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PubMed1987

Comparative disk and broth dilution susceptibility test results with ticarcillin and timentin against Pseudomonas aeruginosa and Pseudomonas maltophilia.

A total of 500 clinical isolates of Pseudomonas aeruginosa and 14 isolates of Pseudomonas maltophilia were examined for susceptibility to ticarcillin and timentin (ticarcillin plus clavulanic acid). Clavulanic acid enhanced the activity of ticarcillin against only 34 of 500 isolates of P. aeruginosa. Among 23 isolates of P. aeruginosa, that had yielded divergent disk diffusion results, there were 3 major discrepancies (3 = ticarcillin-resistant by disk diffusion, but susceptible by broth dilution test criteria) and 1 very major discrepancy (timentin-susceptible by disk diffusion, but resistant by broth dilution test criteria). Clavulanic acid enhanced the activity of ticarcillin against 12 of 14 isolates of P. maltophilia; there were 2 major discrepancies (ticarcillin resistance in terms of disk diffusion, but susceptibility according to ticarcillin MICs). Consequently, it was decided to continue employing timentin disks alone, rather than add ticarcillin disks in our Bauer-Kirby test battery for Pseudomonadaceae.

Clavulanic Acids↗
PubMedDate not supplied

Evolution of beta-lactamase inhibitors.

The production of beta-lactamase is the most important mechanism of bacterial resistance to beta-lactam antibiotics. Attempts to find an inhibitor of beta-lactamase were made as early as the 1940s and 1950s but without success. In the early 1950s, it was found that certain semisynthetic penicillins could function as beta-lactamase inhibitors, but none found a clinical place in this capacity. A program of screening microorganisms for the production of naturally occurring inhibitors was begun in 1967. This process led to the discovery of the olivanic acids and clavulanic acid. Clavulanic acid, formulated with amoxicillin and later with ticarcillin, became available for clinical use in 1981. Since the introduction of clavulanic acid, other beta-lactamase inhibitors have been developed, including sulbactam and tazobactam. It remains to be seen whether these will have any advantage over clavulanate for clinical use.

Anti-Bacterial Agents↗
PubMed1986

Structure-activity relationships amongst beta-lactamase inhibitors.

Using a variety of beta-lactamases including those from Escherichia coli (TEM-1), Enterobacter cloacae P99 and Staphylococcus aureus the inhibition profiles (I50 values) were determined for various groups of compounds including penicillins, penicillanic acid derivatives (sulphone and beta-halo substitutions), olivanic acids and clavulanic acid derivatives including substituted ethers and amines. Some of the latter compounds had higher activity than clavulanic acid with and without preincubation of enzyme with inhibitor but they still had poor activity against the P99 enzyme. Improvements in activity against Class I cephalosporinases were obtained with some derivatives of clavulanic acid but this was usually achieved at the expense of activity against clavulanate susceptible beta-lactamases. The olivanic acids had the highest activity against the widest range of beta-lactamases.

Bacteria↗
PubMed1990

[Influence of bacterial combinations on the post-antibiotic effect].

A study of the post-antibiotic effect (PAE) and letality curves of different concentrations of clavulanic acid, amoxycillin, amoxycillin + clavulanic acid, netilmycin and ofloxacin on mixed cultures of S. aureus and E. coli. The post-antibiotic effect was measured after one hour of exposure of bacteria to antimicrobial and the elimination of the latter by the dilution method. Amoxycillin did not induce PAE on the association. PAE only appeared at high concentrations on S. aureus when evaluated alone. Clavulanic acid induced a greater PAE than amoxycillin. The association clavulanic acid + amoxycillin was synergistic and induced a greater PAE than its components. Netilmycin and ofloxacin were the drugs that induced the greatest PAE on the bacterial association and on its strains independently evaluated.

Amoxicillin↗
PubMedDate not supplied

Amoxicillin-clavulanic acid-induced hepatitis.

