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Ticarcillin–clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants 90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary.

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.

Background The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. Objectives The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). Methods This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. Results A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL. Conclusions The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

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 pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

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.

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.

Background and purpose An increased incidence of post-surgical infectious complications in children admitted with a diagnosis of perforated appendicitis led to development of a disease-specific antibiogram and modification of our post-operative antibiotic regimen. Methods A historical control group comprised of 32 pediatric patients receiving ampicillin, gentamicin, and clindamycin (group AGC) was compared to a cohort of 32 children receiving ticarcillin/clavulanate plus gentamicin (group TG). The surgical procedure, peri-operative management, and inclusion, exclusion and discharge criteria were the same for each group. Outcome measures including length of stay, time to defervesce, incidence of infectious complications, and clinical failures to the antibiotic regimen were compared. Results The groups were similar with respect to gender, age, weight, surgical time, pre-operative leukocytes, and number of intra-operative bacterial isolates cultured per patient. Length of stay was 10.1 days in group TG and 12.5 days for group AGC (p = 0.0197). The number of clinical failures was reduced from 9 (28.1%) to 2 (6.3%) in group TG (p = 0.02). The time to defervesce was decreased by 1.4 days, and the number of infectious complications was reduced to 2.5-fold in group TG patients. Conclusions Ticarcillin/clavulanate plus gentamicin was clinically more effective than ampicillin, gentamicin, and clindamycin combination therapy in the management of perforated appendicitis in our pediatric population.

OBJECTIVETo provide an overview of the clinical pharmacokinetics and pharmacodynamics of ticarcillin/clavulanic acid and to reassess traditional dosage recommendations based on contemporary pharmacokinetic and pharmacodynamic principles.DATA SOURCESPublished ticarcillin and clavulanic acid pharmacokinetic data derived from infants and children combined with data obtained from a rigorous, dose-escalation study performed in 12 healthy adults. Pharmacodynamic correlates were derived from published in vitro susceptibility data for the combination drug ticarcillin/clavulanic acid.DATA SYNTHESIS:Limited differences were observed in the pharmacokinetic disposition profiles between ticarcillin and clavulanic acid and relative to subject age. Integration of these data with defined pathogen minimum inhibitory concentrations underscores the appropriateness of an extended dosing interval (e.g., q8h to q12h) for many infections and demonstrates the probable therapeutic interchangeability of the following three intravenous dosing regimens: 3.1 g every 6 hours, 75 mg/kg every 8 hours, and 100 mg/kg every 12 hours of a 30:1 ticarcillin/clavulanic acid combination.CONCLUSIONSIntegration of pharmacokinetic and pharmacodynamic data is an appropriate means to assess/reassess dosing recommendations for antimicrobial agents. Initial ticarcillin/ clavulanic acid dose recommendations did not account for known dynamic interactions for this combination antibiotic. Pharmacokinetic data in infants, children, and adults support a less frequent dosing interval (q8h to q12h) for the treatment of infections arising outside the central nervous system.

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.

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.

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 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.

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.

A pharmacokinetic trial with ticarcillin/clavulanate was undertaken in patients with severe burns. Timentin 5.2 g (ticarcillin 5 g + clavulanate 200 mg) was administered by iv infusion over 20 min, two or three times daily. Fifteen patients with varying amounts of total body surface (TBS) burned could be evaluated for pharmacokinetic calculations (group A, greater than 20% TBS, n = 7; group B, less than 10% TBS, n = 8). Both groups presented similar pharmacokinetic behaviour. Compared with healthy volunteers, the volume of distribution for both ticarcillin and clavulanate was increased 2.5 times. For ticarcillin the mean elimination half-lives in serum were 95.1 (A) and 86.1 min. (B), respectively; for clavulanate, the half-lives were 144.0 (A) and 132.1 min (B), respectively. The 0-8-h urine recovery of ticarcillin was 84% (A) and 83% (B), and for clavulanate it was 86% (A) and 88% (B) of the administered dose. As a consequence of the increased distribution volumes and the increased AUC's in severely burned patients the highest recommended dose of ticarcillin/clavulanate appears suitable.

