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There are very limited data on ticarcillin-clavulanate elimination by haemofiltration. We measured in vitro ticarcillin-clavulanate adsorption to polyacrylonitrile (PAN) filters and the sieving coefficient using a well-described bench model of haemofiltration. The dose of ticarcillin-clavulanate was 60/2 mg or 180/3 mg, and 0 or 12 g albumin was added to the 1 L of circulating blood-crystalloid mixture to produce four different experimental conditions. The experiment was repeated four times under each condition. Median (interquartile range [IQR] ) ticarcillin adsorption varied from 28 (27-30) mg to 85 (78-90) mg. Adsorption was increased when the dose of ticarcillin was higher (P

Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (n = 3) and additive (n = 2) effects of TLc + AT against SPM-1 producers, while TLc + C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLc + AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.

Inducible expression of L1 and L2 β-lactamases is the principal mechanism responsible for β-lactam resistance in Stenotrophomonas maltophilia. Ticarcillin-clavulanate (TIM) is one of the few effective β-lactams for S. maltophilia treatment. Clavulanate (CA) is a β-lactamase inhibitor that specifically targets class A, C, and D β-lactamases. In view of the presence of class B L1 β-lactamase, it is of interest to elucidate why TIM is valid for S. maltophilia treatment. The L1-L2 allelic variation and TIM susceptibilities of 22 clinical isolates were established. Based on L1 and L2 protein sequences and TIM susceptibility, three L1-based phylogenetic clusters (L1-A, L1-B, and L1-C) and three L2-based phylogenetic clusters (L2-A, L2-B1, and L2-B2) were classified. The contribution of each L1- and L2-based phylogenetic cluster to ticarcillin (TIC) and TIM susceptibility was investigated. All the L1s and L2s tested contributed to TIC resistance. The L1s tested were inert to CA; nevertheless, the sensitivities of L2s to CA were widely different. In addition, the genetic organizations upstream of the L1 gene varied greatly in these isolates. At least three different L1 promoter structures (K279a type, D457 type, and none) were found among the 22 isolates assayed. The differences in the L1 promoter structure had a great impact on TIC-induced L1 β-lactamase activities. Collectively, the L1 promoter activity in response to TIC challenge and L2 susceptibility to CA are critical factors determining TIM susceptibility in S. maltophilia.

A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C.Medical records of subjects aged18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed.Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P.001; r = 0.260, P.001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments.Although our results need to be confirmed, they suggest that children receiving long courses of therapy (2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C.

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

BACKGROUND: The empirical use of antibiotic treatments is widely accepted as a means to treat cancer patients in chemotherapy who have fever and neutropenia. Intravenous monotherapy, with broad spectrum antibiotics, of patients with a high risk of complications is a possible alternative. METHODS: We conducted a prospective open-label, randomized study of patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy. Patients received either monotherapy with ticarcillin/clavulanic acid (T) or ceftriaxone plus amikacin (C+A). RESULTS: Seventy patients who presented 136 episodes were evaluated, 68 in each arm of the study. The mean neutrophil counts at admission were 217cells/mm³ (T) and 201cells/mm³ (C+A). The mean duration of neutropenia was 8.7 days (T) and 7.6 days (C+A). Treatment was successful without the need for modifications in 71% of the episodes in the T group and 81% in the C+A group (p=0.23). Treatment was considered to have failed because of death in two episodes (3%) in the T group and three episodes (4%) in the C+A group, and because of a change in the drug applied in one episode in the T group and two episodes in the C+A group. Overall success was 96% (T) and 93% (C+A). Adverse events that occurred in group T were not related to the drugs used in this study. CONCLUSION: In pediatric and adolescent patients with leukemia or lymphoma, who presented with fever and neutropenia, during chemotherapy, ticarcillin/clavulanic acid was as successful as the combination of ceftriaxone plus amikacin. It should be considered an appropriate option for this group of patients at high risk for infections.

The prevalence of Stenotrophomonas maltophilia resistance to ticarcillin-clavulanate has dramatically increased in our hospital over the past few years. Sixty-six clinical isolates, collected from 61 patients, were tested for antibiotic susceptibility and genotyped by two different enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) systems. Although two small outbreaks were identified in the medical intensive care unit, the remaining 58 strains generated 48 different PCR patterns. The rapid emergence of resistance in S. maltophilia occured in absence of an epidemic and was probably influenced by increasing-b-lactam use in our hospital.

