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PubMed1999

[In vitro activity of piperacillin-tazobactam against Klebsiella pneumoniae clinical isolates, producers or not of extended spectrum beta-lactamases].

The aim of this study was to determine the in vitro activity of piperacillin-tazobactam against 81 clinical isolates of Klebsiella pneumoniae. The clinical specimens were processed according to standard microbiological procedures and 81 K. pneumoniae isolates were identified using MicroScan Panels following the manufacturer's recommendations. A double disk diffusion method was applied to detect extended spectrum betalactamases (ESBL) (43 isolates were positive and 38 were negative). Minimum inhibitory concentrations (MIC) were determined by an agar dilution technique using Mueller-Hinton. The following antibiotics were studied: piperacillin with 4 mg/l of tazobactam, amoxicillin-clavulanic acid in a 2:1 proportion, cefotaxime, ceftriaxone, cefepime, imipenem and meropenem. The MIC(90) were 16/4 mg/l for piperacillin-tazobactam, 16/8 for amoxicillin-clavulanic acid, 16 for ceftriaxone, 16 for cefotaxime, 4 for cefepime, 0.25 for imipenem and 0.032 for meropenem in ESBL-positive strains. In ESBL-negative strains the MIC90 were as follows: 4/4 mg/l for piperacillin-tazobactam, 8/4 for amoxicillin-clavulanic acid, 0.064 for ceftriaxone, 0.125 for cefotaxime, 0.125 for cefepime, 0.125 for imipenem and 0.016 for meropenem. All betalactams showed excellent in vitro activity against ESBL non-producer K. pneumoniae. Moreover, piperacillin-tazobactam and both carbapenems showed good in vitro activity against EBSL-producer K. pneumoniae.

Drug Therapy, Combination↗
PubMed1994

Clinical isolates of Escherichia coli producing multiple TEM mutants resistant to beta-lactamase inhibitors.

Twenty clinical isolates of Escherichia coli resistant to amoxycillin and ticarcillin, both in combination with clavulanic acid, were studied. The ranges of MICs for these strains as determined by the agar dilution method were as follows: amoxycillin, 2048- > 4096 mg/L; ticarcillin, 512- > 4096 mg/L; piperacillin, 32-256 mg/L; mecillinam, 0.5-8 mg/L; and cephalothin 4-16 mg/L. Combining amoxycillin with beta-lactamase inhibitors, each at a fixed concentration of 4 mg/L, had only modest potentiating effects on the activities of this agent, the ranges of MICs falling to 256- > 2048 mg/L in the presence of clavulanic acid or sulbactam and to 64-1024 mg/L and 128-2048 mg/L in the presence of tazobactam and brobactam respectively. The pI values for the beta-lactamases produced by the 20 isolates were 5.2 for 15 strains, 5.4 for four strains and 7.4 for a single strain. Colony hybridization with oligonucleotides was performed in order to detect substitutions of arginine at position 241 (Arg-241) and methionine at position 67 (Met-67). Based on this technique, the four beta-lactamases with pI values of 5.4 were grouped into two oligotypes (+ = hybridization, - = non-hybridization)-Arg-241+, Met-67- (n = 3) and Arg-241+, Met-67+ (n = 1); in one of the three mutants which did not hybridize with the Met-67 probe, leucine had been substituted for methionine at position 67. The beta-lactamases with pI values of 5.2 which were identified in 15 strains were grouped into the following three oligotypes: Arg-241-, Met-67+ (n = 7); Arg-241-, Met-67- (n = 6); and Arg-241+, Met-67- (n = 2). In three of the 13 mutants which failed to hybridize with the Arg-241 probe, serine residues had replaced arginine residues at position 241. Substitutions of Arg-241 or Met-67 led to reduced affinities of the mutant enzymes for the beta-lactams tested. The results of the hybridization studies demonstrate that, amongst E. coli clinical isolates, there is a diversity of mutant TEM enzymes mediating resistance to beta-lactamase inhibitors.

Amoxicillin↗
PubMedDate not supplied

Susceptibility of clinical isolates to expanded-spectrum beta-lactams alone and in the presence of beta-lactamase inhibitors.