The pharmacokinetics of ticarcillin 5.0 g and clavulanic acid 0.2 g were examined both alone and combined (3.0 or 5.0 g ticarcillin + 0.2 g clavulanic acid as 3.2 or 5.2 g timentin) after a 15 min infusion in ten healthy volunteers. At the same time, the serum bactericidal activity of 5.0 g ticarcillin alone and 5.2 g Timentin was determined against two ticarcillin resistant strains each of Klebsiella oxytoca and Pseudomonas aeruginosa in the first and sixth hour after administration. The serum kinetics of both ticarcillin and clavulanic acid could best be described by an open 2-compartment model. Both substances showed similar kinetic behaviour in serum with a T 1/2 beta of 74.8 +/- 11.5 min for ticarcillin and 76.6 +/- 4.6 min for clavulanic acid. The total clearance of clavulanic acid was 158 +/- 23 ml/min and thus clearly exceeded that of ticarcillin (112 +/- 9 ml/min). The recovery rate in the 24 h urine was 41.3% for clavulanic acid as compared to 79.4% for ticarcillin. Concomitant administration of both substances led to a limited change in the kinetics of both ticarcillin and clavulanic acid. A significant enhancement of the serum bactericidal action of ticarcillin and clavulanic acid was only detected for both Klebsiella species and not for the Ps. aeruginosa species, and only in the first hour.

Twenty-one patients with infected burns were treated with 5.2 g Timentin (ticarcillin 5 g + potassium clavulanate 200 mg) three times a day for an average of 8.3 days. Staphylococcus aureus was the commonest pathogen, there being ten cases of septicaemia with this organism and all were cured. Three patients with Pseudomonas aeruginosa septicaemia and infections with methicillin-resistant S. aureus failed. No drug related side effects were noted.

The single-dose pharmacokinetics of ticarcillin and clavulanic acid (Timentin) were evaluated in children and young adults with cystic fibrosis after a 0.5-hour intravenous infusion of both a 3.1 and a 3.2 gm formulation (representing 3.0 gm ticarcillin combined with 100 mg and 200 mg clavulanic acid, respectively) in a crossover design. A 75 mg/kg dose of the ticarcillin component was used. Model-dependent and noncompartmental pharmacokinetic parameters were congruous. The disposition of ticarcillin and clavulanic acid was characterized adequately by a one-compartment open model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of ticarcillin from serum were 1.19 hours, 0.231 L/kg, and 0.150 L/hr/kg, respectively, for the 3.1 gm formulation and 1.21 hours, 0.211 L/kg, and 0.123 L/hr/kg, respectively, for the 3.2 gm formulation. For ticarcillin, 86% and 93% of the dose of the 3.1 and 3.2 gm formulations, respectively, were excreted unchanged in urine during the first 6 hours after infusion. Concomitant renal clearance values were 0.120 and 0.112 L/hr/kg for the 3.1 and 3.2 gm formulations, respectively. Approximately 50% of a clavulanic acid dose was excreted unchanged in urine during the 6-hour postinfusion period for both formulations. For ticarcillin, no significant differences were observed between the 3.1 and 3.2 gm formulations. For clavulanic acid, a significant difference between the two formulations was observed in comparison of the area under the serum concentration vs time curve and dose size (P less than 0.01). Linear inverse relationships were identified between demographic factors (e.g., age, weight, height, body surface area) and both the apparent volume of distribution and total body clearance of ticarcillin and clavulanic acid for both formulations. The ticarcillin/clavulanic acid combination in either the 3.1 or 3.2 gm formulation is suitable for microbiologic and clinical evaluation in patients with cystic fibrosis.

