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Charts of 16 patients on ticarcillin-clavulanic acid were examined. Eight patients were found to have hypokalemia, yet not all were screened routinely for potassium imbalance. Some physicians prescribing ticarcillin-clavulanic acid seem unaware of the drug's side effect.
Recently, a second copy of a gene encoding proclavaminate amidinohydrolase (pah1), an enzyme involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus, was identified and isolated. Using Southern analysis, we have now isolated second copies of the genes encoding the carboxyethylarginine synthase (ceaS) and beta-lactam synthetase (bls) enzymes. These new paralogues are given the gene designations ceaS1 and bls1 and are located immediately upstream of pah1 on the chromosome. Furthermore, sequence analysis of the region downstream of pah1 revealed a second copy of a gene encoding ornithine acetyltransferase (oat1), thus indicating the presence of a cluster of paralogue genes. ceaS1, bls1, and oat1 display 73, 60, and 63% identities, respectively, at the nucleotide level to the original ceaS2, bls2, and oat2 genes from the clavulanic acid gene cluster. Single mutants defective in ceaS1, bls1, or oat1 were prepared and characterized and were found to be affected to variable degrees in their ability to produce clavulanic acid and clavam metabolites. Double mutants defective in both copies of the genes were also prepared and tested. The ceaS1/ceaS2 and the bls1/bls2 mutant strains were completely blocked in clavulanic acid and clavam metabolite biosynthesis. On the other hand, oat1/oat2 double mutants still produced some clavulanic acid and clavam metabolites. This may be attributed to the presence of the argJ gene in S. clavuligerus, which encodes yet another ornithine acetyltransferase enzyme that may be able to compensate for the lack of OAT1 and -2 in the double mutants.
The beta-lactamase inhibitors clavulanic acid and sulbactam were combined with mecillinam. beta-Lactamase-containing Escherichia coli resistant to mecillinam was synergistically inhibited by both clavulanic acid and sulbactam. beta-Lactamase-containing Enterobacter was synergistically inhibited, but strains lacking beta-lactamases were not synergistically inhibited. Synergistic inhibition was noted for beta-lactamase-containing, mecillinam-resistant Klebsiella, Citrobacter, Serratia, and Salmonella isolates, but only 18% of beta-lactamase-containing Proteus mirabilis, Providencia rettgeri, Providencia stuartii, and Morganella morganii were synergistically inhibited by the combinations.
The efficacy and safety of ticarcillin plus clavulanic acid in the treatment of patients with infections of soft tissue, bone, and joint were evaluated in this open study. Clinical diagnoses included osteomyelitis, soft tissue abscess or ulcer, cellulitis, bite wound, traumatic or postoperative cellulitis, necrotizing fasciitis, septic arthritis, septic bursitis, and septic thrombophlebitis. Trauma or underlying disease such as diabetes mellitus or vascular insufficiency was common (more than 50 percent) in the patient population. Clinical efficacy was evaluable in 66 patients who received 3 g of ticarcillin and 0.1 g of clavulanic acid every four or six hours for a mean of 23.4 days. A satisfactory clinical response was observed in 92 percent of the patients. Major pathogens isolated were Enterobacteriaceae, anaerobic cocci, Staphylococcus aureus, and beta-hemolytic Streptococcus. Of the 143 isolates recovered from 55 bacteriologically evaluable cases, 87 percent were eradicated by therapy. Overall, a satisfactory bacteriologic outcome occurred in 93 percent of the patients, and the pathogen(s) persisted in 7 percent. More than 98 percent of the isolates were susceptible to ticarcillin plus clavulanic acid in vitro. Emergence of resistance during therapy occurred with three strains of Pseudomonas aeruginosa. Adverse drug-related reactions required discontinuation of treatment in two patients, although other minor abnormal laboratory findings were common. These results indicate that ticarcillin plus clavulanic acid offers safe and effective therapy for infections of soft tissue, bone, and joint.