A total of 303 bacterial strains isolated from bronchoaspirates of Intensive Care Unit (ICU) patients, collected through June and December 1993, were tested for susceptibility to ticarcillin/clavulanic acid, imipenem, amikacin, ceftazidime, ciprofloxacin and piperacillin. The minimal inhibitory concentration (MIC) for each antibiotic was determined according to the NCCLS, by means of serial dilution on microplates. The isolates, 80.8% of which were beta-lactamase producing strains, belonged to Pseudomonas aeruginosa (79 strains), Pseudomonas fluorescens (8 strains), Xanthomonas maltophila (25 strains), Escherichia coli (16 strains), Klebsiella-Enterobacter-Serratia (KES) (62 strains), Proteus spp. (15 strains), Acinetobacter spp. (22 strains), Moraxella spp. (15 strains), Bacteroides catarrhalis (8 strains), Haemophilus spp. (11 strains), Staphylococcus aureus (32 strains), Enterococcus faecalis (10 strains). The highest rate of susceptibility to ticarcillin/clavulanic acid (100%) was detected among E. faecalis (MIC 2-16 micrograms/ml), B. catarrhalis (MIC 1-4 micrograms/ml) and Haemophilus spp. (MIC 1-4 micrograms/ml). Among the non-fermenting microorganisms ticarcillin/-clavulanic acid showed good activity toward P. aeruginosa and P. fluorescens (86% and 75% respectively). It was also very active against X. maltophilia with a susceptibility of 96%. Susceptibility to the other antibiotics tested was within the range of 16% and 28%.

The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.

Susceptibility tests were performed on 2402 of consecutive isolates of Enterobacteriaceae and 254 strains of Pseudomonas aeruginosa in five separate medical centres. Five beta-lactams were evaluated with and without a beta-lactamase inhibitor. The effect of different inhibitors was species specific and the rank order of decreasing efficacy against all enteric bacilli was: cefoperazone-sulbactam > piperacillin-tazobactam > cefoperazone > ticarcillin-clavulanic acid > piperacillin > co-amoxiclav > ampicillin-sulbactam > ticarcillin > ampicillin > amoxycillin.

The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.

Resume Xanthomonas maltophilia est une bacterie opportuniste susceptible d'entrainer des infections severes en particulier chez les malades hospitalises en reanimation. Les principaux problemes poses par l'isolement de ce germe sont la necessite de distinguer colonisation et infection et sa multiresistance habituelle aux antibiotiques. Une etude sur 31 souches isolees aux CHU de Dijon et de Nice a montre que l'ensemble des souches produisait une metalloenzyme entrainant une resistance constante a l'imipeneme ; 28 souches produisaient egalement une beta-lactamase inductible hydrolysant la ticarcilline, la piperacilline, le cefotaxime, la ceftazidime et l'aztreonam. Parmi les combinaisons beta-lactamines/inhibiteurs de beta-lactamases testees, seule l'association de l'acide clavulanique avec la ticarcilline ou l'aztreonam a montre une synergie. L'activite de la formulation ticarcilline + acide clavulanique a ete confirmee chez 13 malades hospitalises dans le service de reanimation de l'hopital Nord du CHU d'Amiens et traites, en monotherapie dans 10 cas, pour pneumopathie ou septicemie. Une guerison clinique et une eradication bacteriologique ont ete obtenues dans 12 cas sur 13. La formulation ticarcilline + acide clavulanique seule ou en association aux quinolones constitue donc une therapeutique efficace in vitro et in vivo des infections a Xanthomonas maltophilia .

Resume La neutropenie associee a la chimiotherapie represente actuellement une cause majeure de morbidite et de mortalite des traitements antineoplasiques en particulier dans la situation extreme de la greffe de moelle osseuse. Dans cette situation de neutropenie, une antibiotherapie probabiliste doit etre administree qui doit se baser non pas exclusivement sur la frequence des germes rencontres mais plutot sur la gravite potentielle des germes en cause. Le Claventin® a deja ete utilise avec succes chez le neutropenique notamment en association avec des aminosides. Pendant une periode de 16 mois, 115 patients consecutifs receveurs de greffe de moelle ont recu de facon empirique une association de Claventin® + tobramycine avec adjonction a 48 heures de vancomycine en cas de non reponse totale de l'hyperthermie. Cent sept patients sont evaluables et ont presente 108 episodes febriles. Trente-sept episodes (34 %) ont ete documentes (Staphylocoque coag neg : 20 (47 %); Staphylococcus aureus : 2 (5 %); Streptocoque : 10 (24 %); Gram negatif : 3 (8 %). Un succes primaire a ete obtenu pour 84 % des patients avec l'association Claventin®-tobramycine, associee ou non a la vancomycine et/ou l'amphotericine B administrees dans 59 % et 40 % des cas respectivement avant la 48eme heure. Une modification de l'antibiotherapie initiale a ete necessaire chez 14 % des patients. Un patient est decede d'infection (Pseudomonas aeruginosa). Ces resultats confirment la bonne adequation de la strategie Claventin® + tobramycine ± vancomycine et de la posologie choisie de Claventin® (3 g × 4).

