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PubMedDate not supplied

Antistaphylococcal activity of amoxicillin and ticarcillin when combined with clavulanic acid. Evaluation of oxacillin-resistant and oxacillin-susceptible isolates.

The beta-lactamase inhibitor, clavulanic acid, was combined with amoxicillin and with ticarcillin for in vitro studies with 586 staphylococci: 97 stock cultures of oxacillin-resistant strains recovered before 1982, and 489 blood or wound isolates collected from 40 separate medical centers during 1987-1988 (300 were oxacillin resistant). Over 92% of the staphylococci produced beta-lactamase enzymes and were thus resistant to both penicillins. However, with the addition of clavulanic acid, oxacillin-susceptible strains were rendered susceptible to low concentrations of amoxicillin and ticarcillin. Staphylococcus aureus strains with borderline or partial borderline resistance to penicillinase-resistant penicillins occurred infrequently (72 of 325 S. aureus isolates). Those strains were susceptible to both clavulanic acid combinations, because their methicillin resistance is thought to be due to an excess beta-lactamase production. Strains with chromosomally mediated intrinsic heteroresistance were relatively resistant to both drug combinations. Minimal inhibitory concentration (MIC) breakpoints that best separated those heteroresistant strains from oxacillin-susceptible isolates were as follows: amoxicillin/clavulanic acid, less than or equal to 2.0/1.0 micrograms/ml for susceptible; and ticarcillin/clavulanic acid, less than or equal to 4.0/2.0 micrograms/ml for susceptible. When the broth was supplemented by 2% NaCl, MICs for both drug combinations were increased by less than one doubling dilution. Although oxacillin and methicillin broth microdilution tests were more reliable when 2% NaCl was added, tests with the two drug combinations were only minimally improved by adding 2% NaCl to the broth medium.

Amoxicillin↗
PubMedDate not supplied

Antimicrobial prophylaxis in hysterectomies: a double-blind, randomized, comparative study of a single dose of piperacillin (2 g) versus a single dose of amoxicillin-clavulanic acid (2.2 g).

A double-blind, randomized comparative study of piperacillin (2 g) versus amoxicillin-clavulanic acid (2.2 g) as a single dose 30 minutes before the initiation of hysterectomy was performed. A total of 595 patients (of which 307 were in the piperacillin group) were evaluable for efficacy. Infectious complications were infrequent in both arms. One case of (mild) sepsis was observed in the piperacillin group and two cases of wound infection were observed in the amoxicillin-clavulanic acid group. Urinary tract infection was observed in 5.5% of the patients in the piperacillin group and in 2.4% of the amoxicillin-clavulanic acid group. A relatively high incidence of asymptomatic bacteriuria was seen in both groups: 11.8% in the piperacillin group and 8.7% with amoxicillin-clavulanic acid. A marked difference was seen between the two different hospital locations: a 15% incidence in the hospital where midstream urine was used for culture (Sittard), versus 5% in the hospital where catheter urine was used (Geleen). It is concluded that both antibiotics are associated with a low rate of infectious complications and that catheter urine must be used for sample collection.

Amoxicillin↗
PubMed1990

A sensitive assay for clavulanic acid and sulbactam in biological fluids by high-performance liquid chromatography and precolumn derivatization.

Precolumn derivatization procedures using 1,2,4-triazole for the detection and quantitation of sulbactam and clavulanic acid spiked into urine and blood serum at trace levels have been developed. Sulbactam and clavulanic acid produced derivatives which absorbed maximally at 325 and 315 nm, respectively. The methods allow the detection of clavulanic acid and sulbactam down to 0.05 micrograms ml-1 in serum and 0.5 micrograms ml-1 in urine. The relative standard deviation for five replicate analyses of sulbactam and clavulanic acid at a concentration of 20 micrograms ml-1 in serum and urine ranged from 2-6%. In further HPLC experiments with sulbactam in phosphate buffer solution, ampicillin was found as a contaminant (0.5% by mass) in the sulbactam sample provided. The significance of this finding is discussed.

Chromatography, High Pressure Liquid↗
PubMed1977

Binding of thienamycin and clavulanic acid to the penicillin-binding proteins of Escherichia coli K-12.

