Combination Of Sulbactam Research Articles

Risk of underdosing of ampicillin/sulbactam in patients with acute kidney injury undergoing extended daily dialysis—a single case

The fixed antibacterial combination of ampicillin and sulbactam is frequently used for various infections. The normal kidneys eliminate approximately 60% of ampicillin (371.39 Da) and sulbactam (255.22 Da). Concomitant with the decline in renal function, the terminal elimination half-life increases from 1 up to 24 h in patients with ESRD. Patients on three times weekly low flux haemodialysis exhibit a half-life of 2.3 h on and 17.4 h off dialysis. In contrast, in the present observation the elimination half-life in a single patient with acute kidney injury undergoing extended daily dialysis (EDD) with a polysulphone membrane was 1.5 h, indicating that the current dosing regimen for haemodialysis outpatients (ampicillin/sulbactam 2.0/1.0 g/day) would result in a significant underdosing for patients undergoing EDD.

In vitro activity of cefepime combined with sulbactam against clinical isolates of carbapenem-resistant Acinetobacter spp.

The aim of this study was to assess the in vitro activity of cefepime combined with sulbactam against carbapenem-resistant clinical isolates of Acinetobacter spp. The checkerboard method was used to determine whether combinations act synergistically against these strains. Twenty-three Acinetobacter baumannii and one Acinetobacter junii found to be carbapenem resistant were included in the study. The susceptibility results for cefepime and sulbactam were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were used as quality control strains. The combination of cefepime and sulbactam demonstrated the following interactions: 33.3% (8/24) synergism; 58.3% (14/24) partial synergism; 4.2% (1/24) additive; 4.2% (1/24) indifference; and no antagonism (minimum and maximum fractional inhibitory concentration index 0.25 and 1.5, respectively). According to our in vitro study results, combinations of cefepime with sulbactam have moderate synergistic activity against some carbapenem-resistant strains of Acinetobacter spp., which could be beneficial for the treatment of infections due to multidrug-resistant strains of Acinetobacter spp.

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data

We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. Sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. Piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC 90 values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa (53–57% in either 2:1 or 4:1 ratios) and A. baumannii (38–46% in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam) isolates. Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. Piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.

Short Communication: Pharmacokinetics of an Ampicillin–Sulbactam (2:1) Combination after Intravenous and Intramuscular Administration to Chickens

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination were studied in 6 sheep, after intravenous and intramuscular injection at a single dose rate of 20 mg/kg body weight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam). The drugs were distributed according to an open 2-compartment model after intravenous administration and a onecompartment model with first order absorption after intramuscular administration. The apparent volumes of distribution calculated by the area method of ampicillin and sulbactam were 0.32 ± 0.06 L/kg and 0.42 ± 0.04 L/kg, respectively and the total body clearances were 0.69 ± 0.07 and 0.38 ± 0.03 L/kg-h, respectively. The elimination halflives of ampicillin after intravenous and intramuscular administration were 0.32 ± 0.05 h and 0.75 ± 0.27 h, respectively, whereas for sulbactam the half-lives were 0.74 ± 0.10 h and 0.89 ± 0.16 h, respectively. The bioavailability after intramuscular injection was high and similar in both drugs (72.76 ± 9.65 % for ampicillin and 85.50 ± 8.35% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.25 ± 0.10 h and 0.24 ± 0.08 h, respectively) and peak concentrations were also similar but nonproportional to the dose of both products administered (13.01 + 7.36 mg/L of ampicillin and 10.39 3.95 mg/L of sulbactam). Both drugs had a similar pharmacokinetic behavior after intramuscular administration in sheep. Since the plasma concentrations of sulbactam where consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillinsulbactam combination in a higher than 2:1 ratio.

In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii

Meropenem and imipenem are often the drugs of choice for the treatment of infections due to multidrug-resistant Acinetobacter baumannii. The present study aimed at evaluating the interaction between meropenem and sulbactam through microdilution and checkerboard methods against 48 clinical isolates of A. baumannii collected from Brazilian hospitals. All the isolates presented elevated minimum inhibitory concentration (≥2 μg/mL) to either meropenem or sulbactam. The checkerboard method with the combination of meropenem and sulbactam demonstrated 29.2% (14/48) synergism, 47.9% (23/48) partial synergism, 10.5% (5/48) additive, 6.2% (3/48) indifference, and 6.2% (3/48) antagonism (ΣFIC min = 0.09 and ΣFIC max = 8). Thus, combinations of meropenem and sulbactam may show synergism or partial synergism for most A. baumannii isolates. Further studies may help identify treatment options for patients with infections caused by these organisms, particularly with this combination, where both drugs have time-dependent activities and might be suitable for therapy optimization studies.

