The influence of the polyamino acid polyaspartic acid (PAA) on experimental aminoglycoside nephrotoxicity was determined. PAA prevented all measured functional and pathologic evidence of gentamicin nephrotoxicity for less than or equal to 27 d of study. All the animals given PAA, either alone or with gentamicin, developed prominent cytoplasmic vacuoles in the cells of the renal proximal convoluted tubules; the vacuoles in rats given just PAA differed from those observed in rats given PAA plus gentamicin. Rats given PAA plus gentamicin accumulated roughly 10 times more renal aminoglycoside as did rats given gentamicin alone. Immunohistochemical localization studies confirmed the presence of increased amounts of gentamicin in the cytoplasm of the tubular cells of animals given gentamicin plus PAA. PAA did not alter the in vitro antimicrobial activity of gentamicin versus Escherichia coli or Pseudomonas aeruginosa. These studies demonstrate the ability of PAA to prevent experimental gentamicin nephrotoxicity.

The influence of vancomycn on tobramycin nephrotoxicity was assessed in male Fischer rats. Treatment groups included controls receiving diluent and groups receiving vancomycin alone at a dosage of 200 mg/kg (body weight) per day, tobramycin alone at a dosage of 80 mg/kg per day, and a combination of vancomycin and tobramycin at the above dosages. All regimens were injected on a twice-a-day schedule. The animals were sacrificed on days 1, 3, 10, 14, 17, and 21. When compared with controls, animals receiving vancomycin alone exhibited no detectable renal toxicity. Compared with the case with controls, tobramycin alone was toxic, as manifested by lower mean animal weights, increased blood urea nitrogen concentrations on days 14 and 17 (P < 0.005), increased serum creatinine concentrations on days 17 and 21 (P < 0.005), and the presence of renal cortical tubular necrosis and regeneration. When compared with tobramycin alone, the combination of vancomycin and tobramycin caused earlier and more severe toxicity. By day 10, the magnitude of weight loss, the rise in blood urea nitrogen, and the increase in serum creatinine concentration were all greater in the rats given the combination of vancomycin plus tobramycin than in the animals given tobramycin alone (P < 0.005). In addition, there was more proximal tubular necrosis and regeneration in rats given vancomycin plus tobramycin compared with those given tobramycin alone. In this animal model, vancomycin alone caused no detectable renal injury, tobramycin alone produced minimal proximal tubular damage, and the combination of vancomycin and tobramycin resulted in a greater degree of kidney injury than observed with tobramycin alone.In recent years, clinical indications for combination antimicrobic therapy with vancomycin and an aminoglycoside have increased. Selected examples are prosthetic valve endocarditis caused by Staphylococcus epidermidis (9), serious infections caused by methicillin-resistant Staphylococcus aureus (10), and endocarditis caused by group D streptococci in patients allergic to penicillin (8,15).The dose-dependent nephrotoxic potential of the aminoglycosides is well known. The nephrotoxic potential of vancomycin is uncertain. Early clinical studies with vancomycin described patients who developed granular casts, increases in blood urea nitrogen (BUN), and severe anemia and even died from acute renal failure. Subsequently, impurities present in the initial vancomycin preparations were removed (7, 17). More recent clinical studies describe a very low incidence of renal injury in patients given only vancomycin (1,3,4,13,14). However, it has been suggested that vancomycin given concomitantly with an aminoglycoside may increase the frequency of aminoglycoside nephrotoxicity (3). Farber and Moellering described, retrospectively, more nephrotoxicity in patients given the combination of vancomycin and an aminoglycoside than in patients administered only vancomycin (3). Unfortunately, the latter study did not include a control group of patients given only an...

Clostridium difficile causes approximately 25% of nosocomial antibiotic-associated diarrheas and most cases of pseudomembranous colitis. We evaluated C. DIFF CHEK, a new screening test that detects glutamate dehydrogenase of C. difficile. Our results showed that this test was comparable to PCR in sensitivity and specificity and outperformed bacterial culture.

The phenotypic resistance of selected organisms to ciprofloxacin, levofloxacin, and trovafloxacin was defined as a MIC of >4 g/ml. The dynamics of resistance were studied after single and sequential drug exposures: clinical isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa were utilized. After a single 48-h exposure of a large inoculum to four times the initial MIC for the organism, the frequency of selection of resistant mutants of MSSA was greater for trovafloxacin than levofloxacin (P ‫؍‬ 0.008); for E. cloacae, the frequency was highest for ciprofloxacin and lowest for levofloxacin and trovafloxacin; for S. marcescens, the frequency was highest for trovafloxacin and lowest for ciprofloxacin (P ‫؍‬ 0.003). The results of serial passage experiments were analyzed both by the Kaplan-Meier product-limited method as well as by analysis of variance of mean inhibitory values. By both methods, MSSA and MRSA expressed mutants resistant to ciprofloxacin after fewer passages than were required for either levofloxacin or trovafloxacin. For the aerobic gram-negative bacilli, two general patterns emerged. Mutants resistant to trovafloxacin appeared sooner and reached higher mean MICs than did mutants resistant to levofloxacin or ciprofloxacin. Mutants resistant to ciprofloxacin appeared later and reached mean MICs lower than the MICs of the other two drugs studied. Even though individual strain variation occurred, the mean MICs were reproduced when the serial passage experiment was repeated using an identical panel of E. coli isolates. In summary, the dynamic selection of fluoroquinolone-resistant bacteria can be demonstrated in experiments that employ serial passage of bacteria in vitro.