Tazobactam and BRL 42715 are relatively new penems which inhibit a wide range of plasmid- as well as chromosomally mediated bacterial beta-lactamases that include Richmond and Sykes type I, II, III, IV and V beta-lactamases, staphylococcal penicillins and extended-spectrum beta-lactamases. However, clavulanic acid, which is a potent inhibitor of class III beta-lactamases, is one of the first discovered compounds. We used a total of 645 recent clinical isolates, consisting of 305 Enterobacteriaceae, 180 gram-positive cocci and 160 other gram-negative bacteria to evaluate the ability of beta-lactamase inhibitors for potentiation of piperacillin, ticarcillin and amoxycillin. Minimum inhibitory concentrations for all the 42 strains of methicillin-susceptible Staphylococcus aureus were reduced 4- to 16-fold in the presence of beta-lactamase inhibitors. They were also highly effective in inhibiting the beta-lactamase of a wide variety of gram-negative bacteria, thereby changing their MIC values for amoxycillin, ticarcillin and piperacillin from a 'resistant' to a 'susceptible' range. Commonly resistant bacteria like Klebsiella, Enterobacter, Serratia, Acinetobacter and Pseudomonas were rendered susceptible to piperacillin and ticarcillin in the presence of clavulanic acid, tazobactam and BRL 42715. Of the commercially available formulations for clinical use, piperacillin/tazobactam (Tazocin) was found to be more inhibitory towards both gram-positive and gram-negative bacteria.

Amoxicillin↗
PubMed1996

Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial.

To investigate the effect of oral antibiotics in purely neuropathic ulcers (Wagner grade 1-2, no osteomyelitis), a double blind placebo-controlled study was performed. Forty-four patients were enrolled and subjected to standard treatment with absolute pressure relief (half shoes), daily wound cleansing (topical disinfectant), sterile dressings (specialized nurse). Patients were randomized to an antibiotic (amoxicillin plus clavulanic acid), or placebo. The study was stopped when the antibiotic proved unsuitable according to swab result, or on clinical grounds (no improvement within 6 days of recruitment). Main outcome measure was the ulcer closing rate during 20 days, as assessed by standardized photographs. All ulcers except one were infected. Of the placebo group (n = 22), 2 patients had to be withdrawn within 6 days, versus 3 patients of the antibiotic-group (n = 22). In the placebo group, 10 ulcers were healed versus 6 ulcers in the antibiotic group (NS). Mean (95% CI) reduction in ulcer radius was 0.41 (0.21-0.61) mm day-1 in the placebo group versus 0.27 (0.15-0.39) mm day-1 in the antibiotic group (NS). In conclusion, there is no benefit from antibiotic treatment with amoxicillin plus clavulanic acid as a supplement to standard therapy in uncomplicated neuropathic foot ulcers, provided pressure relief is complete, and wound care is performed strictly supervised. However, a Type-II statistical error cannot be excluded in this small study.

Administration, Oral↗
PubMed1999

Class A beta-lactamases--enzyme-inhibitor interactions and resistance.

Beta-Lactamases of Ambler's Class A are the most commonly encountered mechanism of bacterial resistance to beta-lactam antibiotics. In the face of selective pressure arising from use of either newer cephalosporins or beta-lactam/beta-lactamase inhibitor combinations, mutations arose among Class A beta-lactamase genes, leading to resistance. Clavulanic acid, a naturally occurring clavam, and the penicillanic acid sulfones sulbactam and tazobactam are the inhibitors in clinical use. This review focuses on the mechanism of inhibition by these currently marketed beta-lactamase inhibitors and on the mechanism by which specific amino acid substitutions might lead to resistance. The key amino acid positions important for inhibitor-resistance include Met69, Ser130, Arg244, Arg275, and Asn276. Ser130 is vital to the chemical mechanism of inhibition. Arg244 appears to be coordinated to Arg275 and Asp276 by hydrogen bonds. Arg244 is involved in positioning beta-lactams, especially penicillins and beta-lactamase inhibitors, via their carboxyl groups. Site-directed mutagenesis studies confirm the role of Arg244 and its coordinating partners in beta-lactam turnover and in the reactions leading to enzyme inactivation. This mechanism is dependent on the donation of a proton via a water coordinated to Arg244 and Val216 to clavulanic acid to allow formation of a favorable leaving group. This proton donation is probably not required for formation of a favorable leaving group for the sulfone inhibitors sulbactam and tazobactam. Therefore, some amino acid substitutions have differing effects on inhibition by clavulanic acid compared with the penicillanic acid sulfones. Met69 may play a more structural role in beta-lactam positioning within the oxyanion hole.

Anti-Bacterial Agents↗
PubMed1997

Evaluation of Haemophilus influenzae isolates with elevated MICs to amoxicillin/clavulanic acid.