Nosocomial and community-acquired Enterobacter cloacae bloodstream infection: risk factors for and prevalence of SHV-12 in multiresistant isolates in a medical centre

In a medical centre in northern Taiwan, 60 patients had bloodstream infection caused by Enterobacter cloacae from 1 January 2002 to 30 April 2003. Forty (66.7%) were nosocomial and 26 were caused by multiresistant isolates. Twenty patients died due to the infection. Central venous catheterization and mechanical ventilation were relative risks for nosocomial E. cloacae infection. Age and mechanical ventilation were risk factors for multiresistant E. cloacae infection. Mortality was associated with multiresistant isolates and polymicrobial infection. Pulsed-field gel electrophoresis (PFGE) analysis showed, the 26 multiresistant isolates comprised 12 different types, with type A predominating (12 isolates). Excluding the patients infected with PFGE type A, central venous catheterization was a relative risk for infection, and polymicrobial infection was a risk factor for mortality. All but one of the 26 multiresistant isolates had the extended-spectrum β-lactamase SHV-12. TEM-1 and ampC β-lactamase genes were also detected in 25 of the 26 multiresistant isolates. Southern blotting indicated that the SHV-12 gene was located on plasmids. Eleven of the 26 multiresistant isolates had minimum inhibitory concentrations (MIC) ≥16 mg/L for cefepime, which was reduced by the addition of sulbactam for most isolates, resulting in susceptibility. The combination of cefepime and sulbactam may be effective in the treatment of multiresistant E. cloacae bloodstream infection.

Pharmacokinetics of an ampicillin–sulbactam combination after intravenous and intramuscular administration to neonatal calves

The pharmacokinetics of a 2:1 ampicillin–sulbactam combination after intravenous (i.v.) and intramuscular (i.m.) injection at a single dose rate of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were studied in 10-day-old neonatal calves ( n=10). The plasma concentration–time data of both antibiotics were best fitted to an open two-compartment model after i.v. administration. After i.m. administration, an open two-compartment model demonstrated first order absorption. The apparent volumes of distribution of ampicillin and sulbactam, calculated by the area method, were 0.20 ± 0.01 and 0.18 ± 0.01 L/kg, respectively, and the total body clearances were 0.51 ± 0.03 and 0.21 ± 0.01 L/kg h. The elimination half-lives of ampicillin after i.v. and i.m. administration were 0.99 ± 0.03 and 1.01 ± 0.02 h, respectively, whereas for sulbactam the half-lives were 2.24 ± 0.02 and 3.44 ± 0.94 h. The bioavailability after i.m. injection was high and similar for both drugs (70.31 ± 0.2% for ampicillin and 68.62 ± 4.44% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.47 ± 0.02 and 0.72 ± 0.01 h, respectively) and peak concentrations were also similar but not proportional to the dose administered (17.88 ± 0.91 mg/L of ampicillin and 12.92 ± 0.79 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after i.m. administration. Since the plasma concentrations of sulbactam were consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillin–sulbactam combination in a ratio higher than 2:1.

Antibiotic resistance and molecular epidemiology of Shigella spp. in northeastern Argentina

To evaluate the antibiotic resistance of strains of Shigella spp. isolated from feces samples from northeastern Argentina and to characterize the strains in terms of their molecular epidemiology. We studied 132 isolates of Shigella spp. obtained from feces samples from 132 patients with diarrhea who were seen at various private and public laboratories in the Argentine provinces of Chaco and Corrientes during the period of 1998 to 2002. Each strain was characterized according to its serotype, its resistance to 13 individual or combination antibiotics, and its sensitivity to pyocins. With 52 strains selected in relation to their antimicrobial susceptibility profiles we conducted plasmid profile analysis using alkaline lysis, and the repetitive extragenic palindromic sequences were determined by amplifying repetitive DNA segments using polymerase chain reaction. The chi-square test was used to compare proportions, with a level of statistical significance of 0.05. Shigella flexneri was the most common species (78%), followed by S. sonnei (22%). In general, the resistance of S. flexneri to the antibiotics studied was greater than that of S. sonnei, and this difference was statistically significant (P < 0.001) for ampicillin, tetracycline, chloramphenicol, and the combination of ampicillin and sulbactam. The S. flexneri strains also showed multiple resistance more often than S. sonnei strains (84.5% vs. 31.0%; P < 0.001). The strains isolated from S. flexneri were grouped into five pyocin types, three plasmid profiles, and five patterns of repetitive palindromic sequences. The strains of S. sonnei formed three pyocin types, two plasmid profiles, and three patterns of repetitive palindromic sequences. Given that the Shigella species that were studied showed a high level of resistance to the most frequently used antibiotics, surveillance activities should be implemented in order to detect and control the appearance of new resistant strains. Applying epidemiological typing techniques can provide more precise information about the distribution and evolution of resistant strains of circulating microorganisms.