A model of localised abscess formation was used to establish mixed infections caused by Escherichia coli and Bacteroides fragilis. The beta-lactamase producing, ticarcillin-resistant strains E. coli E96 and B. fragilis VPI 8708 were used to produce one infection, and in another infection, a beta-lactamase hyperproducing strain E. coli 41548 was combined with a ticarcillin-susceptible strain, B. fragilis B3. Treatment, at doses producing clinically achievable concentrations in mouse serum, began 1 h after inoculation, and continued three times daily for four days. Bacterial numbers in infected tissue were measured at intervals. Against both infections, ticarcillin was ineffective in preventing bacterial growth and abscess formation in all mice. Piperacillin prevented abscess formation in 60% of the mice infected with E. coli E96/B. fragilis VPI 8708, and in 40% of those in the E. coli 41548/B. fragilis B3 group. Therapy with ticarcillin/clavulanic acid or cefoxitin reduced the number of both organisms at the site of infection, and thus prevented abscess formation in 100% treated animals.

Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen, causing infections whose management is often problematic due to its inherent resistance to many antibiotics, making co-trimoxazole the main therapeutic option. However, there are cases in which either due to antimicrobial resistance or allergic reactions and intolerance to co-trimoxazole this antibiotic cannot be administered. We sought to evaluate the available clinical evidence regarding potentially effective alternative antibiotics for the treatment of S. maltophilia infections.The literature search was performed in the PubMed and Scopus databases. The search string used was 'Stenotrophomonas maltophilia OR Xanthomonas maltophilia'.Thirty-one case reports and 5 case series were retrieved including a total of 49 patients with a variety of infections. Twenty of 49 cases (40.8%) were treated with ciprofloxacin as monotherapy or in combination with other antibiotics; 12 of 49 cases (24.5%) were treated with ceftriaxone- or ceftazidime-based regimens; and 6 of 49 cases (12.2%) were treated with ticarcillin- or ticarcillin/clavulanate-based regimens. The cure or improvement rates were 18 cases (90%), 8 (75%) and 4 (66.7%), respectively. The remaining 11 patients received various antimicrobials including aminoglycoside-based regimens, carbapenems, levofloxacin, chloramphenicol, aztreonam, minocycline and other beta-lactams.The limited available data suggest that ciprofloxacin, ceftazidime or ceftriaxone, and ticarcillin/clavulanate, alone or in combination with other antibiotics, may be considered as alternative options beyond co-trimoxazole.

We evaluated the efficacy of ticarcillin-clavulanic acid plus amikacin (TCA) with ceftazidime plus amikacin (CFA) as empiric therapy of fever in acute leukemia in a total of 127 episodes. The overall success rate of the therapy (survival) was 93% in TCA group and 92% in CFA group. Success without therapy modifications (afebrile at 72 hours) was 39% for TCA, 31% for CFA; success with modifications was 55% and 61% respectively. Failure (death due to documented or presumed infection) was 6% for TCA and 8% for CFA. Differences were not statistically significant. The success without modifications was higher in the group of patients with fever of unknown origin (FUO) than in documented infections (DI), mainly with CFA. No differences were documented in the resistance rate and in clinical outcome during severe neutropenia (ANC100 microl). In our experience TCA is as effective as CFA as first-line treatment in severe neutropenic patients with acute leukemia, although in both regimens patients with DI are likely to require modifications in treatment.

The exposure of bacteria to various groups of antimicrobials at different concentrations can produce damage to the bacteria that persists even after removal of the antimicrobial agent. The post antibiotic effect (PAE) of beta-lactams on aerobic gram-negative bacilli is relatively short (

This study tested whether levofloxacin, at a new high dose of 750 mg, was effective for the treatment of complicated skin and skin-structure infections (SSSIs). Patients with complicated SSSIs (n=399) were randomly assigned in a ratio of 1:1 to 2 treatment arms: levofloxacin (750 mg given once per day intravenously [iv], orally, or iv/orally) or ticarcillin-clavulanate (TC; 3.1 g given iv every 4-6 hours) followed, at the investigator's discretion, by amoxicillin-clavulanate (AC; 875 mg given orally every 12 hours). In the clinically evaluable population, therapeutic equivalence was demonstrated between the levofloxacin and TC/AC regimens (success rates of 84.1% and 80.3%, respectively). In the microbiologically evaluable population, the overall rate of eradication was 83.7% in the levofloxacin treatment group and 71.4% in the TC/AC treatment group (95% confidence interval, -24.3 to -0.2). Both levofloxacin and TC/AC were well tolerated. These data demonstrate that levofloxacin (750 mg once per day) is safe and at least as effective as TC/AC for complicated SSSIs.