Thienamycin and clavulanic acid are new beta-lactam derivatives with structures markedly different from those of penicillins or cephalosporins. Both derivatives had the same general mode of action as typical beta-lactam antibiotics since they bound to precisely the same proteins as [(14)C]benzylpenicillin. Thienamycin showed high affinity for penicillin-binding proteins 1, 2, 4, 5, and 6 and a lower affinity for protein 3. Protein 2 had the highest affinity for thienamycin, and concentrations from the minimal morphological change concentration (0.1 mug/ml) up to about 0.6 mug/ml resulted in the conversion of Escherichia coli KN126 into large osmotically stable round cells. Above a concentration of 0.6 mug/ml, rapid cell lysis occurred with the release of the cell contents as spheroplasts. Clavulanic acid showed good affinity for penicillin-binding protein 2, moderate affinity for proteins 1, 4, 5, and 6, and low affinity for protein 3. Protein 2 had the highest affinity for clavulanic acid, and concentrations from the minimal morphological change concentration (30 mug/ml) up to about 50 mug/ml produced a mixture of slightly elongated, swollen, bulging, and lemon-shaped cells. Above a concentration of 50 mug/ml, rapid lysis occurred with production of spheroplasts. The properties of thienamycin and clavulanic acid were compared with those of the penicillins, cephalosporins, and amidinopenicillanic acids.

Anti-Bacterial Agents↗
PubMed1979

An in vitro evaluation of clavulanic acid, a potent, broad-spectrum beta-lactamase inhibitor.

The in vitro efficacy of clavulanic acid, a new broad-spectrum inhibitor of enterobacterial beta-lactamases, was investigated. In conventional agar dilution tests, the presence of a sub-inhibitory level of clavulanic acid (8 microgram/ml) lowered the minimum inhibitory concentration of ampicillin for many resistant enterobacteria to therapeutically achievable levels. When tested against dense populations of Escherichia coli and klebsiella strains in a static turbidimetric system and in an in vitro model of the treatment of bacterial cystitis, clavulanic acid plus ampicillin suppressed bacterial growth for periods far exceeding the normal interdose interval at concentrations at which neither agent alone was effective. In addition to its activity as a beta-lactamase inhibitor, clavulanic acid may interact with other beta-lactam antibiotics in a second, distinct way. Because of this synergic interactions may occur with non-beta-lactamase producing organisms, and the overall synergic effect obtained with beta-lactamase producers may be compounded of two separate elements.

Ampicillin↗
PubMed1995

The asparagine to aspartic acid substitution at position 276 of TEM-35 and TEM-36 is involved in the beta-lactamase resistance to clavulanic acid.

TEM-35 (inhibitor resistant TEM (IRT)-4) and TEM-36 (IRT-7) clavulanic acid-resistant beta-lactamases have evolved from TEM-1 beta-lactamase by two substitutions: a methionine to a leucine or a valine at position 69 and an asparagine to an aspartic acid at position 276. The substitutions at position 69 have previously been shown to be responsible for the resistance to clavulanic acid, and they are the only mutations encountered in TEM-33 (IRT-5) and TEM-34 (IRT-6). However, the N276D substitution has never been found alone in inhibitor-resistant beta-lactamases, and its role in resistance to clavulanic acid was thus unclear. The N276D mutant was constructed, purified, and kinetically characterized. It was shown that the substitution has a direct effect on substrate affinities and leads to slightly decreased catalytic efficiencies and that clavulanic acid becomes a poor substrate of the enzyme. Electrospray mass spectrometry demonstrated the simultaneous presence of free and inhibited enzymes after incubation with clavulanic acid and showed that a cleaved moiety of clavulanic acid leads to the formation of the major inactive complex. The kinetic properties of the N276D mutant could be linked to a salt-bridge interaction of aspartic acid 276 with arginine 244 that alters the electrostatic properties in the substrate binding area.

Base Sequence↗
PubMed1995

Identification, cloning, sequencing, and overexpression of the gene encoding proclavaminate amidino hydrolase and characterization of protein function in clavulanic acid biosynthesis.