PCR typing of genetic determinants for metallo-beta-lactamases and integrases carried by gram-negative bacteria isolated in Japan, with focus on the class 3 integron.

From January 2001 to December 2002, 587 strains of gram-negative bacterial isolates demonstrating resistance to ceftazidime and a combination of sulbactam and cefoperazone were subjected to a disk diffusion screening test using sodium mercaptoacetic acid; 431 strains (73.4%) appeared to produce metallo-beta-lactamase (MBL). Of these 431 strains, 357 were found by PCR to carry genes for IMP-1 type MBL (bla(IMP-1)), while only 7 and 67 strains carried the IMP-2 gene (bla(IMP-2)) and the VIM-2 gene (bla(VIM-2)), respectively. Neither VIM-1 nor SPM-1 type MBL genes were found among the strains tested. Of 431 strains, 427 carried the intI1 gene, and 4 strains carrying both the intI1 and intI3 genes were reidentified as Pseudomonas putida harboring bla(IMP-1). Of these four P. putida strains, three strains and one strain, respectively, were separately isolated from two hospitals located in the same prefecture, and the three strains showed very similar pulsed-field gel electrophoresis patterns. Of 357 bla(IMP-1) carriers, 116, 53, 51, 47, and 30 strains were identified as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, P. putida/fluorescens, Serratia marcescens, and Acinetobacter baumannii, respectively. Four strains carrying bla(IMP-2) were reidentified as P. putida. Sixty-three P. aeruginosa strains and four P. putida strains carried bla(VIM-2). Of 427 intI1-positive strains, 180, 53, 51, 47, and 35 were identified as P. aeruginosa, A. xylosoxidans, P. putida/fluorescens, S. marcescens, and A. baumannii, respectively. In the present study, it was confirmed that strains carrying bla(IMP-1) with a class 1 integron are the most prevalent type in Japan, although several intI3 carriers have also been identified sporadically in this country.

Beta-lactam/beta-lactamase inhibitor combinations in empiric management of pediatric infections.

Beta-lactam antibiotics have long played a central role in the management of pediatric infections. However, widespread beta-lactam resistance among community- and hospital-acquired pathogens, mainly due to beta-lactamase production, has reduced the usefulness of these trusted and well-tolerated agents. Many regions have reported an increase in beta-lactamase-mediated resistance to cephalosporins and carbapenems as well as penicillins among clinically important Gram-positive and Gram-negative aerobes and anaerobes. For some pathogens such as Moraxella catarrhalis, Klebsiella species and Pseudomonas aeruginosa, virtually all strains worldwide are beta-lactamase producers. The development of beta-lactamase inhibitors for co-administration with a number of established beta-lactam agents has restored their usefulness in pediatric patients. The combination of ampicillin plus sulbactam has broad anti-aerobic and anti-anaerobic activity in vitro and achieves high concentrations in many body tissues and fluids. The availability of a mutual oral prodrug, sultamicillin, has enabled the development of an oral formulation. Excellent clinical response and bacterial eradication rates with ampicillin/sulbactam and sultamicillin have been demonstrated for upper and lower respiratory tract infections, urinary tract infections, osteomyelitis, and meningitis in pediatric patients and neonates. Furthermore, many studies have demonstrated an excellent tolerability profile. Thus, ampicillin/sulbactam has an important role in the management of pediatric infections.

Epigallocatechin gallate synergy with ampicillin/sulbactam against 28 clinical isolates of methicillin-resistant Staphylococcus aureus.

Compared with ampicillin, oxacillin, cefmetazole and imipenem, the combination of ampicillin and sulbactam at a constant ratio of 2:1 showed the greatest effect against 28 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), but MICs of ampicillin/sulbactam were still above the resistance breakpoint. When ampicillin/sulbactam was further combined with epigallocatechin gallate (EGCg, a main constituent of tea catechins), the MIC90 of ampicillin/ sulbactam was reduced to 4 mg/L, the susceptibility breakpoint. The fractional inhibitory concentration indices were between 0.19 and 0.56 in combination with 6.25 and 25 mg/L EGCg, respectively, indicating that ampicillin/sulbactam and EGCg combination may be effective against MRSA infections.