Um total de 40 cepas do grupo B. fragilis foi isolada de espécimes clínicos em dois centros hospitalares de Fortaleza no período de 1993 a 1997. A espécie mais frequentemente isolada foi Bacteroides fragilis (19 cepas) tendo a maioria dos microrganismos sido isolada de infecção intra-abdominal e ferida cirúrgica infectada. Foi traçado o perfil de sensibilidade à cefoxitina, cefoperazona e associação ticarcilina-ácido clavulânico, utilizando-se o método de referência de diluição em ágar. Todas as espécies testadas apresentaram sensibilidade à ticarcilina-ácido clavulânico (128/2mig/ml). Percentuais de resistência de 15 e 70% foram detectados para cefoxitina (64mig/ml) e cefoperazona (64mig/ml) respectivamente. A espécie B. fragilis apresentou os menores percentuais de resistência quando comparada com as demais espécies do grupo. Estes resultados regionais permitem uma melhor orientação na escolha deste grupo de antibióticos, para profilaxia ou terapêutica, principalmente com relação à cefoxitina que é frequentemente empregada nos centros hospitalares estudados. A total of 40 strains of the B. fragilis group was isolated from clinical specimens in two hospital centers in Fortaleza from 1993 to 1997. The most frequently isolated species was Bacteroides fragilis (19 strains) and most isolates came from intra-abdominal and wound infections. The susceptibility profile was traced for cefoxitin, cefoperazone and ticarcillin-clavulanate by using the agar dilution reference method. All isolates were susceptible to ticarcillin-clavulanate (128/2mug/ml). Resistance rates of 15 and 70% were detected to cefoxitin (64mug/ml) and cefoperazone (64mug/ml), respectively. Such regional results permit a better orientation in choosing this group of antibiotics for prophylaxis and therapy especially in relation to cefoxitin, which is frequently used in the hospital centers studied.

A mouse model of intestinal colonization with vancomycin-resistant enterococci (VRE) was used to study the effect of different beta-lactam antibiotics on establishment of VRE colonization. A clinical VanB VRE isolate, Enterococcus faecium C68 (102 or 104 cfu), was inoculated by gastric gavage in conjunction with subcutaneous administration of antibiotics. The MIC of ceftriaxone and ticarcillin against VRE strain C68 is >10,000 microg/mL, and the MIC of piperacillin is 1250 microg/mL. Ceftriaxone and ticarcillin-clavulanate treatment groups developed persistently high levels of stool VRE compared with both the saline and the piperacillin-tazobactam (Pip-Taz) groups (P

Quality control guidelines for standardized antimicrobial susceptibility test methods are critical to the continuing accuracy of the tests. In this report, quality control limits were proposed for 22 organism-antimicrobial combinations with minimum inhibitory concentration (MIC) ranges of three or four log2 dilution steps. Disk diffusion zone diameter ranges were proposed for azithromycin compared with Neisseria gonorrhoeae ATCC 49226 and ticarcillin with and without clavulanic acid tested against Staphylococcus aureus ATCC 25923. The data from five or six participating laboratories produced > or = 94.7% of results within proposed MIC limits, and 94.3%-99.0% of zones were found within suggested zone guidelines. These proposed quality control ranges should be validated by in-use results from clinical laboratories.

The efficacy of an antimicrobial agent in the therapy of infection depends upon the interaction of bacteria, antibiotic and phagocytes. The influence of both ticarcillin/clavulanic acid and amoxycillin/clavulanic acid on the phagocytic and bactericidal activity of human PMNs in vitro was investigated. The results show that clavulanic acid, with its beta-lactamase inhibitory properties, potentiated the efficacy of both ticarcillin and amoxycillin, resulting in a significantly increased susceptibility of a beta-lactamase producing strain of Klebsiella pneumoniae to phagocytic and microbicidal activities of human PMNs. Overall, amoxycillin/clavulanic acid showed greater enhancement of the killing of K. pneumoniae by human PMNs.

The activity of 14 antimicrobial agents against 253 clinical isolates of anaerobic bacteria from pediatric infections was assessed by the agar dilution method. Fifty-eight percent of the isolates were from intraabdominal sites. The drugs tested were ampicillin/sulbactam, ticarcillin/clavulanate, ampicillin, sulbactam, piperacillin, cefoxitin, cefotaxime, cefoperazone/sulbactam, clarithromycin, azithromycin, erythromycin, clindamycin, metronidazole, and chloramphenicol. Ticarcillin/clavulanate was active against all isolates. Clarithromycin was the most active macrolide; combination of this agent with its 14-hydroxy metabolite did not result in synergy. Sixty-two percent of Bacteroides fragilis group isolates, 13% of B. fragilis isolates, and 22% of peptostreptococcal isolates were resistant to clindamycin at a concentration of 4 micrograms/mL. The distribution of these strains in clinical specimens and the patterns of antimicrobial susceptibility documented were different from the findings for isolates from adults in the Los Angeles area.

