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PubMed1982

The history and background of Augmentin.

Bacterial resistance to the beta-lactam group of antibiotics is frequently due to the production of beta-lactamase which brings about the inactivation of the antibiotic. Clavulanic acid is a naturally occurring inhibitor of beta-lactamase which is capable of rendering penicillin- and cephalosporin-resistant organisms sensitive. The compound is obtained by fermentation from Streptomyces clavuligerus. Clavulanic acid shows some structural similarity to the penicillins and cephalosporins and functions as a progressive inhibitor of a wide range of beta-lactamases including those found in Escherichia coli, Klebsiella aerogenes, Proteus species, Bacteroides fragilis, Haemophilus influenzae, Neisseria gonorrhoeae and Staphylococcus aureus. Clavulanic acid is well absorbed when given by mouth and a formulation with amoxycillin (Augmentin; Beechams) is now available for clinical use.

Amoxicillin↗
PubMedDate not supplied

Antibiotic susceptibility profile of Xanthomonas maltophilia. In vitro activity of beta-lactam/beta-lactamase inhibitor combinations.

The susceptibility of 42 strains of Xanthomonas (Pseudomonas) maltophilia to 37 antibiotics (mainly beta-lactams, aminoglycosides, and fluorinated quinolones) was tested. Xanthomonas maltophilia was resistant to most beta-lactams, with ceftazidime, moxalactam, and ICI-194008 being the most active ones. Aminoglycosides had a very modest activity, with quinolones showing only moderate activity against this species. Trimethoprim/sufamethoxazole was effective against all strains tested. We also tested the synergy of several beta-lactam/beta-lactamase inhibitors against X. maltophilia. Only aztreonam/clavulanic acid at 3:1, 1:1 and, mainly, 2:1 combinations had synergistic activity, decreasing the rate of resistance from 92.8% for aztreonam alone to 32.4% for aztreonam-clavulanic acid at 1:1 and 0% for aztreonam-clavulanic acid at 2:1.

4-Quinolones↗
PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

Fundamental and clinical studies have been performed on the BRL 25000 granules (combination of amoxicillin (AMPC) and potassium clavulanate (CVA) in 2: 1 ratio) in the pediatric field. In bacteriological studies a potentiated antibacterial activity of BRL 25000 was recognized against AMPC-resistant and beta-lactamase producing clinical isolates. The pharmacokinetics of the BRL 25000 granules were studied at dose levels from 10 to 20 mg/kg. The peak serum concentrations of AMPC and CVA achieved approximately 1 hour after dosing were 4.29-9.55 micrograms/ml and 3.87-4.78 micrograms/ml, respectively. The serum half-life was found to be 0.90-1.31 hours for AMPC and 1.01-1.22 hours for CVA. Six-hour urinary excretion rates were 29.5-62.6% for AMPC and 12.6-37.9% for CVA. In the clinical studies, the BRL 25000 granules were administered to 36 pediatric patients (15 with upper and lower respiratory tract infections, 10 with urinary tract infections and 11 with skin or soft tissue infections, etc.) at dose levels of 30-50 mg/kg/day. Clinical results in all cases were excellent or good. In particular, good bacterial and clinical effects were obtained against infections caused by beta-lactamase producing AMPC-resistant strains except E. cloacae 1 strain. No adverse reactions or abnormal laboratory findings were recognized in any patient.

Administration, Oral↗
PubMed2003

Following the reactions of mechanism-based inhibitors with beta-lactamase by Raman crystallography.