The in vitro activity of sulbactam combined with third generation cephalosporins against third generation cephalosporin-resistant bacteria

The in vitro activity of the β-lactamase inhibitor sulbactam combined with cefuroxime, cefotaxime or ceftazidime in the ratio of 1:1 was studied against ceftazidime- or cefuroxime-resistant Gram-negative rods and Staphylococcus aureus. Sulbactam enhanced the antibacterial activities of cefuroxime, cefotaxime and ceftazidime against Gram-negative rods. The MIC 90 of ceftazidime against Escherichia coli, Enterobacter cloacae, Citrobacter freundii, Acinetobacter spp. and Pseudomonas aeruginosa was reduced 4-fold and that of cefotaxime against E. coli, E. cloacae, C. freundii and Acinetobacter spp. reduced by 2–4-fold. However, sulbactam did not enhance the activities of cefuroxime, cefotaxime or ceftazidime against S. aureus, enterococci and Stenotrophomonas maltophilia. With the combination of sulbactam and ceftazidime at the ratio of 1:1, 38.4% of E. coli, 45.3% of E. cloacae, 66.6% of C. freundii and 60% of Acinetobacter spp. initially resistant to ceftazidime became susceptible.

In vitro activities of nontraditional antimicrobials against multiresistant Acinetobacter baumannii strains isolated in an intensive care unit outbreak.

Fifteen multiresistant Acinetobacter baumannii isolates from patients in intensive care units and 14 nonoutbreak strains were tested to determine in vitro activities of nontraditional antimicrobials, including cefepime, meropenem, netilmicin, azithromycin, doxycycline, rifampin, sulbactam, and trovafloxacin. The latter five drugs were further tested against four of the strains for bactericidal or bacteriostatic activity by performing kill-curve studies at 0.5, 1, 2, and 4 times their MICs. In addition, novel combinations of drugs with sulbactam were examined for synergistic interactions by using a checkerboard configuration. MICs at which 90% of the isolates tested were inhibited for antimicrobials showing activity against the multiresistant A. baumannii strains were as follows (in parentheses): doxycycline (1 microg/ml), azithromycin (4 microg/ml), netilmicin (1 microg/ml), rifampin (8 microg/ml), polymyxin (0.8 U/ml), meropenem (4 microg/ml), trovafloxacin (4 microg/ml), and sulbactam (8 microg/ml). In the kill-curve studies, azithromycin and rifampin were rapidly bactericidal while sulbactam was more slowly bactericidal. Trovafloxacin and doxycycline were bacteriostatic. None of the antimicrobials tested were bactericidal against all strains tested. The synergy studies demonstrated that the combinations of sulbactam with azithromycin, rifampin, doxycycline, or trovafloxacin were generally additive or indifferent.

Treatment of experimental staphylococcal endocarditis due to a strain with reduced susceptibility in vitro to vancomycin: efficacy of ampicillin-sulbactam.

We evaluated several 3-day antimicrobial regimens in the treatment of experimental endocarditis caused by an oxacillin-resistant Staphylococcus aureus strain exhibiting intermediate susceptibility in vitro to vancomycin (VISA). Neither vancomycin alone nor trovafloxacin exhibited in vivo efficacy; addition of amikacin to vancomycin yielded a modest in vivo effect. In contrast, the combination of ampicillin and sulbactam was highly effective in vivo, causing a mean decrease in VISA vegetation densities of >5 log(10) CFU/g versus those of untreated controls.

An evaluation of susceptibility testing methods for ampicillin‐sulbactam using a panel of β‐lactamase‐producing bacteria

Bacteria possessing TEM-1-like beta-lactamases are generally regarded as susceptible to ampicillin-sulbactam (SAM), while those harboring OXA-1 enzymes are considered resistant. The current study was undertaken to compare susceptibility testing using various combinations of ampicillin and sulbactam to improve clinical correlation. Members of the Enterobacteriaceae family harboring TEM-1, SHV-1 or OXA-1-like beta-lactamases were tested using the agar dilution method. A substantial proportion of strains harboring OXA-1-like beta-lactamases showed false susceptibility to SAM at the 1:1 ratio or fixed sulbactam concentration of 8 microg/ml. At a fixed sulbactam concentration of 4 microg/ml, the activity of ampicillin-sulbactam appeared to be reduced, with large numbers of TEM-1 producers becoming frankly resistant. Results obtained with the 2:1 ratio exhibited the closest correlation with that obtained by the currently recommended disk diffusion test. However, very major errors were still found between the disk diffusion test and agar dilution test, suggesting the necessity for consideration of a change in criteria for interpretation of disk diffusion test results. In conclusion, SAM susceptibility testing by agar dilution using other than a 2:1 ratio is not recommended and results should be interpreted with caution.