MICs of eight beta-lactams (piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone) were determined by agar dilution against 64 penicillin-susceptible, 70 intermediately penicillin-resistant, and 66 fully penicillin-resistant pneumococci. The MICs of piperacillin with and without tazobactam for 90% of the susceptible, intermediately resistant, and resistant strains tested (MIC90s) were < or = 0.064, 2.0, and 4.0 micrograms/ml, respectively. By comparison, those of ampicillin with and without sulbactam were 0.125, 2.0, and 4.0 micrograms/ml and those of ceftriaxone were < or = 0.064, 1.0, and 2.0 micrograms/ml, respectively. Strains were less susceptible to ticarcillin with and without clavulanate (MIC90s, 2.0, 64.0, and 128.0 micrograms/ml) and ceftazidime (MIC90s, 1.0, 8.0, and 32.0 micrograms/ml).

A five-laboratory coordinated study was undertaken to determine whether ticarcillin and ticarcillin-clavulanic acid disk susceptibility tests could accurately detect resistance among enteric bacilli. Each facility performed disk tests and broth microdilution susceptibility tests with reagents distributed from a common source, and appropriate controls were included in order to ensure methodologic uniformity. Each institution tested 500 consecutively isolated enteric bacilli against ticarcillin and ticarcillin-clavulanic acid. The prevalence of discrepancies between disk tests and dilution tests with 2,435 unselected enteric bacilli provided a valid estimate of the true error rate for tests with the two disks. The current interpretive criteria for susceptibility tests with ticarcillin and ticarcillin-clavulanic acid disks were found to be reliable; i.e., there were major or very major discrepancies between MIC categories and disk test results for less than 1% of all strains and minor discrepancies for only 5 to 10%. Even lower error rates would occur if the zone size-interpretive criteria were modified, but at this time it is difficult to determine whether the practical problems created by making such changes can be justified by the magnitude of the problem that is being resolved.

The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log10 CFU/g), or delayed until 24 h after infection, when the vegetations usually contained greater than 9 log10 CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by beta-lactamase-producing strains of S. aureus, illustrating the beta-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal beta-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.

A model of acute Legionella pneumophila pneumonia in neutropenic weanling rats was developed as a means of assessing the efficacies in vivo of the beta-lactams ticarcillin, ticarcillin-clavulanic acid, and clavulanic acid, agents active against the organism in vitro. Weanling rats were dosed with cyclophosphamide 3 days before and immediately prior to infection by intrabronchial intubation with L. pneumophila. The bacteria persisted in the lungs of untreated animals at high counts (5.0 to 7.0 log10 CFU/g of lung tissue) for up to 168 h after infection, and the histological characteristics of the infection were similar to those of the disease in humans. Transmission electron micrography revealed the presence of L. pneumophila multiplying within alveolar macrophages. Therapy with ticarcillin was ineffective in reducing the bacterial numbers in the lung tissue, whereas ticarcillin-clavulanic acid and clavulanic acid were active, producing bactericidal effects similar to those of erythromycin. The ticarcillin-clavulanic acid combination was significantly more efficacious (P less than 0.01) than corresponding doses of clavulanic acid alone. Synergistic activity between ticarcillin and clavulanic acid against L. pneumophila has been demonstrated in vivo, and the combination showed activity similar to that of erythromycin.

Postpartum endometritis continues to be the leading cause of morbidity following cesarean section. This infection is commonly polymicrobial, involving aerobic, facultative, and obligate anaerobic gram-negative bacteria as well as gram-positive bacteria. The major risk factor for the development of post-cesarean section endometritis is duration of labor with ruptured amniotic membranes of greater than 6 hours. The most frequently utilized antibiotic regimen employed for treatment of postpartum endometritis is the combination of clindamycin and gentamicin. The combination ticarcillin/clavulanate has a spectrum of activity resembling that of clindamycin and gentamicin. In the data reported, cure rates among patients treated with ticarcillin/clavulanate were similar to the rates for those treated with clindamycin plus gentamicin as well as those for cefoxitin.

Recent reports of decreased susceptibility to amoxycillin/clavulanate and ticarcillin/clavulanate combinations amongst Escherichia coli isolates have been attributed to an increased frequency of hyperproduction of TEM-1 beta-lactamase. To test this claim we compared the activities of clavulanate combinations against consecutive E. coli isolates producing TEM-1 beta-lactamase that were obtained from clinical material at The London Hospital during 1982 (n = 50) and 1989 (n = 46). Enzyme production was quantified and related to the level of clavulanate required to potentiate amoxycillin and ticarcillin. The levels of TEM-1 enzyme production varied 150-fold amongst the isolates, partly because of variation in the gene copy number. A clear correlation existed between enzyme quantity and levels of resistance to the clavulanate combinations. However, there was no significant difference (P greater than 0.05, Mann-Whitney U test) between the isolates obtained in 1982 and 1989 in terms of the clavulanate concentrations required to potentiate the penicillins, or in the distribution of beta-lactamase activities present.