The reactions between three clinically relevant inhibitors, tazobactam, sulbactam, and clavulanic acid, and SHV beta-lactamase (EC 3.5.2.6) have been followed in single crystals using a Raman microscope. The data are far superior to those obtained for the enzyme in aqueous solution and allow us to identify species on the reaction pathway and to measure the rates of the accumulation and decay of these species. A key intermediate on the reaction pathway is an acyl enzyme formed between Ser70 and the lactam ring's C=O group. By using the E166A deacylation deficient variant of the enzyme, we were able to focus on the process of acyl enzyme formation. The Raman data show that all three inhibitors form an enamine-type acyl enzyme reaching maximal populations at 10, 22, and 29 min for sulbactam, clavulanic acid, and tazobactam, respectively. The enamine intermediate exhibits a characteristic and relatively intense band near 1595 cm(-1) due to a stretching motion of the O=C-C=C-NH moiety that shifts to lower frequency upon NH <--> ND exchange. This feature was used to follow the kinetics of enamine buildup and decay in the crystal. Quantum mechanical calculations support the assignment of the 1595 cm(-1) band, as well as several other bands, to a trans-enamine species. The Raman data also demonstrate that the lactam ring opens prior to enamine formation since the lactam ring carbonyl (C=O) peak disappears prior to the appearance of the enamine 1595 cm(-1) band. Tazobactam appears to form approximately twice as much enamine intermediate as sulbactam and clavulanic acid, which correlates with its superior performance in the clinic, a finding that may bear on future drug design.

Amines↗
PubMed1992

beta-Lactamase inhibitors and the inducibility of the beta-lactamase of Mycobacterium tuberculosis.

Ten clinical isolates and the type strain (H37Rv) of Mycobacterium tuberculosis were shown to produce an intracellular beta-lactamase. Crude enzyme preparations were extracted from acetone cell powders by grinding with zirconium beads in 0.133 M glycine with 1.0% Triton X-100. The enzymes had identical patterns on isoelectric focusing, with two major bands at isoelectric points of 4.9 and 5.1. The beta-lactamase was highly susceptible to the new beta-lactamase inhibitor BRL 42715, with an I50 of 0.0001 microgram/ml. The enzyme was also susceptible to clavulanic acid with an I50 (0.05 microgram/ml), which was similar to the value for the common bacterial beta-lactamase TEM-1 (0.01 microgram/ml). The latter result is consistent with previous MIC studies with M. tuberculosis, which have shown synergy between clavulanic acid and amoxicillin. BRL 42715 and clavulanic acid were more active than sulbactam, tazobactam, and cloxacillin. These studies support the potential value of penicillin/clavulanic acid and penicillin/BRL 42715 combinations in the treatment of tuberculosis.

Dose-Response Relationship, Drug↗
PubMed2001

Comparison of five different methods for detection of SHV extended-spectrum beta-lactamases.

Five different methods for detection of different types of SHV extended-spectrum beta-lactamases (ESBL) were compared: minimum inhibitory concentration (MIC) determination of beta-lactam with and without clavulanic acid, double-disk synergy test (DDST), inhibitor potentiated disk diffusion test (IPDDT), three-dimensional test (TDT) and PCR/Nhe I test. MIC determination of beta-lactam with and without clavulanic acid was the most sensitive method regardless of the type of beta-lactamase. However the specificity of this method was a little above 90%. IPDDT turned out to be a very sensitive method too but it lacks specificity because 26.9% of ceftazidime sensitive strains (putative ESBL negative), gave a positive result. It is important to put all four disks on the plate because ceftazidime and aztreonam were more sensitive indicators for SHV-5 and SHV-12 beta-lactamase producers while cefotaxime and ceftriaxone were more reliable in detecting SHV-2 beta-lactamase producers. The DDST detected all SHV-5 and SHV-12 beta-lactamase producers and 95.2% of SHV-2, so it was less sensitive than MIC determination but was highly specific, since there were no false negative results observed. The sensitivity of DDST can be improved by using all four disks and placing them at the smaller distance from the central disk (2.5 cm). The TDT was the least sensitive method, particularly for SHV-5 and SHV-12 beta-lactamase producers. The PCR/Nhe I test for detection of ESBL blaSHV genes is a highly sensitive and specific method but it is rather laborious and thus not very practical for use in routine clinical laboratories. Nevertheless it has potential to serve as the gold standard in epidemiological investigations on ESBLs. According to the results of this investigation MIC determination of beta-lactam with and without clavulanic acid, even if only one antibiotic is used and the PCR/Nhe I tests are the most reliable methods for detection of SHV ESBLs.