OBJECTIVES: The aim of this study was to report a rare side effect of amoxicillin-clavulanic acid resulting in drug-induced hepatitis in the treatment of chronic rhinosinusitis. METHODS: This is a case report and literature review of amoxicillin-clavulanic acid-induced hepatitis in the treatment of chronic rhinosinusitis. A MEDLINE search of the published literature from 1966 to 2006 was performed using the term "amoxicillin-clavulanic acid + hepatitis." RESULTS: We report a case of a 53-year-old man who developed drug-induced hepatitis after the use of amoxicillin-clavulanic acid for the treatment of chronic rhinosinusitis. After a 4-week course of amoxicillin-clavulanic acid, the patient developed pruritus and jaundice. Liver function tests revealed elevated aminotransferase levels. Serologic examination result for hepatitis A, B, and C was negative. The amoxicillin-clavulanic acid was discontinued and the patient was treated conservatively. The pruritus and jaundice gradually resolved and the patient had no long-term complications. The literature review revealed this is the first reported case of amoxicillin-clavulanic acid-induced hepatitis for the treatment of chronic rhinosinusitis. CONCLUSIONS: Drug-induced hepatitis is a rare side effect of amoxicillin-clavulanic acid. Care must be taken in prescribing this drug to elderly patients and patients with liver disease. In general, the hepatitis is mild to moderate, rarely leads to liver failure, and can be managed conservatively.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1996

Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.

Animals↗
PubMed1991

Evolution of beta-lactamase inhibitors.

In most clinical isolates that are resistant to penicillins, cephalosporins and related compounds, the mechanism of resistance is the production of beta-lactamase enzymes. These enzymes hydrolyze the amide bond in the beta-lactam ring of the compound, producing acidic derivatives that have no antibacterial properties. The rationale for beta-lactamase inhibitors is to overcome this resistance. Early study of beta-lactamase inhibition was begun in the 1940s without success. Interest in beta-lactamase inhibition was renewed with the development of the semisynthetic penicillins in the early 1960s, when it was found that certain of these compounds could function as inhibitors. However, none found clinical application. The screening of microorganisms for possible production of naturally occurring beta-lactamase inhibitors resulted in the discovery of the olivanic acids and, later, clavulanic acid. A formulation of clavulanic acid with amoxicillin was introduced in 1981, and a formulation of clavulanic acid with ticarcillin appeared shortly thereafter. More recently, other beta-lactamase inhibitors have been developed, including sulbactam and tazobactam. A formulation of sulbactam with ampicillin has appeared recently. As a result of beta-lactamase inhibition, amoxicillin and clavulanate and ticarcillin and clavulanate are active against a high proportion of amoxicillin resistant and ticarcillin resistant pathogens. These formulations have been shown to be safe and effective in the treatment of many infections that would not be expected to respond to amoxicillin or ticarcillin alone.

Anti-Bacterial Agents↗
PubMed1992

TRC-1: emergence of a clavulanic acid-resistant TEM beta-lactamase in a clinical strain.

A novel TEM-derived plasmid-encoded beta-lactamase, resistant to inhibition by clavulanic acid, has been identified in a clinical strain of Escherichia coli found in Scotland. The beta-lactamase gene was carried on an 81-kb plasmid that conferred no other resistances. The novel enzyme conferred resistance to the amoxycillin/clavulanic acid combination on the host bacterium. The beta-lactamase has a pI of 5.25 and lies between the PSE-4 and SAR-1 beta-lactamases on an isoelectric focusing gel. This beta-lactamase has a Mr value of 25,000, similar to the TEM-1 enzyme and a comparable substrate profile. Its most significant difference is that it is inhibited by clavulanic acid 100-fold less efficiently than the TEM-1 enzyme. The enzyme was confirmed to be derived from the TEM enzymes by probing the plasmid DNA with an intragenic gene probe for TEM-1. This is the first report of a clinical bacterium carrying a TEM-enzyme that confers resistance to clavulanic acid combinations and we have designated the beta-lactamase as TRC-1.

Clavulanic Acid↗
PubMed2004

The vitro efficacy of beta-lactam and beta-lactamase inhibitors against multidrug resistant clinical strains of Mycobacterium tuberculosis.

