endocarditis (PVE) due to a new infection. There were 6 instances of bacteremia early after xenograft valve insertion with no early infection, no valve dysfunction, and 1 instance of late PVE. Eleven patients had PVE on a porcine xenograft. Blood cultures in the 10 patients treated with antibiotics promptly became negative. There were 3 valve-related deaths: 2 from valve incompetence and 1 from mitral and aortic xenograft stenosis. Our experience suggests that the Hancock porcine xenograft is: (1) as resistant to infection as are rigid prostheses in active infective endocarditis; (2) resistant to early postoperative bacteremias; and (3) easier to sterilize than rigid prostheses and more durable than other tissue valves in the face of PVE.

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.

Imipenem-cilastatin in the treatment of methicillin-sensitive and methicillin-resistant Staphylococcus aureus infections.

Imipenem-cilastatin was evaluated for efficacy and toxicity as an antistaphylococcal agent in 23 patients; 11 of these patients were infected with methicillin-resistant Staphylococcus aureus (MRSA), and 12 were infected with methicillin-susceptible S. aureus (MSSA). There were 15 soft tissue, 5 endovascular, and 3 skeletal infections and a total of nine patients with bacteremia. As determined by in vitro susceptibility testing, the MICs for 90% of the MRSA and MSSA isolates tested were 6.25 and 0.39 micrograms/ml, respectively. Two MRSA isolates were resistant to a concentration of greater than 16 micrograms/ml. When 11 MRSA isolates and 7 MSSA isolates were incubated for 48 h the MICs for 90% of the isolates increased to greater than 50 micrograms/ml for the MRSA isolates and 6.25 micrograms/ml for the MSSA isolates. Three S. aureus isolates emerged resistant. Ten of 11 (91%) MRSA infections and 11 of 12 (92%) MSSA infections were clinically cured. Adverse reactions occurred in 25% of the imipenemcilastatin-treated patients. These reactions included gastrointestinal intolerance (7% of the patients), rash or pruritis (6%), eosinophilia (6%), thrombocytosis (4%), and a positive, direct Coomb test without hemolysis (3%). One of the two patients for whom therapy was discontinued because of gastrointestinal intolerance had antibiotic-associated colitis. Imipenem appears to be an effective antistaphylococcal agent against both MRSA and MSSA infections.

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.

Single-dose cephalexin therapy for acute bacterial urinary tract infections and acute urethral syndrome with bladder bacteriuria.

The efficacy of single-dose therapy with 3 g of cephalexin was evaluated in 129 women with symptoms of acute uncomplicated lower urinary tract infections. Of 91 patients with significant bacteriuria, 61 (67%) were cured of their original infection; this was similar to the 54 to 79% cure rates reported in unselected populations of women of a wide age range treated for acute uncomplicated urinary tract infections with a single dose of amoxicillin or trimethoprim-sulfamethoxazole (J. Rosenstock, L. P. Smith, M. Gurney, K. Lee, W. G. Weinberg, J. N. Longfield, W. B. Tauber, and W. W. Karney, Antimicrob. Agents Chemother. 27:652-654, 1985; N. E. Tolkoff-Rubin, M. E. Wilson, P. Zuromskis, I. Jacoby, A. R. Martin, and R. H. Rubin, Antimicrob. Agents Chemother. 25:626-629, 1984). The cure rates of (87%) for our younger patients, those less than 25 years of age, was better than that (46%) for our patients over 40 years of age (P less than 0.001). Patients with infections that were negative in an antibody-coated bacteria test were cured at a significantly higher rate than those with infections that were positive in an antibody-coated bacteria test (71 versus 19%; P = 0.003). Those patients with infections caused by cephalexin-susceptible organisms were cured at a rate similar to that for patients with infections caused by cephalexin-resistant organisms (68 versus 50%; P = 0.62). The cure rate for suburban patients was 90%, versus 45% for inner-city patients (P = 0.008). Of the 28 women with acute urethral syndrome due to low-level bacteriuria, 27 were cured.

Pneumococcal psoas abscess.

Primary extrapulmonary pneumococcal disease has become a rarity in modern times. We describe a 40-year-old patient who developed an abscess of the psoas muscle as the only evidence of pneumococcal disease. A predisposing local condition was prior trauma of the psoas muscle, documented by the existence of myositis ossificans circumscripta. This case emphasizes the importance of considering unusual sites of involvement of pneumococcal disease.

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.