Anti-Bacterial Agents↗
PubMed1993

Selection of variants of the TEM-1 beta-lactamase, encoded by a plasmid of clinical origin, with increased resistance to beta-lactamase inhibitors.

A TEM-1 derived variant beta-lactamase with increased resistance to beta-lactamase inhibitors was selected in vitro. The variant beta-lactamase was obtained from the parent strain Escherichia coli J62-2 containing resistance plasmid R1 which encodes the TEM-1 beta-lactamase. The variants were obtained by repeated subculture of E. coli J62-2 (R1) for five days in the presence of sub-inhibitory concentrations of amoxycillin plus clavulanic acid. Comparison of this variant beta-lactamase with a clinically isolated TEM derived beta-lactamase, with increased resistance to beta-lactamase inhibitors, suggests that they are the same enzyme. Both beta-lactamases have the same pI at 5.25 and have similar ID50 values for the beta-lactamase inhibitors clavulanic acid, sulbactam and tazobactam.

Amoxicillin↗
PubMed2003

Three-day intravenous triple therapy is not effective for the eradication of Helicobacter pylori infection in patients with bleeding gastro-duodenal ulcer.

AIM: To test the efficacy of an ultra-short intravenous triple therapy against Helicobacter pylori infection in patients with bleeding peptic ulcer against standard oral 1-week triple therapy in a randomised, double-blind prospective trial. METHODS PATIENTS: (n = 75) with haemorrhagic peptic ulcer and H. pylori infection were randomised into: an Intravenous Group to receive omeprazole, clarithromycin and amoxicillin-clavulanic acid intravenously b.d. for 3 days followed by 7 days of oral omeprazole plus placebo of clarithromycin and amoxicillin; an Oral Group to receive intravenous omeprazole plus placebo of clarithromycin and amoxicillin-clavulanic acid followed by 7 days of oral omeprazole, clarithromycin and amoxicillin b.d. Gastric biopsies were obtained for urease test. A 13C-urea breath test was performed to check for H. pylori eradication. RESULTS: Intention-to-treat eradication was 50% (19/38) in the Intravenous Group and 78% (29/37) in the Oral Group (odds ratio 3.63; 95% confidence interval 1.32-9.94; P < 0.01; number needed to treat (NNT) = 4). Per protocol eradication was 50% (14/28) in the Intravenous Group and 86% (24/28) in the Oral Group (P < 0.005). There were no statistically significant differences in adverse events between the two treatment groups. CONCLUSIONS: An ultra-short, 3-day, intravenous, triple therapy containing omeprazole, clarithromycin and amoxicillin-clavulanic acid cannot be recommended as an effective eradication regimen for H. pylori infection related to haemorrhagic gastro-duodenal ulcer.

Amoxicillin↗
PubMed2003

Understanding resistance to beta-lactams and beta-lactamase inhibitors in the SHV beta-lactamase: lessons from the mutagenesis of SER-130.

Bacterial resistance to beta-lactam/beta-lactamase inhibitor combinations by single amino acid mutations in class A beta-lactamases threatens our most potent clinical antibiotics. In TEM-1 and SHV-1, the common class A beta-lactamases, alterations at Ser-130 confer resistance to inactivation by the beta-lactamase inhibitors, clavulanic acid, and tazobactam. By using site-saturation mutagenesis, we sought to determine the amino acid substitutions at Ser-130 in SHV-1 beta-lactamase that result in resistance to these inhibitors. Antibiotic susceptibility testing revealed that ampicillin and ampicillin/clavulanic acid resistance was observed only for the S130G beta-lactamase expressed in Escherichia coli. Kinetic analysis of the S130G beta-lactamase demonstrated a significant elevation in apparent Km and a reduction in kcat/Km for ampicillin. Marked increases in the dissociation constant for the preacylation complex, KI, of clavulanic acid (SHV-1, 0.14 microm; S130G, 46.5 microm) and tazobactam (SHV-1, 0.07 microm; S130G, 4.2 microm) were observed. In contrast, the k(inact)s of S130G and SHV-1 differed by only 17% for clavulanic acid and 40% for tazobactam. Progressive inactivation studies showed that the inhibitor to enzyme ratios required to inactivate SHV-1 and S130G were similar. Our observations demonstrate that enzymatic activity is preserved despite amino acid substitutions that significantly alter the apparent affinity of the active site for beta-lactams and beta-lactamase inhibitors. These results underscore the mechanistic versatility of class A beta-lactamases and have implications for the design of novel beta-lactamase inhibitors.