Proclavaminate amidino hydrolase (PAH) catalyzes the reaction of guanidinoproclavaminic acid to proclavaminic acid and urea, a central step in the biosynthesis of the beta-lactamase inhibitor clavulanic acid. The gene encoding this enzyme (pah) was tentatively identified within the clavulanic acid biosynthetic cluster in Streptomyces clavuligerus by translation to a protein of the correct molecular mass (33 kDa) and appreciable sequence homology to agmatine ureohydrolase (M.B.W. Szumanski and S.M. Boyle, J. Bacteriol. 172:538-547, 1990) and several arginases, a correlation similarly recognized by Aidoo et al. (K. A. Aidoo, A. Wong, D. C. Alexander, R. A. R. Rittammer, and S. E. Jensen, Gene 147:41-46, 1994). Overexpression of the putative open reading frame as a 76-kDa fusion to the maltose-binding protein gave a protein having the catalytic activity sought. Cleavage of this protein with factor Xa gave PAH whose N terminus was slightly modified by the addition of four amino acids but exhibited unchanged substrate specificity and kinetic properties. Directly downstream of pah lies the gene encoding clavaminate synthase 2, an enzyme that carries out three distinct oxidative transformations in the in vivo formation of clavulanic acid. After the first of these oxidations, however, no further reaction was found to occur in vitro without the intervention of PAH. We have demonstrated that concurrent use of recombinant clavaminate synthase 2 and PAH results in the successful conversion of deoxyguanidinoproclavaminic acid to clavaminic acid, a four-step transformation. PAH has a divalent metal requirement, pH activity profile, and kinetic properties similar to those of other proteins of the broader arginase class.

ATP-Binding Cassette Transporters↗
PubMed1987

Effect of clavulanic acid on susceptibility of Campylobacter jejuni and Campylobacter coli to eight beta-lactam antibiotics.

The effect of clavulanic acid on the susceptibility of 32 strains of Campylobacter jejuni and Campylobacter coli to eight beta-lactam agents was studied. Almost all strains tested became susceptible to amoxicillin and ticarcillin with 1 microgram of clavulanic acid per ml. This compound had little or no effect on susceptibility to penicillin G, cephalothin, cefamandole, and cefoxitin. Clavulanic acid had a marginal effect on cefotaxime and moxalactam susceptibility.

Anti-Bacterial Agents↗
PubMed2006

[A randomized study comparing amoxicillin-clavulanic acid with cefazolin as antimicrobial prophylaxis in laparotomic gynecologic surgery].

AIM: The aim of this paper was to compare amoxicillin-clavulanic acid with cefazolin as ultra-short term prophylaxis in laparotomic gynecologic surgery. METHODS: A prospective randomized study was conducted to compare 2 antimicrobial regimens in the surgical prophylaxis of laparotomic surgery. Patients were randomly allocated to receive amoxicillin-clavulanic acid (2.2 g, group A) or cefazolin (2 g, group B) as a single dose 30 min before surgery. Each patient was assessed daily until discharge to evidence febrile status and the presence of infections at the operative site, urinary tract and respiratory tract. RESULTS: In the amoxicillin-clavulanic acid (group A) and cefazolin (group B) groups, overall 346 and 352 patients, respectively, were evaluable for prophylactic efficacy at hospital discharge. Infectious complications were infrequent in both arms. Febrile morbidity occurred in 21 (6.1%) and 26 (7.4%) patients respectively in the amoxicillin-clavulanic acid and cefazolin groups. Wound infection and urinary tract infection were also higher, but not significantly in the cefazolin group (1.1% versus 0.5% and 2.5% versus 2%, respectively). There was one respiratory tract infection (0.2%) in group B and no septic death in either groups. CONCLUSIONS: Ultra-short term prophylaxis with both amoxicillin-clavulanic acid and cefazolin is safe in elective laparotomic gynecologic surgery.

Adult↗
PubMed2006

Optimization of nutritional requirements and feeding strategies for clavulanic acid production by Streptomyces clavuligerus.

The present work reports the nutritional requirements and environmental conditions for submerged culture of Streptomyces clavuligerus for clavulanic acid production using orthogonal matrix method (Taguchi L(16) design) and also fed-batch fermentation for clavulanic acid production by feeding glycerol, arginine and threonoine to the fermentation medium intermittently. Clavulanic acid production was increased by 18% with the span of feeding glycerol and reached a maximum at 1.30mg/ml with 120h glycerol feeding as compared to 1.10mg/ml in the control. The production also increased with the span of feeding amino acids and reached a maximum of 1.31 and 1.86mg/ml with feeding arginine and threonine, respectively in 120h. There was an overall increase of 18% and 9% in clavulanic acid production with arginine and threonine feeding as compared to the respective controls (1.10 and 1.70mg/ml, respectively).

Arginine↗
PubMed2002

Variable absorption of clavulanic acid after an oral dose of 25 mg/kg of Clavubactin and Synulox in healthy cats.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin and formulation was B Synulox; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2 = 1.24 +/- 0.28 h, Cmax = 12.8 +/- 2.12 microg/ml), and that of clavulanic acid 0.6 h (t1/2 = 0.63 +/- 0.16 h, Cmax = 4.60 +/- 1.68 microg/ml). There is a ninefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varies by a factor of two. The highest clavulanic acid AUCt values indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin-to-clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products" high efficacy against susceptible microorganisms.

