Sulbactam/Ampicillin: In Vitro Spectrum, Potency, and Activity in Models of Acute Infection

Retsema, James A.; English, Arthur R.; Girard, Arthur E.; Lynch, John E.; Anderson, Misty; Brennan, Lori; Cimochowski, C.; Faiella, J.; Norcia, W.; Sawyer, Perry S.

doi:10.1093/clinids/8.supplement_5.s528

Cited by 100 publications

(31 citation statements)

References 8 publications

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“…Multiple studies have demonstrated that the in vitro activities of j-lactam-p-lactamase inhibitor combinations against MRSA are within the range of the clinically achievable concentrations in serum (2,7,11,13,14,19,34). Also, the majority (7,14,34,40), but not all (10), of the animal model studies suggest that such combinations are effective in vivo.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model

Kernodle

Kaiser

1993

Antimicrob Agents Chemother

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Although some j-lactams and K1-lactam-13-lactamase inhibitor combinations exhibit activity against methicillin-resistant Staphylococcus aureus, there remains the concern that therapeutic failures may result from the selection of resistant subpopulations. The prophylactic use of these antibiotics in clean surgery, however, may prove adequate since wound infections arise from the inoculation of small numbers of bacteria. In (4,28,41).The detection of resistance in MRSA and ,B-lactamaseproducing S. aureus, including BSSA, is inoculum size dependent (6,8,15,22,35,36). Although small numbers of bacteria may appear to be susceptible to ,B-lactam antibiotics in vitro, the testing of large inocula facilitates the recognition of resistance. The clinical implications of this observation are that the use of any ,-lactam cannot be recommended as therapy against infection by MRSA, and vancomycin is the preferred treatment (1,15,39). Similarly, although 1-lactamase-susceptible antibiotics such as penicillin G exhibit marked in vitro activity against small numbers of P-lactamase-producing S. aureus (36), penicillin G is ineffective in * Corresponding author. treating infections caused by these strains (3, 6). The penicillinase-resistant antistaphylococcal penicillins are the therapy of choice for serious infections caused by such strains (39).Since wound infections that complicate clean surgical procedures are believed to originate with the inoculation of small numbers of bacteria into the surgical field (12,16,17), the prophylactic use of ,-lactams, including relatively ,-lactamase-labile antibiotics, may prove to be effective in preventing these infections. In this clinical setting, heterogeneity in the phenotypic expression of 1-lactam resistance among MRSA may permit in vivo antibiotic efficacy. Similarly, the amount of preformed and induced P-lactamase accompanying 3-lactamase-producing S. aureus within the wound site may be insufficient to protect the strain against antibiotics in the serum and tissues. To test this hypothesis, we determined the prophylactic efficacies of ampicillin and cefazolin, alone and in combination with ,-lactamase inhibitors, against two MRSA strains and one BSSA strain using a low-inoculum guinea pig model of wound infection. MATERIALS AND METHODS

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Section: Discussionmentioning

confidence: 99%

Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model

Kernodle

Kaiser

1993

Antimicrob Agents Chemother

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“…that are devoid of ␤-lactamases (an important exception are ampicillin-resistant strains of H. influenzae that do not contain a ␤-lactamase and often have substitutions in PBP sequences) (194,257). In combination with sulbactam, the activity extends to ␤-lactamase-containing S. aureus, H. influenzae, M. catarrhalis, E. coli, Proteus spp., Klebsiella spp., and anaerobes (59,362,444). When the combination of ampicillin at 2.0 g and sulbactam at 1.0 g was marketed in 1987, this broad-spectrum activity made ampicillin-sulbactam ideal therapy for polymicrobial infections such as abdominal and gynecological surgical infections, aspiration pneumonia, odontogenic abscesses, and diabetic foot infections.…”

Section: ␤-Lactamase Inhibitors In Clinical Practicementioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

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“…These enzymes, however, can be blocked by different ,B-lactamase antagonists. Among them, sulbactam is a potent and irreversible P-lactamase inhibitor that restores and extends the spectrum of ampicillin against resistant strains of many pathogenic bacteria (5,8,16). In the present study, we examined the pharmacokinetics and the dose-dependent bactericidal activity of ampicillin-sulbactam in rabbits with meningitis caused by a P-lactamase-producing strain of E. coli.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Guerra-Romero

Kennedy

Fournier

et al. 1991

Antimicrob Agents Chemother

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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...

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Sulbactam/Ampicillin: In Vitro Spectrum, Potency, and Activity in Models of Acute Infection

Cited by 100 publications

References 8 publications

Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model

Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model

Three Decades of β-Lactamase Inhibitors

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

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