A 1994 to 1995 national Haemophilus influenzae surveillance study of 1910 strains showed that 13 strains (0.7%) were resistant to amoxicillin/clavulanic acid (MIC, > or = 8/4 micrograms/ml). These and other selected strains were investigated further in this study. Susceptibility of the surveillance study strains was determined with the commercial microdilution trays used in the original study and in triplicate with reference broth microdilution trays prepared by the investigators, as well as by Etest and disk diffusion. Amoxicillin/clavulanic acid resistance was confirmed for only one of the surveillance study strains. This strain produced double zones of growth with Etest and disk-diffusion methods, with the double zone containing spheroplasts. When the amoxicillin/clavulanic acid MICs of all beta-lactamase positive strains were compared, MIC results obtained with surveillance study trays and the Etest were one to two dilutions higher than MICs obtained with reference trays. The distribution and modal amoxicillin/clavulanic acid MICs of beta-lactamase-positive and -negative strains was essentially the same for a comparison group of strains using reference trays, in contrast to a fourfold higher modal MIC for beta-lactamase-positive strains using surveillance study reagents and strains. These differences in MICs could be attributed to variations in inoculum, the presence of spheroplasts, and/or a difference in potency of amoxicillin and/or clavulanic acid in the tray and Etest reagents used. Methods for assessing the adequacy of the clavulanic acid content are not adequate, amoxicillin control values and a beta-lactamase-positive H. influenzae control strain are required.

Amoxicillin↗
PubMed1990

Kinetics of antimicrobial activity of amoxicillin/clavulanic acid and metronidazole against beta-lactamase-producing Bacteroides fragilis group.

Bacteroides fragilis group are the most common anaerobic bacteria isolated in clinical specimens. The use of a beta-lactam with a beta-lactamase inhibitor should result in a marked increase in the group's sensitivity to the beta-lactams. Since the activity (MIC) shown by the amoxicillin + clavulanic acid combination against Bacteroides fragilis group is good, other parameters of in vitro activity have been studied. This study was also done with metronidazole. The minimum inhibitory concentration (MIC) was determined in 26 strains of Bacteroides fragilis group (14 B. fragilis; 5 B. thetaiotaomicron; 4 B. vulgatus; 3 B. distasonis). Likewise, the minimum bactericidal concentration (MBC), the killing curve, the sub-MIC and post-antibiotic effect were determined. The MIC ranged between 0.5 and 32 mg/l. The MBC was two- to four-fold the MIC for amoxicillin/clavulanic acid, and one- to two-fold the MIC for metronidazole for most strains. The killing curve showed a continuous decrease, sloping most sharply between 0-2 hours and 6-8 hours. Amoxicillin + clavulanic acid showed a post-antibiotic effect between 2 and 4 hours. The inhibitory minimum antibiotic concentration was one-half the MIC for most strains.

Amoxicillin↗
PubMed1987

[The frequency of group A beta-hemolytic Streptococcus in acute tonsillopharyngitis and therapy with cefadroxil, clavulanic acid-amoxicillin combination and erythromycin in patients unresponsive to procaine penicillin therapy].

In January, February and March 1987, the frequency of Group A beta hemolytic streptococcus among 468 patients with acute tonsillopharyngitis who admitted to Dr. Sami Ulus Children's Hospital was % 41. Ten day procaine penicillin therapy was not successful in the % 29.5 patients. Cefadroxil (Duricef), clavulanic acid-amoxicillin combination (Augmentin) and erythromycin were tried in these patients. While the success rate of Duricef therapy was % 55, the results of other drug therapies were not been successful.

Acute Disease↗
PubMed1991

Newer beta-lactam agents and the Bacteroides fragilis group.

A continuing nationwide susceptibility survey of the Bacteroides fragilis group, begun in 1981, is being conducted at the New England Medical Center. Review of susceptibility testing in years 1986 through 1988 is reported here. Totals of 557 strains in 1986, 506 in 1987, and 534 in 1988 were obtained from seven centers in the United States. The most active beta-lactam drugs were beta-lactamase-inhibitor combinations ticarcillin-clavulanic acid, ampicillin-sulbactam, cefoperazone-sulbactam and the carbapenem imipenem. These drugs had virtually no resistance detected. Their rank order of activity was imipenem, ampicillin-sulbactam, ticarcillin-clavulanic acid, and cefoperazone-sulbactam, all with activity levels greater than cefoxitin or piperacillin, which, in turn, had activity levels greater than moxalactam, ceftizoxime, cefotetan, cefotaxime, cefoperazone, and ceftazidime. No metronidazole- or chloramphenicol-resistant isolates were found. Clindamycin resistance averaged 6% over the 3 years of testing. Ticarcillin-clavulanic acid, ampicillin-sulbactam, imipenem, and the non-beta-lactam drugs displayed uniform excellent activity against the five species of the B. fragilis group tested. The other beta-lactams displayed significant variability of activity among the various species.