Administration, Oral↗
PubMed2002

The clavulanic acid biosynthetic cluster of Streptomyces clavuligerus: genetic organization of the region upstream of the car gene.

The genetic organization of the region upstream of the car gene of the clavulanic acid biosynthetic gene cluster of Streptomyces clavuligerus has been determined. Sequence analysis of a 12.1 kb region revealed the presence of 10 ORFs whose putative functions, according to database searches, are discussed. Three co-transcriptional units are proposed: ORF10-11, ORF12-13 and ORF15-16-17-18. Potential transcriptional terminators were identified downstream of ORF11 (fd) and ORF15. Targeted disruption of ORF10 (cyp) gave rise to transformants unable to produce clavulanic acid, but with a considerably higher production of cephamycin C. Transformants inactivated at ORF14 had a remarkably lower production of clavulanic acid and similar production of cephamycin C. Significant improvements of clavulanic acid production, associated with a drop in cephamycin C biosynthesis, were obtained with transformants of S. clavuligerus harbouring multiple copies of plasmids carrying different constructions from the ORF10-14 region. This information can be used to guide strain improvement programs, blending random mutagenesis and molecular cloning, to optimize the yield of clavulanic acid.

Base Sequence↗
PubMed1979

Clavulanic acid and penicillin treatment of Staphylococcus aureus renal infection in mice.

Clavulanic acid, an inhibitor of beta-lactamase, was used together with penicillin to treat infection caused by a penicillinase-producing Staphylococcus aureus. Clavulanic acid + penicillin administered to mice, prophylactically or in treatment of established infection, reduced morbidity, bacterial counts in the kidneys, and/or mortality; these differences were statistically significant when compared with those obtained by using penicillin or clavulanic acid alone.

Animals↗
PubMedDate not supplied

Antibacterial activity and kill kinetics of amoxicillin-clavulanic acid combinations against Escherichia coli and Klebsiella aerogenes.

Combinations of amoxicillin and clavulanic acid were tested against 11 Escherichia coli strains and five Klebsiella aerogenes strains. Apart from one E. coli, the strains were highly resistant to amoxicillin due to beta-lactamase production. Synergy was demonstrated in all strains by agar dilution. Synergy was detected against the beta-lactamase-producing strains under simulated in vivo conditions with constantly decreasing concentrations simulating in vivo pharmacokinetics. The correlation between antibacterial activity determined by minimum inhibitory concentrations and bacterial kill kinetics in the in vivo simulation model was acceptable. A higher bacterial kill rate was observed when the antibiotic dosage was increased beyond the minimum concentration where an antibacterial effect was seen; this was not demonstrable by traditional agar dilution tests. In combination, a greater relative amount of amoxicillin compared to clavulanic acid allows a reduction in the total amount of antimicrobial agents with the same degree of antibacterial activity.

Amoxicillin↗
PubMed1995

Functional analysis of the gene encoding the clavaminate synthase 2 isoenzyme involved in clavulanic acid biosynthesis in Streptomyces clavuligerus.

A Streptomyces clavuligerus mutant disrupted in cas2, encoding the clavaminate synthase (CAS2) isoenzyme, was constructed by a gene replacement procedure. The resulting cas2 mutant showed no clavulanic acid production when grown in starch-asparagine medium. However, in soy medium, the cas2 mutant did produce clavulanic acid, although in amounts less than those produced by wild-type cultures. This medium-dependent leaky phenotype correlated well with the presence of the cas1 transcript, encoding the CAS1 isoenzyme, in cultures grown in soy medium and with its absence from those grown in starch-asparagine medium. This suggested that CAS1 and CAS2 both contribute to clavulanic acid production but that their production is regulated differently. Under nutritional conditions in which cas1 expression is blocked, cas2 becomes essential for clavulanic acid production. Northern (RNA) analysis revealed that while cas1 is transcribed as a 1.4-kb monocistronic transcript only, cas2 is transcribed both as a 1.2-kb monocistronic transcript and as part of a 5.3-kb polycistronic transcript. High-resolution S1 nuclease analysis located the transcription start point of the monocistronic cas2 transcript at a C residue 103 nucleotides upstream from the cas2 start codon.

Base Sequence↗
PubMed2003

Comparative in vitro potency of amoxycillin-clavulanic acid and four oral agents against recent North American clinical isolates from a global surveillance study.