Beta-Lactamase production and agar dilution sensitivities to amoxycillin, amoxycillin/clavulanate, ticarcillin, ticarcillin/clavulanate, cefoxitin, imipenem and metronidazole were determined for 737 Bacteroides fragilis group strains isolated between 1986 and 1988 from 33 US centres. The strains comprised 441 B. fragilis, 114 B. thetaiotaomicron, 35 B. ovatus, 58 B. distasonis, 58 B. vulgatus, 26 B. uniformis and five B. caccae. Overall, addition of clavulanate lowered the geometric mean MICs of of amoxycillin from 46.7 to 0.6 mg/l, and of ticarcillin from 37.2 to 1.3 mg/l. Addition of clavulanate increased the number of strains sensitive to amoxycillin from 9.5% to 90.0%, and to ticarcillin from 68.0% to 98.6%. However, synergy was not observed following addition of clavulanate to amoxycillin and ticarcillin for 48 strains (6.5%). These comprised 15 B. fragilis, two B. ovatus, 21 B. distasonis, six B. vulgatus and four B. uniformis strains. Ten of the 15 non-synergic B. fragilis isolates had the features of B. fragilis homology group II and were susceptible to amoxycillin alone; the other five strains were resistant to amoxycillin and ticarcillin. Geometric mean MICs (% susceptibility) of the non-synergic strains were as follows: amoxycillin, 6.2 mg/l (68.8); amoxycillin/clavulanate, 4.8 mg/l (72.9); ticarcillin, 11.8 mg/l (75.0); ticarcillin/clavulanate, 9.4 mg/l (77.1). Twenty-six strains (3.5% were resistant (greater than 32 mg/l) to cefoxitin, and two strains (0.3%) were resistant (4 mg/l) to imipenem. All were susceptible to metronidazole. Thus, on the basis of in-vitro activity, metronidazole, imipenem, ticarcillin/clavulanate, cefoxitin and amoxycillin/clavulanate are indicated for treatment of infections with B. fragilis strains. The clinical significance of the lack of synergy with clavulanate in the B. fragilis group is unclear; relatively low beta-lactam MICs for most of these strains suggests that they may be amenable to therapy with high doses of beta-lactams. Results of this study indicate that it cannot be assumed that clavulanate will uniformly inhibit beta-lactamases in the B. fragilis group (especially B. distasonis) and indicate the need for identification and susceptibility testing, especially in cases of serious infections with these strains.

beta-Lactamase production (nitrocefin disk method) and agar dilution susceptibility of amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole were determined for 320 Bacteroides species (not Bacteroides fragilis group) and 129 fusobacteria from 28 U.S. centers. Overall, 64.7% of Bacteroides species and 41.1% of fusobacteria were beta-lactamase positive. Among the Bacteroides species, positivity rates were highest for B. bivius (85.0%), followed by B. splanchnicus (83.3%), B. eggerthii (77.8%), and B. oralis (77.1%); 54.5% of black-pigmented Bacteroides species were beta-lactamase positive. Among the fusobacteria, Fusobacterium mortiferum showed the highest rate of beta-lactamase positivity (76.9%). MICs of amoxicillin (128 micrograms/ml) and ticarcillin (64 micrograms/ml) for 90% of all beta-lactamase-positive strains were reduced to 4 and 2 micrograms/ml, respectively, with the addition of clavulanate. MICs of amoxicillin and ticarcillin for 90% of all beta-lactamase-negative strains were 1 and 4 micrograms/ml, respectively, and greater than or equal to 98.4% of the strains were susceptible to the beta-lactams tested. Of the beta-lactamase-producing strains, 45.9% were susceptible to amoxicillin at less than or equal to 4 micrograms/ml and 93.4% were susceptible to ticarcillin at less than or equal to 64 micrograms/ml; the addition of clavulanate raised the rates to 90.4 and 100%, respectively. All strains were susceptible to cefoxitin, imipenem, and metronidazole. The activity of amoxicillin against 29 beta-lactamase-producing strains (10 Bacteroides species and 19 fusobacteria) was not enhanced by the addition of clavulanate; however, 82.7% of these strains were susceptible to amoxicillin, and all were susceptible to ticarcillin. Although beta-lactamase positivity is on the increase in non-B. fragilis group Bacteroides species and fusobacteria, amoxicillin-clavulanate, ticarcillin, cefoxitin, imipenem, and metronidazole should be suitable for the treatment of infections with these strains. The addition of clavulanate does not appreciably improve the efficacy of ticarcillin against these organisms.

The susceptibility of 234 Bacteroides non-fragilis strains and 56 fusobacteria from 12 European centers to amoxicillin, amoxicillin/clavulanate, ticarcillin, ticarcillin/clavulanate, cefoxitin, imipenem and metronidazole was tested and related to beta-lactamase production. Beta-lactamase production was detected in 42.3 % of the Bacteroides strains and 26.8% of the fusobacteria. The MIC90 of amoxicillin for beta-lactamase-negative strains was 0.5 microgram/ml and the MIC90 of ticarcillin 2.0 micrograms/ml. In the case of beta-lactamase-positive strains the MIC90 of amoxicillin (32 micrograms/ml) and ticarcillin (16 micrograms/ml) dropped to less than or equal to 1.0 microgram/ml upon addition of clavulanate; 65.8% of these strains were susceptible to amoxicillin and 98.2% to ticarcillin, but all were susceptible when clavulanate was added. All strains were susceptible to imipenem and metronidazole, and 99.3% to cefoxitin.