Ampicillin↗
PubMedDate not supplied

Single dose treatment of gonococcal urethritis with augmentin in Ibadan.

Augmentin, a new orally absorbed broadspectrum antibacterial agent comprising of amoxycillin trihydrate and potassium clavulanate, was investigated in the treatment of gonococcal urethritis in Ibadan, Nigeria, where penicillinase producing Neisseria gonorrhoeae (PPNG) constitute about 80% of the circulating strains of gonococci. Two different formulations of the agent were employed in the study. The first formulation consisting of 3.0 g amoxycillin and 125 mg clavulanic acid, achieved a cure rate of 75% (i.e. eighteen out of twenty-four patients) among PPNG infections, but 100% cure rate among nine patients with non-PPNG infections. The second formulation consisting of 3.0 g amoxycillin and 250 mg clavulanic acid, had a cure rate of 86% (i.e. fifty-seven out of sixty-six patients) among PPNG infections, and 91% (i.e. ten out of eleven patients) among non-PPNG infections. Clavulanic acid appears to potentiate and enhance the activity of amoxycillin against the beta-lactamase produced by the gonococci. Augmentin seems to be a good and acceptable agent for the treatment of gonococcal infections, in this environment and further studies on its efficacy are therefore justified, such as the simultaneous administration of probenecid.

Amoxicillin↗
PubMed1988

Simple assay of beta-lactamase with agar medium containing a chromogenic cephalosporin, pyridinium-2-azo-p-dimethylaniline chromophore (PADAC).

A new beta-lactamase assay method with agar plates containing pyridinium-2-azo-p-dimethylaniline chromophore (PADAC) (50 microM), a beta-lactamase-labile, chromogenic cephalosporin, was examined. On the PADAC plates inoculated with beta-lactamase-producing gram-negative bacteria (10(4) CFU per spot) and incubated at 37 degrees C, a yellow zone showing hydrolysis of PADAC by beta-lactamase was formed around the colony. The zone diameter increased with incubation time. Examination with Enterobacter cloacae GN7471 revealed that beta-lactamase activity was present in the agar around the colony, decreasing exponentially with increasing distance from the colonial margin; this suggests that the PADAC hydrolysis zone is formed by an extracellular enzyme. At 18 h, significant correlations were obtained between the zone diameters of the 10 species (clinical isolates) examined and their periplasmic beta-lactamase activities determined spectrophotometrically. The addition of clavulanic acid (0.5 to 10 micrograms/ml) inhibited zone formation on the PADAC plates inoculated with type IIIa, Va, Vb, PSE-1, and Ic beta-lactamase producers. When the clinical isolates were tested on plates with clavulanic acid (2 micrograms/ml), inhibition was observed in 41 to 58% of the Escherichia coli, Serratia marcescens, and Pseudomonas aeruginosa isolates and in all isolates of Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus vulgaris. Thus, the use of the inhibitor made it possible to detect penicillinase or type Ic cephalosporinase producers. These results proved that the PADAC plate might be a useful tool permitting easy, semiquantitative determination of beta-lactamase activity.

Agar↗
PubMed1992

Characterization of penicillin-binding protein 2 of Staphylococcus aureus: deacylation reaction and identification of two penicillin-binding peptides.