The in vitro activity of amoxycillin-clavulanic acid was compared with four comparator oral antimicrobial agents; ampicillin, azithromycin, cefuroxime and trimethoprim-sulphamethoxazole against 4536 recent clinical isolates covering 29 species isolated in the US and Canada between 1997 and 1999. Based upon Minimum inhibitory concentrations (MICs), amoxycillin-clavulanic acid was the most active agent against many Gram-positive species and phenotypes including methicillin susceptible Staphylococcus aureus (MSSA) Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae including penicillin intermediate and macrolide resistant strains and was as active as ampicillin against Streptococcus agalactiae, penicillin resistant S. pneumoniae and viridans streptococci. Against Enterobacteriaceae amoxycillin-clavulanic acid in general, displayed weak activity with only Proteus mirabilis and Proteus vulgaris displaying levels of susceptibility above the 90th percentile. Amoxycillin-clavulanic acid had significant activity against many species of Gram-negative non-Enterobacteriaceae including Haemophilus influenzae, Haemophilus parainfluenzae and Moraxella catarrhalis but negligible activity against Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Amoxycillin-clavulanic acid continues to retain excellent activity against the majority of targeted pathogens despite 20 years of clinical use.

Administration, Oral↗
PubMed1986

The activity of ticarcillin in combination with clavulanic acid against Bacteroides species: an in-vitro comparison with other antibiotics.

The in-vitro activity of ticarcillin alone and with 4 and 8 mg/l of clavulanic acid, has been studied on 100 strains of Bacteroides (66 Bacteroides fragilis, 13 B. ovatus, 11 B. vulgatus, 6 B. distasonis, 4 B. thetaiotaomicron) by an agar-dilution method and compared to that of latamoxef cefoxitin, cefotaxime, ceftizoxime, ceftriaxone, cefmenoxime, ceftazidime and metronidazole. All the strains tested were susceptible to the combination of ticarcillin-clavulanic acid (MIC less than or equal to 8 mg/l), to metronidazole (MIC less than or equal to 4 mg/l), and to cefoxitin (MIC less than or equal to 32 mg/l). The combination of ticarcillin and clavulanic acid has an activity superior to that of ticarcillin alone. The MIC90 was 32 mg/l for ticarcillin alone, 1 and 0.5 mg/l for ticarcillin combined with 4 and 8 mg/l of clavulanic acid respectively. Against all the tested strains, cefoxitin was the most active of the cephalosporins, followed by latamoxef (3% of all strains with an MIC greater than 32 mg/l), cefotaxime (5%), ceftizoxime (9%), ceftriaxone (13%), cefmenoxime (17%) and ceftazidime (33%). Differences in sensitivity to cephalosporins were observed within species; the B. ovatus was clearly more resistant than B. fragilis and B. vulgatus. In all species, the combination of ticarcillin and clavulanic acid was always highly active, with MICs less than or equal to 0.01-8 mg/l.

Bacteroides↗
PubMed1997

[Liver damage associated with the combination drug amoxicillin-clavulanic acid (Augmentin)].

OBJECTIVE: To describe the case histories of patients with liver damage associated with the antibacterial combination amoxicillin-clavulanic acid. DESIGN: Descriptive. SETTING: University Institute for General Practice, Rotterdam, the Netherlands. METHOD: All reports (n = 40) of hepatic injury, attributed to amoxicillin-clavulanic acid (causal relationship 'possible', 'probable' or 'certain') and received by the Drug Safety Unit of the Inspectorate for Health Care since the registration of the combination (1982) until August 1996 were described and evaluated. RESULTS: The reports concerned 28 men and 12 women with an average age of 61 years who had used the drug mostly for a respiratory tract infection. The latency period between first in-take and onset of the reaction was 3 weeks on average. The mean duration of hepatic injury was approximately 6 weeks. The liver injury resolved fully. Five patients had had the reaction on more than one occasion. The main symptoms were jaundice, nausea, pruritus and abdominal pain. The pattern of hepatic injury was mostly cholestatic or mixed hepatocellular-cholestatic. CONCLUSION: Since liver damage to amoxicillin-clavulanic acid appears to be infrequent, this adverse effect is probably not caused by amoxicillin alone. The risk of liver damage to amoxicillin-clavulanic acid is highest in elderly patients treated with the combination on several occasions. Doctors should restrict the use of this combination to the treatment of infections with amoxicillin-resistant bacteria.

Amoxicillin↗