The ability of clavulanic acid to inactivate beta-lactamase was investigated using 47 amoxicillin-resistant bacteria. In the presence of 10 mg/l clavulanic acid most strains of staphylococci, Escherichia coli, Klebsiella and Proteus mirabilis became fully amoxicillin-sensitive. This effect of clavulanic acid was in most instances not observed with Serratia marcescens, Proteus inconstans, Pseudomonas aeruginosa, Enterobacter and indole-positive Proteus species.
The comparative in vitro activity of amoxicillin alone and in combination with clavulanic acid against 15 isolates of Mycobacterium tuberculosis was evaluated by broth dilution susceptibility testing. Amoxicillin inhibited 4 of 15 isolates at 8 micrograms/ml or less but was not bactericidal against any of the isolates at that concentration. Amoxicillin in combination with clavulanic acid was bactericidal for 14 of 15 isolates tested at an amoxicillin concentration of 4 micrograms/ml or less and a clavulanic acid concentration of 2 micrograms/ml or less.
Because the insensitivity of Bacteroides fragilis to penicillins is due to betalactamase formation, the potentiating effect of the betalactamase inhibitor clavulanic acid on the action of amoxycillin and benzylpenicillin against this bacterium was studied in vitro and in an experimental infection in mice. The addition of clavulanic acid to amoxycillin and benzylpenicillin resulted in a marked synergistic effect against B. fragilis, as assessed by both MIC determinations and in 4-h growth curves. In the experimental infection, where co-inoculation with Escherichia coli was obligatory for the outgrowth of B. fragilis, both penicillins had a dose-dependent effect on both species. However, the addition of clavulanic acid to amoxycillin and benzylpenicillin did not increase the effect of the penicillins against B. fragilis or against E. coli. Because a synergistic effect might have remained undetected in vivo, the experimental conditions were varied, i.e. the drugs were administered in the proliferation phase of B. fragilis, the clavulanic acid to betalactam ratios were varied, and the drugs were given after inoculation of B. fragilis in which betalactamase production has been induced. However, even after variation of the experimental conditions the addition of clavulanic acid to benzylpenicillin did not result in a potentiation of the effect of benzylpenicillin against B. fragilis.
Tissue penetration of amoxicillin and clavulanic acid given for antibiotic prophylaxis was studied in 15 patients. On induction of anesthesia patients were given 2 g amoxicillin and 200 mg clavulanic acid. The same dose was given two hours later. At time of surgical incision amoxicillin and clavulanate levels were 15.9 +/- 7.7 micrograms/g and 2.23 +/- 2.69 micrograms/g in abdominal wall fat and 16.6 +/- 10.5 and 1.72 +/- 1.35 micrograms/g in epiploic fat, respectively. Similar levels were measured at time of closure of the abdomen. In colonic wall, amoxicillin et clavulanate levels were 22.7 +/- 13.4 micrograms/g and 2.65 +/- 2.35 micrograms/g. By comparison with blood levels, tissue penetration of both drugs was 20 to 30 p. cent into fatty tissues and 60 to 70 p. cent into colonic wall.
A stopped-flow mixing technique is used to determine clavulanic acid in human plasma after plasma deproteinisation with acetonitrile and removal of the organic solvent by extraction with dichloromethane. The reaction kinetic profiles for the reaction between clavulanic acid and imidazole are determined by measuring the absorbance at 312 nm of the imidazole derivative. The reaction rates are proportional to the concentration of the clavulanic acid and by plotting reaction rates against clavulanic acid concentrations linear calibration curves could be constructed over the range 0.30-10.0 microg/ml.