Penetration of ampicillin and sulbactam into human epididymis and testis.

Urologic refertilization microsurgery such as vaso-vasostomy or vaso-epididymostomy benefits from perioperative antibiotic prophylaxis. The ability of ampicillin and sulbactam to penetrate sufficiently into mixed epididymis or testis tissue was investigated in nine patients (bodyweights ranged from 58 kg to 92 kg, mean 77.3 kg) undergoing orchiectomy for testicular cancer or advanced prostatic cancer. Each patient received a single infusion of 3 g ampicillin/sulbactam (ratio 2:1) preoperatively for antibiotic prophylaxis. The concentrations of both components were determined in serum and in epididymis/testis tissue samples taken 30 min to 65 min after infusion. Ampicillin was determined by bioassay and sulbactam was determined by gas chromatography/ mass spectrometry. Mean tissue concentrations of ampicillin were 38.5 +/- 15.9 mg/kg. Mean tissue concentrations of sulbactam at the same time were 19.8 +/- 5.2 mg/kg. Comparison of the tissue/serum ratios for both agents showed no significant difference. These values indicate that both compounds achieve high concentrations in the scrotal organs. The concentrations exceed the MIC (minimal inhibitory concentration) values of important bacterial pathogens such as Staphylococcus aureus involved in postoperative wound infections. The combination of ampicillin and sulbactam may be effective for perioperative prophylaxis in reconstructive scrotal urologic surgery.

Single-dose pharmacokinetics of ampicillin/sulbactam (2:1) combination after intravenous administration to sheep and goats

The pharmacokinetic behaviour of a combination of ampicillin and sulbactam (2:1) in six sheep and six goats after single intravenous doses of 20 mg kg bodyweight −1 (13·33 mg kg −1 of ampicillin and 6·67 mg kg −1 of sulbactam) was investigated by using a high-performance liquid chromatographic method for determining plasma concentrations. The objective was to determine whether there are differences between sheep and goats in the disposition kinetics of ampicillin and sulbactam. The plasma concentration-time curves were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in both sheep and goats. The mean ( sd) elimination half-lives of ampicillin were 0·32 (0·05) h in sheep and 0·32 (0·04) h in goats, and the half-lives of sulbactam were 0·74 (0·10) h and 0·79 (0·18) h in sheep and goats, respectively. The apparent volumes of distribution of ampicillin and sulbactam were similar in the two species. Mean ( sd) body clearances of ampicillin were 0·69 (0·07) litre h −1 kg −1 in sheep and 0·72 (0·11) litre h −1 kg −1 in goats, and the body clearances of sulbactam were 0·38 (0·03) and 0·38 (0·07) litre h −1 kg −1 in sheep and goats, respectively. There were no significant differences between any of the pharmacokinetic parameters of ampicillin and sulbactam in the sheep and goats.

Molecular aspects of high-level resistance to sulbactam-cefoperazone in Klebsiella oxytoca clinical isolates.

Nine Klebsiella oxytoca strains which demonstrated resistance to the combination of sulbactam and cefoperazone were isolated from geographically separate hospitals in Japan in 1995. Among them, K. oxytoca SB23 showed high-level resistance to sulbactam-cefoperazone (MIC > 128 micrograms/ml) and aztreonam (MIC, 128 micrograms/ml). The sulbactam-cefoperazone resistance was not transferred from strain SB23 to Escherichia coli CSH2 by conjugation, beta-Lactamase RbiA, produced by strain SB23, was purified, and the molecular mass was estimated to be 29 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Kinetic parameters for RbiA revealed that cefoperazone and aztreonam were hydrolyzed efficiently by this enzyme. Moreover, ceftazidime and imipenem were also hydrolyzed weakly by RbiA, although strain SB23 did not show any resistance to these agents. Clavulanate, sulbactam, and tazobactam failed to block the hydrolysis of cefoperazone by RbiA. The structural gene of RbiA (blaRBI) was cloned and sequenced, and the deduced amino acid sequence of RbiA demonstrated high-level similarities to those of the beta-lactamases found in K. oxytoca D488, E23004, and plasmid-mediated MEN-1, which have been classified into Bush functional group 2be. Although RbiA demonstrates high-level molecular similarity to the enzymes in group 2be, from an enzymological point of view, this enzyme might be differentiated from the enzymes in that group. Hybridization analysis revealed that beta-lactamase genes highly similar to blaRBI were generally encoded on the chromosome of the sulbactam-cefoperazone-resistant clinical isolates of K. oxytoca tested in the study, despite their different derivations. This observation suggests that sulbactam-cefoperazone-resistant A. oxytoca strains which produce RbiA-type beta-lactamases have been proliferating in many hospitals in Japan.

Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was significantly more effective than vancomycin against the penicillinase-negative derivative in vivo (P < 0.001), and it sterilized 25% of the vegetations. The combination of penicillin and sulbactam exhibited an in vivo synergistic effect on the penicillinase-producing strain (P < 0.01) but did not produce any advantage over treatment with vancomycin, even when a high dose of sulbactam was used (100 mg/kg of body weight every 6 h). This combination was significantly less effective against the penicillinase-producing strain than was penicillin alone against the penicillinase-negative derivative (P < 0.03). In addition, the most resistant subpopulation of the surviving bacteria, which grew on agar containing 16 micrograms of methicillin per ml, was detected in 5 of 6 animals treated with penicillin and a high dose of sulbactam against the penicillinase-producing strain compared with only 1 of 12 animals treated with penicillin alone against the penicillinase-negative derivative (P < 0.01). We conclude that penicillin is highly effective against penicillinase-negative methicillin-resistant S. aureus and that penicillinase production, rather than methicillin resistance, appears to be the limiting factor for the activity of the penicillin-sulbactam combination against penicillinase-producing, methicillin-resistant S. aureus.

Sulbactam in combination with mezlocillin, piperacillin or cefotaxime: clinical and bacteriological findings in the treatment of serious bacterial infections

An open, multicentre study was performed in hospital in-patients at a total of 12 German hospitals to investigate the efficacy and tolerability of sulbactam combined with mezlocillin, piperacillin or cefotaxime in severe bacterial infections. A total of 155 patients were recruited into the study, of whom 48 were suffering from respiratory tract infections, 66 from intra-abdominal infections, 34 from skin/soft tissue infections including postoperative wound infections, and five from complicated urinary tract infections. Fifty-five patients intravenously received 4 g mezlocillin and 1 g sulbactam three times daily, 52 received 4 g piperacillin and 1 g sulbactam three times daily, and 48 received 2 g cefotaxime and 1 g sulbactam three times daily. The antibiotic and sulbactam combination was administered in all cases by rapid intravenous infusion of both components together, over 20 min. The mean duration of treatment was 20 days. The criteria used to define the outcome of treatment as successful were clinical cure (complete disappearance of the signs and symptoms of infection seen before the start of treatment) or improvement (appreciable diminution or partial resolution of the initial signs and symptoms, no further antibiotic therapy required) and the elimination of the organisms isolated before the start of the study. Of the 153 clinically evaluable patient, 141 (92%) were classed as responders (a cure was obtained in 98 cases and improvement in 43 cases). No response to the study medication was seen in 12 patients (7.8%). The response rates of the combined antibiotic-sulbactam preparations were 91% for mezlocillin/sulbactam, 92% for piperacillin/sulbactam, and 93% for cefotaxime/sulbactam. These response rates are almost identical. A total of 106 patients (68.4%) were bacteriologically evaluable; a total of 192 bacterial organisms were identified in these patients before the start of treatment. Mixed infection was present in 55 patients. The causative organism initially isolated was eliminated in 96 patients (90%), accounting for 180 of 192 strains (94%). Persistence of the causative organism (12 strains) was seen in eight patients (7.6%). Superinfection (four strains) was seen in two patients (1.9%). The study medication was well tolerated; adverse drug effects were seen in only five patients (3.3%). Treatment was discontinued in one patient because of the adverse effect (exanthema). The combination of the β-lactamase inhibitor sulbactam and a ureidopenicillin or cefotaxime was highly effiacious in patients with severe bacterial infections investigated in this study. The availability of sulbactam as a single-agent preparation opens up new avenues for flexible and cost-effective antibiotic therapy and is a valuable contribution to the control of bacterial resistance.