The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log10 CFU/g), or delayed until 24 h after infection, when the vegetations usually contained greater than 9 log10 CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by beta-lactamase-producing strains of S. aureus, illustrating the beta-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal beta-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.

A clinical trial with Timentin (ticarcillin plus clavulanic acid) was undertaken in patients with hospital-acquired lower respiratory tract infections. Two formulations, 3.2 and 5.2 g consisting of 200 mg clavulanic acid and 3 or 5 g ticarcillin, respectively were usually given three times daily. Eighty-one patients were evaluable for clinical efficacy and 89 for tolerance. The clinical cure rate was 96% of the assessable cases even though all patients had severe concurrent or underlying diseases. The pronounced synergism between ticarcillin and clavulanic acid resulted in a bacteriological elimination rate of 94%. Adverse effects were very rare and of a mild nature, and restricted to those usually seen with the well-tolerated penicillins. No toxicological abnormalities could be detected in extensive laboratory screening. Timentin is a highly effective broad-spectrum antibiotic with good tolerance. Its potentiated action in comparison to other penicillins against beta-lactamase-producing strains, could reduce the usage of aminoglycosides in the future.

The safety and tolerance of four intravenous formulations of Timentin (ticarcillin + clavulanic acid) have been evaluated in 1659 patients (1512 adults and 147 paediatric) included in clinical trials conducted in Europe and U.S.A. Timentin 3.2 and 5.2 g were administered respectively to 877 and 635 adults and Timentin 1.6 and 2.6 g to 117 and 30 paediatric patients three, four or six times daily for between 7.7 and 9.0 days in adults and 8.0 and 12.0 days in paediatric cases. Patients with septicaemia were 16%, 14% and 28% respectively of the Timentin 3.2, 5.2 g and paediatric groups, which together with respiratory tract and other serious miscellaneous infections accounted for the majority of cases treated within these three groups. Of the 1659 patients studied, 161 adverse reactions were reported from 151 patients (9.1%), 36 of which (2.2%) resulted in discontinuation of treatment. The reactions were at the injection site in 86 cases (5.2%), hypersensitivity in 35 (2.1%) and miscellaneous systemic symptoms in 40 cases (2.4%). Local reactions, i.e. phlebitis, pain and erythema, were self-limiting and did not necessitate early cessation of treatment. Hypersensitivity reactions occurred equally in all groups and necessitated cessation of treatment in about half of the patients. Gastro-intestinal disturbances were observed in eight, four and one patient within the Timentin 3.2, 5.2 g and paediatric groups. Changes in haemostatic status were reported in nine patients treated with Timentin. In all cases they were associated with contributory pathology and/or concurrent use of anticoagulants. Laboratory monitoring revealed transient variations in haemoglobin, blood cellular or plasma composition and plasma enzymatic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Ticarcillin is resistant to the action of cephalosporinases, which explains its biological activity on a large number of bacterial species, including cephalosporinase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Nevertheless, its antibacterial activity is often limited by the action of some beta-lactamases, mostly plasmid-mediated penicillinases. Clavulanic acid by itself has poor antibacterial activity, but its most important property is to inhibit and inactivate beta-lactamases. The inhibitory properties of clavulanic acid were studied on a large number of beta-lactamases. The penicillinases produced by Staphylococcus aureus, the plasmid-mediated beta-lactamases such as the TEM-type, the chromosomally-mediated penicillinases from Klebsiella pneumoniae and other closely-related beta-lactamases, and a few chromosomally-mediated cephalosporinases, such as that produced by Proteus vulgaris, are powerfully inhibited by clavulanic acid. The plasmid-mediated penicillinases of OXA type and most of the chromosomally-mediated cephalosporinases, such as that produced by Escherichia coli (Amp C), are less or poorly inhibited. Moreover, clavulanic acid has some cephalosporinase-inducing properties. These properties are in good agreement with the bacteriological properties of Timentin.

