Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats

Abstract

Intermittent administration of ampicillin alone has resulted in high failure rates in previously described animal models of enterococcal endocarditis. We developed a rat model of enterococcal endocarditis which permits comparison of continuous intravenous infusion of ampicillin with intramuscular therapy. Continuous low-dose ampicillin infusion (450 mg/kg [body weight] per day) was compared with the same dose given intramuscularly in three divided doses and with high-dose infusion (4.5 g/kg per day) of the drug. For the infecting strain of Streptococcus faecalis, the MIC and MBC were 1 ,ug/ml. Mean ampicillin levels in serum were 53.9 + 4.8 (peak) However, no statistically significant advantage was found for high-dose compared with low-dose ampicillin infusion in lowering bacterial titers in vegetations (P > 0.3).Aside from viridans group streptococci and Staphylococcus aureus, enterococci are the most common pathogens causing bacterial endocarditis, and enterococcal endocarditis represents a major therapeutic challenge (14). Streptococcus faecalis, the most common species of enterococcus to cause human infection, is typically susceptible to ampicillin, but the lack of consistent bactericidal activity of cellwall-active antibiotics against enterococci usually requires that they be combined with an aminoglycoside to obtain a synergistic bactericidal effect (17). However, under appropriate experimental circumstances, experimental enterococcal endocarditis may be successfully treated with ampicillin alone (21). Studies dealing with the effect of antibiotic administration modes on tissue penetration are limited in number and display contradictory results. However, in some situations, continuous infusion of 1-lactam antibiotics may be advantageous (1). The purpose of this study was to evaluate the efficacy of ampicillin administered in a standard fashion by intermittent injection compared with continuous intravenous infusion in experimental enterococcal endocarditis in rats and, further, to compare the effectiveness of low and high doses of ampicillin administered by continuous infusion. These studies assume particular relevance because the recent emergence of S. faecalis isolates containing multiple aminoglycoside-modifying enzymes (16; S. Kathpalia, V. Lorian, R. Levandowski, and G. G. Jackson, Clin. Res. 32:3724, 1984) has created a situation in which penicillin-aminoglycoside therapy is not more effective than penicillin alone and in which the clinician thus has little choice but to use the most active single-drug regimen available when treating endocarditis caused by such organisms. MATERIALS AND METHODS Test organism. S. faecalis 1310 used throughout the study was a clinical blood culture isolate recovered at the Massachusetts General Hospital, Boston, Mass. The MIC and MBC of ampicillin for this strain were 1 jig/ml, determined in dextrose-phosphate broth (GIBCO Diagnostics, Madison, Wis.) by using a macrobroth dilution technique (12).Killing curves. Evaluation of the bactericidal activity of ampicillin agai...

Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

“…The superior effectiveness of continuous infusion over intermittent infusion has been demonstrated for ␤-lactams in animal studies (2,8,25,26); however, clinical data comparing continuous and intermittent infusions are limited and consist primarily of data from small studies and case reports (1,3,6,9,10,11,19,22,28). In most of these studies, similar clinical and microbiological outcomes have been observed for the two administration techniques, but none of the studies have had sufficient power to conclude noninferiority.…”

“…Although the concept of continuous infusion is supported by ␤-lactam pharmacodynamics (8,27), suggesting that maximization of the fT Ͼ MIC should be a critical factor for a positive outcome, clinical studies supporting this are limited. The majority of supporting data have been derived from either in vitro or animal models of infection, which demonstrated equivalent or improved end points with continuous infusion (2,25,26), or from small case reports, retrospective studies, or prospective observational trials (1,9,10,11,14,20,22,28). In one randomized, comparative trial of 100 febrile neutropenic patients, intermittent carbenicillin infusion plus continuous cefamandole infusion achieved a greater effectiveness than intermittent carbenicillin infusion plus intermittent cefamandole infusion in the subgroup of patients with agranulocytosis (absolute neutrophil count, Ͻ100/mm 3 ) (4).…”

The life and times of the Enterococcus

“…Moreover, it is not known whether an MBC, or for that matter any in vitro or animal model criteria, can predict clinical cures. One group reported better success in a rat model of endocarditis by using continuousinfusion ampicillin versus intermittent ampicillin for a strain of enterococcus highly resistant to gentamicin (205). However, that strain also showed a 103-CFU/ml decrease from a 107-CFU/ml inoculum in time-kill curves, using 5, 10, and 250 ,ug of ampicillin per ml, and the authors comment that other strains may display more tolerance to ampicillin.…”

“…To cast further doubt on the bacteriologic identification, all of the enterococci were said to be susceptible to cephalothin and one to clindamycin, unusual properties for enterococci (79). In vitro, vancomycin is usually not bactericidal, and it does no better in animal models than penicillin alone (27,99,104,135,205,217). Among other agents that have been evaluated, ciprofloxacin was less effective than procaine penicillin in controlling enterococcal endocarditis (75,104,195).…”

Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis

“…Most of these conclusions regarding the relation between the pharmacodynamics of antibiotics and optimal dosage have been verified in experimental bacterial endocarditis (9,36,39,50,51,55).…”