Penicillin-binding protein (PBP) 2 is the major PBP of five that have been identified in susceptible strains of Staphylococcus aureus. Beta-lactam antibiotic binding to PBP 2 is important for the antibacterial effect. Antibiotic binding to PBP 2 in strain 209P was examined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis in competition assays using [3H]penicillin as the radiolabel. Clavulanic acid, which is specifically bound by PBP 2, and cefaclor, which is specific for PBP 3, were studied. Cefaclor, which alone appeared not to bind PBP 2, in combination inhibited PBP 2 binding of clavulanic acid. By varying the temperature during radiolabeling with [3H]penicillin in cefaclor competition assays and in direct radiolabeling assays with [3H]cefaclor, it was shown that cefaclor was bound by PBP 2 with high affinity (50% inhibitory concentration, less than or equal to 0.1 microgram/ml) and that the apparent low-affinity binding (50% inhibitory concentration, greater than 10 micrograms/ml) in competition assays performed at 37 degrees C was due to rapid deacylation. Two penicillin-binding peptides of PBP 2 also were identified in fluorographs of PBPs separated by nonequilibrium pH gradient gel and two-dimensional electrophoresis. Rapid deacylation for some antibiotics and the presence of two penicillin-binding peptides are two properties of PBP 2 that should be considered when correlating results of binding assays with effects of beta-lactam antibiotics on S. aureus.

Anti-Bacterial Agents↗
PubMed1993

Molecular epidemiology of the plasmid-encoded TEM-1 beta-lactamase in Scotland.

A survey of the beta-lactamases responsible for ampicillin resistance in urinary Escherichia coli isolated in central Scotland has been performed. The TEM-1 beta-lactamase was found to be most prevalent occurring in 88.2% of ampicillin-resistant isolates tested. Forty-six percent of the TEM-1 producing strains were able to transfer this resistance to E. coli J62-2 at 37 degrees C. Analysis of the resulting transconjugants revealed that the degree of resistance to amoxycillin and amoxycillin in combination with clavulanic acid was related to the specific activity of the TEM-1 beta-lactamase. The variation in specific activity was shown to be related to plasmid type as determined by restriction analysis. No obvious relationship between beta-lactamase specific activity and resistance to amoxycillin and amoxycillin plus clavulanic acid could be demonstrated in the original plasmid donor strains.

Amoxicillin↗
PubMed1989

Evaluation of four newer antimicrobial agents in the Avantage susceptibility test system.

Antimicrobial elution disks containing amoxicillin-clavulanic acid (Augmentin), cefotetan, ciprofloxacin, or norfloxacin were tested in the Avantage automated susceptibility test system. Performance was compared against an agar diffusion procedure in a three-site collaborative study. Results of 1,500 comparison with amoxicillin-clavulanic acid showed a full accord (agreement of both systems) of 93.6% and an essential accord (agreement excluding minor discrepancies) of 97.6%. Results for cefotetan showed a full accord of 95.1% and an essential accord of 98.3% by the two methods. Results for both ciprofloxacin and norfloxacin were in full accord for more than 98% of tests with gram-negative bacilli and staphylococci, but tests with enterococci gave 38 and 26.1% minor discrepancies (the result of one method was resistant or susceptible and the result of the other method was intermediate), respectively. The results indicated that the Avantage test system is accurate and reliable and provides appropriate determination of bacterial susceptibility with the four antibiotics tested.

Amoxicillin↗
PubMed1993

In vitro activity of cefodizime (HR-221) in combination with beta-lactamase inhibitors.

Cefodizime (formerly HR221) was tested either for in vitro microbiological activity or for its stability to beta-lactamases in the presence of two beta-lactamase inhibitors (clavulanic acid, tazobactam). Cefodizime was a poor substrate of class C enzymes but hyperproducer strains were generally resistant with or without a beta-lactamase inhibitor used in combination. On the contrary, class A enzymes were able to hydrolyze cefodizime. However, strains expressing class A beta-lactamase were susceptible to cefodizime in combination with clavulanic acid.

Anti-Bacterial Agents↗
PubMed2004

In vitro and in vivo activities of antimicrobials against Nocardia brasiliensis.