In an open, non-comparative study 40 patients with severe, often life-threatening infections, were treated with Timentin 5.2 g (5 g ticarcillin plus 200 mg potassium clavulanate) by iv infusion every 6 or 8 h. They were suffering from septicaemia (9), obstructed UTI (8), non-obstructed urinary tract infection (10), respiratory tract infection (6), infected burns (4) or malignant otitis externa (3). Many patients had important aggravating factors such as renal transplantation, peritoneal or haemodialysis, leukaemia, extensive burns, renal stones, tracheostomy and diabetes. Pathogens included Pseudomonas aeruginosa (21), Escherichia coli (7), and other Enterobacteriaceae (6). Twenty-four pathogens (13 P. aeruginosa) were ticarcillin-resistant. Thirty-six patients were clinically cured including all cases of malignant otitis externa, infected burns and non-obstructed urinary tract infection. Three patients improved and one patient with obstructed urinary tract infection failed. In 32 patients the pathogen was eradicated, in one patient it persisted and in seven it reappeared. In particular, 11 of 13 patients with infections due to ticarcillin-resistant P. aeruginosa were cured and two improved. There was, however, bacteriological relapse in five. There were no side-effects or evidence of toxicity in any of the patients. In an in-vitro study a synergistic effect between ticarcillin and clavulanate was noted against Enterobacteriaceae but only a slight synergistic effect against P. aeruginosa. Studies in patients with normal liver and kidney function showed pharmacokinetic compatibility of the two agents. Timentin can be recommended for the initial treatment of serious infections.

Piperacillin/tazobactam (YTR 830; CL-298,741) was tested against fresh and stock clinical isolates of Gram-negative bacilli, as well as against Gram-negative bacilli that had stably derepressed Class I beta-lactamases or that were hyperproductive of non-Class I beta-lactamases. Of 63 clinical isolates of the Enterobacteriaceae with ticarcillin (plus clavulanate) minimum inhibitory concentrations (MICs) of greater than or equal to 128 micrograms/ml, 16 had piperacillin/tazobactam MICs of less than or equal to 16/2 micrograms/ml. Of 48 clinical isolates of Pseudomonas spp. with ticarcillin (plus clavulanate) MICs of greater than or equal to 128 micrograms/ml, 35 had piperacillin/tazobactam MICs of less than or equal to 64/8 micrograms/ml. Tazobactam generally reduced piperacillin MICs by two- to greater than or equal to eightfold against stably derepressed mutants for Class I beta-lactamases.

The pharmacokinetics and bacteriological efficacy of ticarcillin and clavulanic acid administered individually or in combination were assessed in rabbits with experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis. The mean penetrations into the cerebrospinal fluid (CSF) of infected animals after a single dose of ticarcillin-clavulanic acid were approximately 11 and 28% for ticarcillin and clavulanic acid, respectively. In continuous-infusion experiments, the mean penetrations into CSF were 14.6 and 35% for ticarcillin and clavulanic acid, respectively, in rabbits with E. coli meningitis and 6.1 and 24%, respectively, in rabbits with H. influenzae meningitis. In animals that received a continuous infusion of the two drugs alone or in combination, the median CSF bactericidal titers for E. coli were less than 1:2, less than 1:2, and 1:2 for ticarcillin, clavulanic acid, and ticarcillin-clavulanic acid, respectively, and for H. influenzae the titers were less than 1:2, less than 1:2, and 1:4, respectively. The addition of clavulanic acid potentiated significantly the bacteriological efficacy of ticarcillin in reducing the number of bacteria in CSF of infected rabbits. Additional studies in animals and humans are required before recommendations can be made regarding the use of ticarcillin-clavulanic acid for treatment of meningitis.

Timentin (ticarcillin + clavulanic acid) combined with an aminoglycoside usually netilmicin, was given to 33 children with neutropenic haematological malignancies. The combination of Timentin and aminoglycoside was effective treatment in 27 (87%) of 31 febrile episodes. There were four failures and three results which could not be interpreted. Bacteriological investigations were positive in 13 patients, three strains were resistant to ticarcillin but all were sensitive to Timentin. Clinical success, based upon reduction of fever within 48 h of treatment, was identical whether an organism was isolated or not. The combination of Timentin plus aminoglycoside was very successful and represents one of the best combinations available for empirical treatment for febrile neutropenic children.

One hundred febrile episodes in neutropenic (PMN less than 500/mm3) patients were treated with Timentin alone or in combination with amikacin. The overall response rate in 87 episodes was 82.9% with Timentin alone and 84.5% with the combination. Eleven out of 15 patients with septicaemia were cured by Timentin alone and 12 out of 13 by the combination, a response rate of 73.3% and 92.4% respectively (not-statistically significant P = 1.307). The rates of superinfection were low. Few side effects occurred. Timentin is a useful antibiotic in the treatment of febrile neutropenic patients and was, in this study, as effective alone as in combination with an aminoglycoside in the initial therapy.

Timentin (ticarcillin + clavulanic acid) and cefamandole were compared in 484 patients undergoing elective thoracic or vascular surgery. Two hundred and forty eight patients received three 3 g/200 mg injections of Timentin and 236 patients received three 0.75 g injections of cefamandole. The patients were evaluated at discharge. Among the 248 patients given Timentin, only six (2.4%) had a post-operative infection, while nine (3.8%) of the 236 patients given cefamandole had a post-operative infection. There was no statistically significant difference between the two treatment regimes. This comparative study shows that Timentin may be used for antibiotic prophylaxis of clean vascular or thoracic surgery.