Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1

Abstract

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a 1-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and >64 ,ug/ml (ampicillin), >256 and >256 ,ug/ml (sulbactam), 2.0 and 4.0 jig/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 ,ug/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only tnoderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were rVduced by 0.6 ± 0.3 log1o CFU/ml/h with the hihest ainpicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was'similar to the tivctericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) p,roduced a significant increase in bactericidal activity (1.1 0.4 log1o CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmnacokinetics in animals with meningitis, may be of limited value in tlg treatment of difficult-to-treat ,l-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.Bacterial meningitis remains a serious disease associated with significant morbidity and mortality despite antibiotic and supportive therapy (10,15,25,28). The infecting organism is a major determinant of the prognosis, which is particularly poor in gram-negative-bacillus meningitis (1, 13, 23). The increasing rate of P-lactamase-producing gramnegative pathogens has prompted a search for effective agents to treat meningitis caused by these bacteria. Newer cephalosporins are generally highly effective in this regard (3,4,12,(19)(20)(21)30). As an alternative approach, the combination of a penicillin-derivative drug and an agent that inhibits the P-lactamase elaborated by the pathogen has attracted interest. Recently, we have examined the combination of piperacillin and tazobactam, a P-lactamase inhibitor, in experimental meningitis due to a ,-lactamase producing Escherichia coli strain (9). We found favorable pharmacokinetic properties for both compounds and showed that the addition of the P-lactamase inhibitor protected the bactericidal activity of piperacillin in cerebrospinal fluid (CSF). However, because of the relatively weak in vitro activity of piperacillin against the test strain, maximal CSF bactericidal activity of the combination was achieved only with extremely high drug concentrations.Sulbactam, a penicillanic acid sulfone, is an irreversible inhibitor of ,-lactamase that extends the spectrm of ampicillin to include strains of Staphylococcus dureus, Haemophilus sp., E. coli, and other P-lactamase-producing gram-negative bacteria (8, 16). Ampicillin-sulbactam is extensively used in clinical practice (11). In the present study, we examined ampicilli...

Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase

“…Similarly, concentrations of bacteria in CSF tended to increase throughout therapy in all animals given either drug alone. In contrast, the combination of piperacillin with tazobactam produced bactericidal activity in the CSF in vivo at all dosages that were investigated ( Piperacillin (80) 6 0.45 ± 0.29 2 (6) Piperacillin (200) 6 0.53 ± 0.10 3 (8) Tazobactam ( (20,23) and for sulbactam in the infected CSF of rabbits (10) and humans (9). In contrast, concentrations of clavulanic acid in human infected CSF are low, as a result of modest penetration and dosage limitations in patients (2,5).…”

Pharmacokinetic study of sulbactomax

“…In the last few years, however, an increase in resistance, especially among Enterobacteriaceae, has been reported, resulting from a continuous spread of broad-spectrum β-lactamases. Guerra-Romero et al (1991) reported a combination of a penicillin-derivative drug (ampicillin) and sulbactam, for the treatment of experimental meningitis caused by a β-lactamase producing strain of E. coli K-1.…”

Pharmacodynamics of antibiotics in the therapy of meningitis: Infection model observations

“…Again, in contrast to in-vitro experiences, which show that /J-lactams achieve maximal activity at concentrations only slightly above the MBC, infection model studies have found a strong dose-response curve between antibiotic concentration and bacteria] killing rates in the CSF. The maximum attainable bacterial killing rate is approximately 1 log, 0 cfu/mL/h at very high doses, and is independently of the class of antibiotic and infecting pathogen examined (Tauber et al, 1984a(Tauber et al, , 1985aKern et al, 1990;Guerra-Romero et al, 1991).…”

“…Many experimental studies have documented that antibiotics have to exceed the in-vitro MBC of the infecting pathogen by at least 10-30-fold (Tauber et al, 1984a(Tauber et al, , 1985aKern et al, 1990;Guerra-Romero et al, 1991). The reasons for this reduced activity of antibiotics in CSF compared with that in vitro are not completely clear, but the specific milieu of the CSF may be a contributing factor, since time-kill curves performed in CSF ex vivo with penicillin G against S. pneumoniae showed that three to ten times higher concentrations were needed to reach the same maximal bacterial activity as in broth (Tauber et al, 1984a).…”