Effective treatment of cephalosporin-rifampin combinations against cryptic methicillin-resistant beta-lactamase-producing coagulase-negative staphylococcal experimental endocarditis.

The efficacy of cefazolin or cefpirome alone or combined with rifampin was compared with that of vancomycin alone or combined with rifampin in an experimental model of methicillin-resistant, beta-lactamase-producing, coagulase-negative staphylococcal endocarditis. Phenotypically, the mecA gene-positive strain used in vivo did not exhibit methicillin resistance by the agar dilution or disk susceptibility method but was resistant in vitro (oxacillin MIC, 64 micrograms/ml) by the microtiter dilution method with 2% NaCl supplementation. Macrodilution broth susceptibilities of standard inocula failed to demonstrate cross-resistance of staphylococci to cefazolin (MIC, 8 micrograms/ml) or cefpirome (MIC, 4 micrograms/ml). In vivo, vancomycin and cefpirome had similar activities, and both regimens were more effective than was cefazolin alone. While the MIC of rifampin was low (0.031 micrograms/ml), monotherapy with rifampin resulted in a bimodal distribution of outcomes due to the expected emergence of resistant mutants. The results in vitro of time-kill synergy studies using rifampin in combination with cefazolin or cefpirome varied with the antimicrobial concentrations tested and did not reliably predict activities in vivo of rifampin-beta-lactam combination therapies. Cefpirome, but not cefazolin or vancomycin, in combination with rifampin was synergistic in vivo. Cefpirome in combination with rifampin was more effective than was cefazolin in combination with rifampin. Both cephalosporin-rifampin regimens were significantly more effective than was cephalosporin or vancomycin monotherapy and were as effective as vancomycin combined with rifampin. These data support further evaluation of rifampin-beta-lactam combinations as possible alternative therapies to vancomycin-containing regimens for selected methicillin-resistant coagulase-negative staphylococcal infections.

Failure of time-kill synergy studies using subinhibitory antimicrobial concentrations to predict in vivo antagonism of cephalosporin-rifampin combinations against Staphylococcus aureus.

Results of in vitro time-kill synergy studies using subinhibitory, inhibitory, or suprainhibitory concentrations of bactericidal agents were compared with treatment outcomes of experimental infective endocarditis due to a methicillin-susceptible strain of Staphylococcus aureus. For rifampin-cephalosporin combinations, in vitro synergy testing using recommended fractions of the MIC failed to predict antagonism in vivo while concentrations above the MIC corresponded with antagonism in vivo.

Relative efficacies of broad-spectrum cephalosporins for treatment of methicillin-susceptible Staphylococcus aureus experimental infective endocarditis.

The effects of treatment with broad-spectrum parenterally administered cephalosporins and cefuroxime, cefazolin, or nafcillin were compared in an experimental model of Staphylococcus aureus infective endocarditis, and the results in vivo were compared with the activities of the study drugs in vitro. After 3 days of treatment, all antimicrobial agents tested were more effective than no treatment in reducing the number of surviving bacteria in cardiac valve vegetations. Nafcillin was the most effective agent studied and was significantly more active than was ceftizoxime, ceftriaxone, cefotaxime, cefoperazone, cefuroxime, or cefazolin (P < or = 0.05). Cefpirome and ceftazidime were the most effective broad-spectrum cephalosporins. The outcome of treatment with cefpirome or ceftazidime was similar to that of treatment with nafcillin and significantly better than that of treatment with ceftizoxime or cefotaxime (P < or = 0.05). Treatment outcome correlated closely with the MICs of the antimicrobial agents for the study strain with the exception of ceftazidime, which was significantly more active in vivo in comparison with other agents than predicted by its MIC (P < or = 0.0003). When ceftazidime was excluded as an outlier, treatment outcome correlated with the MICs of the remaining study drugs (Spearman's correlation coefficient, 0.95; P < or = 0.0004), as well as with the estimated percentage of time during which the concentration of total drug (correlation coefficient, -0.85; P < or = 0.007) or free drug (correlation coefficient, -0.90; P < or = 0.003) exceeded the MIC. A consideration of total or free drug concentrations in relation to MICs did not significantly improve the correlation with outcome observed with the MICs alone.

Animal models as predictors of outcome of therapy with broad spectrum cephalosporins.

Broad spectrum cephalosporins have been studied extensively in animal models of experimental infections. There is generally good correlation between the results of therapy of experimental infections and clinical trials in humans. However, the results of animal model studies are better predictors of the failure than of the success of a chemotherapeutic regimen. Cefotaxime and the new 'fourth' generation agent, cefpirome, were comparable in the treatment of experimental meningitis caused by Streptococcus pneumoniae. Cefpirome was the most effective cephalosporin as therapy for methicillin-susceptible Staphylococcus aureus experimental endocarditis. The most effective broad spectrum cephalosporins for the treatment of Gram-negative experimental pneumonia were cefpirome, cefotaxime and cefodizime. Cefpirome was equivalent to ceftazidime or cefazolin as treatment for Pseudomonas aeruginosa or methicillin-susceptible S. aureus experimental osteomyelitis. Because of its potent activity in vitro and in animal models of experimental infections caused by methicillin-susceptible S. aureus and Gram-negative bacilli, cefpirome may offer a therapeutic advantage over currently available broad spectrum cephalosporins.

Efficacy of cilofungin therapy administered by continuous intravenous infusion for experimental disseminated candidiasis in rabbits.

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.

Immunological responsiveness of chinchillas to outer membrane and isolated fimbrial proteins of nontypeable Haemophilus influenzae.

Thin, nonhemagglutinating fimbriae have been demonstrated on 100% of the clinical isolates of nontypeable Haemophilus influenzae recovered from children with chronic otitis media tested in this laboratory (L. O. Bakaletz, B.M. Tallan, T.M. Hoepf, T.F. DeMaria, H.G. Birck, and D.J. Lim, Infect. Immun. 56:331-335, 1988). Chinchillas with induced otitis media responded to this surface-located antigen of both the infecting and a heterologous strain. Antibodies were found in both serum and middle ear fluids.

Frequency of fimbriation of nontypable Haemophilus influenzae and its ability to adhere to chinchilla and human respiratory epithelium.

To date, we have examined nearly 60 clinical isolates of nontypable Haemophilus influenzae (26 nasopharyngeal, 33 from middle ear effusions) and have found that 100% were fimbriated. The percentage of cells bearing fimbriae within each isolate varied from less than 10 to 100%, with fimbriae being either peritrichous or bipolar in distribution. Fimbriae were approximately 2.4 to 3.6 nm in width; however, there was a high degree of variability in both length and number of fimbriae per individual bacterial cell among these isolates. All isolates tested adhered to both human oropharyngeal cells and chinchilla tracheal epithelium regardless of the degree to which the particular isolate was fimbriate. The level or degree of fimbriation did not correlate with either site of isolation, biotype, strength of hemagglutination reaction, or type of effusion present in the ear. These appendages appear to be quite different from those described for type b H. influenzae in which the ability to adhere and strength of ability to hemagglutinate correlated strongly with degree of fimbriation.