In vitro activity of beta-lactam antibiotics and their beta-lactamase inhibitor combinations were evaluated for their activity against clinical isolates of Mycobacterium tuberculosis and M. tuberculosis H37Ra. Agar dilution, the BACTEC 460 system and beta-lactamase activity tests were used. Results using the BACTEC 460 and enzyme activity tests showed the best beta-lactamase inhibitor for M. tuberculosis H37Ra to be clavulanic acid. Cefazolin-clavulanic acid gave the lowest minimal inhibitory concentration (MIC) values using dilution tests and M. tuberculosis H37Ra. beta-Lactam antibiotics were combined with clavulanic acid and tested for in vitro activity against 50 selected multidrug-resistant (MDR) and 50 susceptible clinical isolates. Seventy-four percent of the isolates were inhibited by cefazolin-clavulanic acid combination. These results suggested that an appropriate combination of beta-lactam and beta-lactamase inhibitors might be useful in the treatment of tuberculosis due to multidrug-resistant strains.

Anti-Bacterial Agents↗
PubMed1997

In vitro activities of beta-lactam-beta-lactamase inhibitor combinations against Stenotrophomonas maltophilia: correlation between methods for testing inhibitory activity, time-kill curves, and bactericidal activity.

The activities of ampicillin, ampicillin-sulbactam, amoxicillin, amoxicillin-clavulanic acid, ticarcillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, aztreonam, and aztreonam-clavulanic against Stenotrophomonas maltophilia strains for which the MICs of penicillins and commercially available beta-lactam-beta-lactamase inhibitor combinations were higher than the breakpoints usually recommended for Pseudomonas aeruginosa in commercially available broth microdilution methods were tested by the agar diffusion, agar dilution, and broth microdilution methods. Time-kill curve studies were performed when discrepancies between these methods were observed. The MICs obtained by the commercially available broth microdilution method, the agar dilution method, and the broth microdilution method were almost identical. Twenty-five percent of the strains tested showed inhibition diameters of > or =15 mm for ticarcillin-clavulanic acid, and 43.7% of the strains tested showed inhibition diameters of > or =18 mm for piperacillin-tazobactam by the agar diffusion method. The time-kill curves for these strains confirmed the results obtained by dilution methods. Aztreonam-clavulanic acid (2:1) at concentrations of < or =16 microg/ml inhibited all of these strains (MIC range, 1 to 16 microg/ml). The time-kill curves confirmed this activity. The addition of piperacillin to this combination did not modify the MICs. The combination aztreonam-clavulanic acid-ticarcillin was two- to fourfold more active than aztreonam-clavulanic acid alone. We studied the inhibitory and bactericidal activities of the two most active combinations (aztreonam-clavulanic acid and aztreonam-clavulanic acid-ticarcillin) against the standard inoculum and 10 and 50 times the standard inoculum. Inoculum modifications did not modify the MICs. Both combinations showed good bactericidal activity against the standard inoculum. With 10 times the standard inoculum, minimum bactericidal concentration (MBC) results were heterogeneous (for 55% of the strains, MBCs were between the MIC and 4-fold the MIC, and for 45% of the strains MBCs were between 8- and >32-fold the MIC). With 50 times the standard inoculum, MBCs were at least 32-fold the MICs for all the strains tested.

Amoxicillin↗
PubMed1989

[Positive direct Coombs' test in acute leukemias and other hemoblastoses: relation to clavulanic acid-containing antibiotics?].

Alerted by a high incidence of positive autologous controls in pretransfusion compatibility testing for patients with acute leukemia, we retrospectively analysed 59 cases of severe hemoblastoses undergoing myelosuppressive treatment. Seventeen (29%) of these patients had a positive direct antiglobulin test (DAT) with the following characteristics: the test was of the IgG and/or C3d type in all but two cases, which reacted with polyvalent antiglobulin sera only; the reaction was very weak throughout; very high concentrations of monospecific sera were needed to elicit positive reactions; free antibodies were never detected in the patients' serum; the eluates of the patients' red cells were non-reactive against a very large panel of test erythrocytes. All these criteria suggested a non-immunologic absorption of proteins under the influence of drugs such as cephalosporins and clavulanic acid. Timenten (ticarcillin and clavulanic acid) was found to be the only common drug which had been administered to the majority of the patients with a positive DAT: 15 of the 17 patients with a positive DAT (88%) had received Timenten against 19 of 42 patients (45%) with negative DAT. 44% of all the patients receiving Timenten thus had a positive DAT, whereas only 8% of the patients without this drug reacted in this way. These data document the role of clavulanic acid in the development of a positive DAT. The literature and our experience show that this kind of unspecific binding of proteins to the red cell membrane is not associated with increased hemolysis. Knowledge of the phenomenon, however, is important for differential diagnosis of anemias and interpretation of difficulties arising during pretransfusional compatibility testing.