Anti-Bacterial Agents↗
PubMed2001

[Use of levofloxacine in primary care for outbreaks in COPD].

OBJECTIVE: To find scientific evidence to support the indication for treating outbreaks in COPD patients on an out-patient basis with levofloxacine, as against conventional treatments. DESIGN: Standardised review, following the criteria of medicine based on the evidence. A bibliographic search of the MEDLINE data base from 1966 to June 2000 was the basis for an analysis of the evidence found. SETTING: Non-hospital treatment. PATIENTS AND OTHER PARTICIPANTS: COPD patients suffering a light outbreak of probable bacterial origin, according to the Anthonisen criteria. INTERVENTIONS: The intervention analysed was treatment with 500 mg/day of levofloxacine taken orally. An attempt was made to compare this with conventional treatments such as amoxycillin-clavulanic acid and acetyl cefuroxime. The indicators of results analysed were reduction in mortality or in the number of hospital admissions. MEASUREMENTS AND MAIN RESULTS: No clinical trial was found that compared levofloxacine and amoxycillin-clavulanic acid. Two clinical trials were found that compared levofloxacine and acetyl cefuroxime. These found no significant differences between the group treated with levofloxacine and the group treated with cefuroxime. CONCLUSIONS: No scientific evidence demonstrating advantages of levofloxacine treatment over amoxycillin-clavulanic acid was found, or over acetyl cefuroxime as empirical PC first-choice treatment for patients with outbreaks of COPD.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1994

In vitro activity of the tribactam GV104326 against gram-positive, gram-negative, and anaerobic bacteria.

GV104326 is the first member of a new class of antibiotics (tribactams) selected for development. It combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to beta-lactamases, and complete stability to dehydropeptidases. Comparative MICs were determined for GV104326 against 415 recent clinical isolates (including beta-lactamase producers), using representative antibacterial agents (imipenem, amoxicillin-clavulanic acid, cefpirome, ciprofloxacin, gentamicin, and erythromycin). GV104326 was particularly active against gram-positive bacteria; in general, its in vitro activity was equivalent to that of imipenem, equivalent to or better than that of amoxicillin-clavulanic acid, and superior to that of cefpirome, ciprofloxacin, and erythromycin. Against gram-negative bacteria, GV104326 possessed activity similar to that of imipenem and cefpirome against enterobacteria and Haemophilus spp. but its activity was superior to that of amoxicillin-clavulanic acid. GV104326 showed excellent antianaerobe activity. GV104326 was stable to all clinically relevant beta-lactamases and was rapidly lethal to susceptible bacteria. In Escherichia coli, GV104326 bound predominantly to PBPs 1a and 2 and at low concentrations osmotically stable round forms were observed. GV104326 showed an affinity for PBPs 2 and 4 of Staphylococcus aureus.

Anti-Bacterial Agents↗
PubMed1998

beta-Lactamase-producing strains in the species Prevotella intermedia and Prevotella nigrescens.

A total of 96 strains were collected that included laboratory strains and clinical isolates classified Prevotella intermedia sensu lato and the type strains of the species P. intermedia sensu stricto and Prevotella nigrescens. Susceptibility to amoxicillin and amoxicillin-clavulanic acid was determined by the Etest. PCR-DNA probe assays were used to speciate each strain as P. intermedia sensu stricto or P. nigrescens. By Etest, 71 strains (74%) were susceptible to both amoxicillin and amoxicillin-clavulanic acid with minimum inhibitory concentrations in the 0.016-0.064 microgram/ml range. In contrast, amoxicillin minimum inhibitory concentrations of 25 strains (26%) were in the range of 1.5-96 micrograms/ml with concomitant amoxicillin-clavulanic acid minimum inhibitory concentrations in the low range 0.016-0.38 microgram/ml, indicating a production of beta-lactamase as confirmed by nitrocefin tests. Of these beta-lactamase-producing strains, 20% (5/25) were identified as P. intermedia sensu stricto by the PCR-DNA probe assay and 72% (18/25) as P. nigrescens. Our results provide support for the major role of P. nigrescens in the failure of therapy using beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed2004

[Bacteriologic features of urinary tract infections in children in the Sousse area, Tunisia].