A new single-antibiotic combination of ticarcillin and clavulanic acid was compared with the standard two-drug regimen of clindamycin and gentamicin in the treatment of post-cesarean endomyometritis. The regimens were as follows: 3 g of ticarcillin plus 100 mg of clavulanic acid intravenously every four hours; or 600 mg of clindamycin intravenously every six hours plus 3 to 5 mg/kg per day of gentamicin intramuscularly. The prospective randomized schedule was calculated such that half the patients were assigned to each treatment group. The diagnosis of endomyometritis was based upon an elevated oral temperature of 100.4 degrees F or higher on any two occasions, excluding the first 24 hours after delivery, uterine tenderness, and the absence of other foci of infection. Lochial discharge was foul in most cases. Forty-seven patients were treated. Treatment was successful in all patients who received clindamycin and gentamicin; ticarcillin plus clavulanic acid failed in two of 23 (9 percent) patients. Patients in whom treatment failed did not appear to be different from those in whom treatment was successful on demographic variables or in terms of risk factors for endomyometritis. The difference between the treatment failure rates was not statistically significant. This study suggests that the single-drug combination of ticarcillin plus clavulanic acid is effective in the treatment of post-cesarean endomyometritis when compared with the standard regimen of clindamycin and gentamicin.
The effects of polymorphonuclear neutrophils (PMNs) and/or clavulanic acid on the bactericidal activity of amoxicillin (at human serum achievable concentrations) against a serotype 3 penicillin-susceptible Streptococcus pneumoniae strain [minimal inhibitory concentration/minimal bactericidal concentration (MIC/MBC) values of penicillin, amoxicillin, and amoxicillin/clavulanic acid (2:1) = 0.01/0.01 microgram/ml] and a serotype 9 penicillin-resistant strain [MIC/MBC of penicillin, amoxicillin, and amoxicillin/clavulanic acid (2:1) = 1/2 microgram/ml] were studied. Against the penicillin-resistant strain, subinhibitory concentrations of amoxicillin reduced the growth rate; this effect was increased by the addition of clavulanic acid. A reduction of the penicillin-resistant initial inocula (3 x 10(6) cfu/ml) at subinhibitory concentrations was obtained only with amoxicillin plus clavulanic acid and PMNs. At suprainhibitory concentrations, both clavulanic acid and PMNs increased the bactericidal activity of amoxicillin, as evidenced by an increased reduction in the penicillin-resistant initial inocula. The combined effect of these antibiotics and immune defenses may help explain the maintenance of their clinical efficacy in respiratory tract infections, despite the increase in the incidence of penicillin-resistant pneumococci.
The efficacy of amoxycillin-clavulanic acid for prevention of postoperative wound infection was compared with that of cefamandole in 150 patients at risk for infected bile while undergoing elective biliary surgery in a prospective, randomized study. The two groups were comparable for age, sex, risk factors, operative procedures and positive bile cultures. Similar numbers of patients had an uncomplicated postoperative course (amoxycillin-clavulanic acid 70%; cefamandole 73%). Four patients in each group developed wound infection. The incidence of postoperative pneumonia, urinary tract infection and number of days (+/- SD) in hospital (amoxycillin-clavulanic acid 10.1 +/- 4.7; cefamandole 9.7 +/- 5.6) were similar. The efficacy of amoxycillin-clavulanic acid and cefamandole in preventing wound sepsis in high-risk patients undergoing biliary surgery was similar. Economic considerations may favour the use of amoxycillin-clavulanic acid.
Three children were receiving ticarcillin-clavulanic acid by continuous venovenous hemofiltration (CVVH). Two of them were also receiving concomitant extracorporeal membrane oxygenation (ECMO). We collected ultrafiltrate hourly to determine the clearance of ticarcillin-clavulanic acid by CVVH. Serum concentrations were also determined at the midpoint of each ultrafiltrate collection. All samples were collected over one dosing interval. The volume of distribution of ticarcillin and clavulanic acid was 0.26 +/- 0.01 and 0.69 +/- 0.23 L/kg, respectively. Total body clearance of ticarcillin, determined from the elimination rate constant and volume of distribution, was 0.038 +/- 0.003 L/kg/hour and for clavulanic acid was 0.18 +/- 0.03 L/kg/hour. The sieving coefficients for ticarcillin and clavulanic acid were 0.83 +/- 0.11 and 1.69 +/- 0.19, respectively. We attempted to estimate the clearances by ECMO, but the result was uninterpretable.
