Imipenem therapy of experimental Staphylococcus epidermidis endocarditis

Abstract

Imipenem was evaluated for its activity against Staphylococcus epidermidis in vitro and in a rabbit model of endocarditis. The MBC for imipenem of 55 methicillin-resistant S. epidermidis isolates from patients with prosthetic valve endocarditis increased by eightfold or greater with increasing inoculum size; there was no inoculum-associated increase in the imipenem MBC for 20 methicillin-susceptible S. epidermidis isolates. Endocarditis was produced in rabbits with either a methicillin-susceptible or a methicillin-resistant S. epidermidis isolate to investigate the correlation in vivo of the in vitro inoculum effect for imipenem. Six days of imipenem treatment eradicated methicillin-susceptible S. epidermidis from vegetations of infected rabbits significantly better than no therapy but was less effective against methicillin-resistant S. epidermidis in this regard. Among methicillin-resistant S. epidermidis-infected rabbits, 6 days of imipenem therapy (i) was not significantly better than that of the control and was significantly worse than that of vancomycin in eradicating bacteria from infected vegetations and (ii) increased the frequency of imipenem-resistant subpopulations in infected vegetations. Resistant subpopulations were not seen in vegetations from untreated or imipenemtreated, methicillin-susceptible S. epidermidis-infected rabbits. Imipenem may not be effective therapy for serious human methicillin-resistant S. epidermidis infections.Prosthetic valve endocarditis (PVE) is a serious illness with mortality rates as high as 60%. Staphylococcus epidermidis is the cause of more episodes of PVE than any other organism, accounting for approximately 40% of cases (3). As many as 80o of S. epidermidis isolates causing prosthetic valve endocarditis are resistant to the semisynthetic penicillinase-resistant penicillins (methicillin-resistant S. epidermidis) and other beta-lactam antibiotics (7). Because of this high incidence of antibiotic resistance, new antibiotics are continuously being sought to which resistant S. epidermidis will be susceptible. Imipenem, a new beta-lactam antibiotic, was shown to be active against methicillin-resistant S. epidermidis when tested in vitro against a low bacterial inoculum (9). However, other beta-lactam antibiotics which appear to be active against methicillin-resistant S. epidermidis when they are tested against a low bacterial inoculum are markedly less active when a higher inoculum is used (7). These antibiotics also show poor efficacy when they are evaluated in vivo (7,11,16). Therefore, to evaluate the activity of imipenem against methicillin-resistant S. epidermidis, we looked at the antibiotic in two ways. First, we tested the antibiotic in vitro against 55 methicillin-resistant S. epidermidis isolates recovered from patients with PVE, using both high and low bacterial inocula. Second, we examined the ability of imipenem to sterilize vegetations from rabbits with experimental endocarditis caused by clinical isolates of either a methicillin-resistant or a methicillinsu...

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

“…Although the susceptibility tests with standard inocula suggested that the MR strain used in vivo was susceptible to cefazolin or cefpirome, at higher inocula resistance to cefazolin and cefpirome corresponded with the rather minimal effect of cephalosporin monotherapy in our study compared with the reported effectiveness of beta-lactam monotherapy in susceptible strains of CoNS (7). Previous studies (3,30,46) have demonstrated cross-resistance in vivo of many beta-lactams with methicillin for MR CoNS, although a previous retrospective clinical study (26) reported a higher cure rate among patients receiving beta-lactam monotherapy for MR CoNS endocarditis than expected.…”

Comparative efficacies of imipenem, oxacillin and vancomycin for therapy of chronic foreign body infection due to methicillin-susceptible and -resistant Staphylococcus aureus

“…When the in-vitro and in-vivo data were compared with those in the literature, we also found that detection of imipenem resistance had been an important part of some earlier studies (Berry et al, 1986;Chandrasekar et al, 1988). Whereas Chandrasekar et al (1988) grew MRSA for 18-24 h at 35°C on mannitol and sodium chloridesupplemented agar and found good in-vitro and in-vivo activity of imipenem against these organisms, opposite results and conclusions were obtained by Berry et al (1986) who enumerated colonies of methicillin-resistant Stapylococcus epidermidis after 72 h of growth at 30 c C. These major differences in incubation times and temperatures could afford an explanation for the conflicting results obtained from the studies, in particular because the former group selected a 24 h growing period which was likely to have been insufficient to detect the slow-growing, highly resistant subpopulations of MRSA.…”

Antimicrobial susceptibility of coagulase-negative staphylococci

“…This resistance, designated methicillin or oxacillin resistance, effectively precludes therapy with any of the currently available beta-lactam antibiotics (23). The gene encoding PBP2a, mecA, is identical by DNA hybrid-ization and nucleotide sequence analysis among all staphylococci with the characteristic phenotype (12,23,63 (16,44,80). However, the presence of a smaller resistant subpopulation for some beta-lactams than for others does not seem to correlate with an improved response of infecting CoNS to therapy.…”