Urinary tract infection (UTI) is frequent in childhood. Our purpose is to determine the bacteriologic profile of UTI in children through a retrospective study of 1281 urinary specimens analysed in the Laboratory of Microbiology of F. Hached University hospital of Sousse between 1997 and 2002 (2000 except). The most frequent pathogens recovered were E. coli (71%), K. pneumoniae (10%) P. mirabilis (8%), Staphylococcus (1.6%), P. aeruginosa (1%) and others (2%). E. coli susceptibility to antibiotics was characterised by the high resistance percentage to amoxicillin (60%), to amoxicilline - acid clavulanic (54%) and to cotrimoxazole (40%). The resistance percentage to third generation cephalosporins, to aminoglycosides and to nitrofurane remained very low, respectively of 1.5%, 1% and 1%. High resistance rates among K. pneumoniae strains towards to amoxicillin - acid clavulanic and Cefotaxim, respectively of 63 and 39% were noticed. The resistance percentages to amikacin and cotrimoxazole were respectively of 17 and 65%, but only of 4% to nitrofurane. 70% of P. mirabilis strains were resistant to amoxicillin, 63% of them remained susceptible to amoxicillin - acid clavulanic. No resistance was shown to amikacin against 31% towards cotrimoxazole.

Bacteria↗
PubMed2007

Biochemical characterisation of the CTX-M-14 beta-lactamase.

Cefotaxime-resistant Escherichia coli TUM1121 was isolated from an abscess of an 83-year-old patient. The CTX-M-14 gene was located on a 70 kb plasmid. The enzyme was purified and its activity was analysed. CTX-M-14 was poorly active against ceftazidime and aztreonam. Aztreonam behaved as a competitive inhibitor. Among the tested suicide substrates for class A beta-lactamases, sulbactam was a rather good substrate. Tazobactam and clavulanic acid behaved as inactivators. The interactions between clavulanic acid and CTX-M-14 were characterised by progressive inactivation of the beta-lactamase. Carbapenems such as imipenem, meropenem or doripenem did not behave as inactivators of CTX-M-14, however very small k(cat) values were observed. This result shows that CTX-M-14 is able to hydrolyse carbapenems.

Cloning, Molecular↗
PubMed2007

Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests.

BACKGROUND: Up to 10% of the patients in whom suspected betalactam hypersensitivity (HS) has been excluded by skin and challenge tests report suspected allergic reactions during subsequent treatments with the same or very similar betalactams. It has been suggested that the reactions may result from a resensitization induced by the challenge performed at the time of the allergological work-up. However, most patients did not undergo a second allergological work-up, to determine if the reactions resulted from betalactam HS or not. OBJECTIVES: We aimed to determine if children diagnosed nonallergic to betalactams have tolerated subsequent treatments with the initially suspected and/or other betalactams, and, in case of a reaction, if the reaction resulted from betalactam HS. METHODS: We sent a questionnaire concerning the clinical history of their children to the parents of 256 children previously diagnosed nonallergic to betalactams. A second allergological work-up was performed in the children reporting suspected allergic reactions during subsequent treatments with the same and/or other betalactams. Skin tests were performed with the soluble form of the suspected (or very similar) betalactams and other betalactams from the same and other classes. Skin test responses were assessed at 15-20 min (immediate), 6-8 h (semi-late) and 48-72 h (late). Oral challenge (OC) was performed in children with negative skin tests, either at the hospital (immediate and accelerated reactions), or at home (delayed reactions). RESULTS: A response was obtained from 141 children (55.3%). Forty-eight (34%) of those children had not been treated with the betalactams for whom a diagnosis of allergy had been ruled out previously. Seven (7.5%) of the 93 children who had been treated again reported suspected allergic reactions. Skin tests and OC were performed in six of those children, and gave negative results in five children. In one child previously diagnosed nonallergic to amoxicillin associated with clavulanic acid, we diagnosed a delayed HS to clavulanic acid and a serum sickness-like disease to cefaclor. Thus, the frequency of reactions resulting from betalactam HS in children with negative skin and challenge tests is very low, and does not exceed 2.1% (2/93) if we consider that the child which refused a second allergological work-up is really allergic to betalactams. CONCLUSION: Our results in a very large number of children show that reactions presumed to result from betalactam HS are rare in children in whom the diagnosis of betalactam allergy has been ruled out previously. Moreover, they suggest that, as shown for the initial reactions, most of the reactions during subsequent treatments are rather a consequence of the infectious diseases for whom betalactams have been prescribed than a result of betalactam HS. Finally, they suggest that the risk of resensitization by OC is very low, and do not support the notion that skin testing should be repeated in children diagnosed nonallergic to betalactams.

Administration, Oral↗