In Mexico mycetomas are mostly produced by Nocardia brasiliensis, which can be isolated from about 86% of cases. In the present work, we determined the sensitivities of 30 N. brasiliensis strains isolated from patients with mycetoma to several groups of antimicrobials. As a first screening step we carried out disk diffusion assays with 44 antimicrobials, including aminoglycosides, cephalosporins, penicillins, quinolones, macrolides, and some others. In these assays we observed that some antimicrobials have an effect on more than 66% of the strains: linezolid, amikacin, gentamicin, isepamicin, netilmicin, tobramycin, minocycline, amoxicillin-clavulanic acid, piperacillin-tazobactam, nitroxolin, and spiramycin. Drug activity was confirmed quantitatively by the broth microdilution method. Amoxicillin-clavulanic acid, linezolid, and amikacin, which have been used to treat patients, were tested in an experimental model of mycetoma in BALB/c mice in order to validate the in vitro results. Linezolid showed the highest activity in vivo, followed by the combination amoxicillin-clavulanic acid and amikacin.

Animals↗
PubMed1995

A piperacillin-tazobactam resistant Escherichia coli strain isolated from a faecal sample of a healthy volunteer.

As part of a surveillance programme of the prevalence of antibiotic resistance, the faecal bacteria of healthy people (n = 1348) were examined, and the antibiotic resistance of the Escherichia coli strains determined. One strain out of 142 amoxycillin-resistant isolates, E. coli strain 1662, was also resistant to piperacillin-tazobactam but susceptible to amoxycillin-clavulanic acid. The piperacillin-tazobactam resistance determinant was transferable to standard E. coli strains by conjugation. However, the strain produced a beta-lactamase with several characteristics very similar to those of the TEM-1 beta-lactamase, i.e. pI of 5.4, an M(r) value of 22,000 and a comparable substrate profile. The enzyme was as efficiently inhibited by clavulanic acid and tazobactam as the TEM-1 and TEM-2 beta-lactamases but more than the amoxycillin-clavulanic acid-resistant TRC-1 enzyme. The transferable resistance to piperacillin-tazobactam appears to be mediated by a novel resistance mechanism that has previously not been described.

Anti-Bacterial Agents↗
PubMed1995

Molecular characterization of nine different types of mutants among 107 inhibitor-resistant TEM beta-lactamases from clinical isolates of Escherichia coli.

DNA-DNA hybridization and sequencing were performed to determine the molecular basis of resistance to clavulanic acid in 107 inhibitor-resistant TEM (IRT) enzymes produced by Escherichia coli clinical isolates. These beta-lactamases derived from TEM-1 enzyme focused at pI 5.2 (n = 68) or 5.4 (n = 39) and were very poorly inhibited by clavulanic acid compared with TEM-1 enzyme. Results showed that the amino acid sequences of 84 of the 107 enzymes differ from TEM-1 by one or two substitutions previously described: Arg-244-->Ser (IRT-2) in 22 strains, Met-69-->Leu (TEM-33) in 17 strains, Met-69-->Val (TEM-34) in 14 strains, Met-69-->Ile (IRT-3) in 6 strains, Met-69-->Leu associated with Asn-276-->Asp (IRT-4) in 13 strains, and Met-69-->Val associated with Asn-276-->Asp (TEM-36) in 12 strains. A new combination, Met-69-->Ile with Asn-276-->Asp, was found in 20 strains and was called IRT-8. Two IRT enzymes not previously described were characterized. The substitution Met-69-->Val associated with a novel substitution Arg-275-->Leu occurred in one strain. The combination Met-69-->Leu and Asn-276-->Asp was associated with the novel substitution Trp-165-->Arg in two strains. These two novel enzymes were called IRT-9 and IRT-10, respectively. The implication of these novel mutated positions, 165 and 275, in resistance to inactivation by clavulanate was supported by crystallographic data on the TEM-1 enzyme and results of site-directed mutagenesis. Molecular characterization of these mutants showed great diversity among the genes coding for inhibitor-resistant TEM enzymes produced by clinical E. coli isolates.

Base Sequence↗