The research programme leading to the discovery of clavulanic acid and the olivanic acids (carbapenems) is reviewed. The beta-lactamase inhibitory properties of clavulanic acid and its development as a formulation with amoxycillin (Augmentina) and ticarcillin (Timentin) are described. The chemistry of clavulanic acid as well as the properties of the carbapenem family of antibiotics is outlined as are the other beta-lactamase inhibitors prompted by the development of clavulanic acid.
Forty-four patients with respiratory tract infections were treated using a new formulation of amoxycillin and clavulanic acid. Clinical diagnosis was classified as follows: 19 cases of acute exacerbations of chronic bronchitis, 10 cases of bronchiectasis, and 15 cases of diffuse or localized pneumonia. Amoxycillin/clavulanic acid combination (amoxycillin 250 mg + clavulanic acid 125 mg per tablet) was administered as 2 tablets three times per day for 7-14 days. The efficacy was as follows: chronic bronchitis 94.7%, bronchiectasis 80.0% and pneumonia 93.3%. No severe adverse reactions occurred in treated patients and no renal, hepatic or hematological toxicity was observed. Amoxycillin/clavulanic acid combination was a safe and effective antimicrobial agent for the treatment of respiratory tract infections.
Toxic hepatitis secondary to amoxycillin-clavulanic acid is an infrequent clinical picture. Most of the cases are reported to have a benign course. We report two cases of severe hepatic failure following amoxycillin-clavulanic acid use. One of the cases had cholestatic features primarily, and the other had hepatocellular injury prominently. The first case had also findings of trombotic trombositic purpura and had a fatal course.
In order to determine the most effective regimen for the prevention of infection after elective hysterectomy, 300 patients were randomly assigned to receive three perioperative doses of either amoxycillin-clavulanic acid (1.2 g intravenous) or metronidazole (1 g suppository). Of the 280 patients who were assessable 138 were given amoxycillin-clavulanic acid and 142 received metronidazole; 268 underwent abdominal hysterectomy and 12 had vaginal hysterectomy. Patients in the amoxycillin-clavulanic acid group had significantly less infectious morbidity (13.8%) than those in the metronidazole group (33.1%). There were also statistically significant differences in favour of amoxycillin-clavulanic acid with respect to operative site infection, duration of hospital stay, need for postoperative antimicrobials, and surgery for operative site infection. But for one isolate of Bacteroides fragilis, all pathogens isolated from wound infections in the metronidazole group were aerobes. No anaerobes were isolated from patients in the amoxycillin-clavulanic acid group. The results suggest that prophylaxis for hysterectomy should consist of an agent, or combination of agents, with activity against both aerobic and anaerobic bacteria. Amoxycillin-clavulanic acid fulfils this criterion and appears to be effective and safe.
The in-vitro activity of ticarcillin in combination with clavulanic acid was compared with that of ticarcillin alone, piperacillin, cefotaxime and, where appropriate, other beta-lactams against a total of 301 recent clinical isolates and characterized beta-lactamase producers. An agar dilution procedure was used to determine MICs and two inocula (10(4) and 10(6) cfu) were used throughout. MICs of the combination of ticarcillin and clavulanic acid were expressed as MICs of ticarcillin in the presence of 5 or 10 mg/l of clavulanic acid. Against most members of the Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii and Serratia marcescens), ticarcillin plus clavulanic acid was as active as or more active than piperacillin. Against Staphylococcus aureus. Haemophilus influenzae and the Bacteroides fragilis group the combination was considerably more active than piperacillin. Piperacillin was more active than the ticarcillin/clavulanic acid combination against Pseudomonas aeruginosa.