Acute Disease↗
PubMed1988

The effect of anaerobiosis on antistaphylococcal antibiotics.

The activity of eight antimicrobial agents which might be used in the treatment of staphylococcal osteomyelitis was tested under anaerobic conditions similar to those found in chronically infected bone. An agar-dilution method was employed to determine the minimum inhibitory concentrations of tobramycin, vancomycin, teicoplanin, ciprofloxacin, clindamycin, ceftriaxone, ticarcillin-clavulanic acid, and amoxicillin-clavulanic acid against 25 coagulase-positive and 25 coagulase-negative staphylococcal strains. The activity of tobramycin against coagulase-positive staphylococci, and of amoxicillin-clavulanic acid and ticarcillin-clavulanic acid against coagulase-negative staphylococci was markedly decreased with anaerobiosis. Vancomycin, teicoplanin, and ciprofloxacin were active against coagulase-positive and coagulase-negative staphylococci under both aerobic and anaerobic conditions. It was also found that antibiotic concentrations comparable to the high levels which might be achieved with local antibiotic therapy of osteomyelitis were not sufficient to overcome the level of resistance (100 micrograms/ml) of staphylococci which were not susceptible to tobramycin, clindamycin, ceftriaxone, and ticarcillin-clavulanic acid.

Amoxicillin↗
PubMed1989

Comparative in vitro activities of piperacillin-tazobactam and ticarcillin-clavulanate.

The in vitro activities of ticarcillin, piperacillin, clavulanic acid, tazobactam, ticarcillin-clavulanate, and piperacillin-tazobactam against 819 bacterial isolates were compared. The two beta-lactamase inhibitors, clavulanic acid and tazobactam, had little useful antibacterial activity but enhanced the activities of the penicillins against beta-lactamase-producing strains of Haemophilus influenzae, Branhamella catarrhalis, and methicillin-susceptible Staphylococcus aureus; all strains were susceptible to both combinations. Both enzyme inhibitors also enhanced the activities of the penicillins against most strains of Escherichia coli, Klebsiella spp., Citrobacter diversus, Proteus spp., Providencia spp., and Bacteroides spp. and against occasional strains of Citrobacter freundii, Enterobacter spp., and Serratia marcescens. Clavulanic acid frequently enhanced the activity of ticarcillin against Xanthomonas maltophilia, and tazobactam frequently enhanced the activity of piperacillin against Morganella morganii. Enhancement was observed primarily with strains relatively resistant to the penicillins. In general, clavulanic acid was more effective than tazobactam in enhancing penicillin activity against Klebsiella spp., C. diversus, X. maltophilia, and Bacteroides spp., whereas tazobactam was more effective against Escherichia coli and Proteeae. There was little or no enhancement of activity against Enterococcus faecalis, Aeromonas hydrophila, Pseudomonas aeruginosa, Pseudomonas cepacia, or Acinetobacter anitratus. Clavulanic acid occasionally antagonized the activity of ticarcillin against ticarcillin-susceptible members of the family Enterobacteriaceae, but those strains were still considered susceptible to the combination. Tazobactam never antagonized the activity of piperacillin. In a direct comparison of the activities of ticarcillin-clavulanate and piperacillin-tazobactam, the two were equally active against H. influenzae, B. catarrhalis, and S. aureus; the latter was more active against E. faecalis. For relatively susceptible strains of members of the family Enterobacteriaceae, neither combination was predictably more active than the other, but relatively resistant strains were generally more susceptible to piperacillin-tazobactam. Piperacillin-tazobactam was more active than ticarcillin-clavulanate against A. hydrophila, P. aeruginosa, and P. cepacia, similar in activity against A. anitratus, and less active against X. maltophilia and Bacteroides spp.

Anti-Bacterial Agents↗