The combination of ticarcillin and clavulanic acid (Timentin) was used in a nonrandomized open study in 28 patients with severe nosocomial infections. The infections were polymicrobial in 19 cases. Ten patients were bacteraemic and all were severely ill, receiving mechanical ventilation and with at least one organ system failure. Seventeen patients were treated with Timentin alone, 11 with a combination of Timentin and aminoglycosides. Timentin was used empirically, before identification of the bacteria in 14 patients (group I) and after identification of all the micro-organisms in 14 patients (group II). In group I, the empirical choice of Timentin was wrong in four cases, because at least one micro-organism was resistant to this drug. In the remaining 24 evaluable patients 12 patients were definitively cured. A relapse of the infection occurred in two cases. Five patients were initially improved but a secondary failure occurred due to a residual abscess in one case and to the underlying disease in four cases. Five initial failures due to the underlying disease in three cases were noted. The antimicrobial spectrum of Timentin is valuable in the management of nosocomial and polymicrobial infection, especially intra-abdominal infections and this study confirms a good clinical efficacy. However, combination with aminoglycosides seems mandatory, at least until the identification of all the micro-organisms involved in the infection.

Fifty-one clinical isolates of ticarcillin-resistant, gram-negative bacilli were tested for susceptibility to combinations of ticarcillin and clavulanic acid (BRL 14151), a potent beta-lactamase inhibitor. Minimal inhibitory concentrations (MICs) were measured by a microdilution method, and minimal bactericidal concentrations for selected strains were measured by the broth dilution method. Ticarcillin MICs were ≥128 μg/ml for all and ≥512 μg/ml for 38 (75%) of the strains. Thirty-nine strains of Enterobacteriaceae tested included Escherichia coli (14), Klebsiella pneumoniae (16), Citrobacter sp. (3), Enterobacter sp. (3), Salmonella enteritidis (1), Serratia marcescens (1), and Proteus mirabilis (1). Ticarcillin MICs for 34 strains (88%) were lowered at least threefold by the addition of 1.0 μg of clavulanic acid per ml. Against 33 strains (85%), the MICs were 64 μg or less per ml in the presence of 5 μg of clavulanic acid per ml. In contrast, the MICs for seven of eight strains of Pseudomonas aeruginosa were unaffected by the addition of up to 10 μg of clavulanic acid per ml. Ticarcillin with 5 μg of clavulanic acid per ml was bactericidal against ticarcillin-resistant (MIC ≥ 2,048 μg/ml) E. coli, K. pneumoniae, Enterobacter , and P. mirabilis .

The efficacy and tolerance of Timentin was studied in 41 patients with various infections of the ears, nose and throat. The pharmacokinetics of Timentin were determined in pus, mucosa and polyps of the nose and paranasal sinuses, the tonsils and submandibular gland as well as in the interstitial fluid collected in Redon vacuum drainage. Experimental pharmacokinetic studies in the guinea pig were performed in the inner ear and eye fluids and in serum. Ticarcillin and clavulanic acid concentrations were determined by a microbiological micromethod. The clinical studies demonstrated that Timentin was very effective and well tolerated. The clinical and experimental pharmacokinetic studies provide a good explanation of this high degree of effectiveness.

The pharmacokinetics of ticarcillin and clavulanic acid were studied by blood and urine assay methods in 25 patients divided into five groups with varying degrees of renal insufficiency i.e. mild, moderate and severe renal insufficiency, almost anuric patients and those requiring haemodialysis (groups A to E). A single dose of 5.2 g Timentin (5.0 g ticarcillin and 200 mg clavulanic acid) was administered intravenously by infusion over 30 min. The average elimination half-life (T1/2) of ticarcillin increased from 0.95 h in patients with creatinine clearance (Clcr) of 80 ml/min to 1.8, 4.4, 6.9 and 11.2 h respectively in mild, moderate and severe renal insufficiency and in almost anuric patients. The T1/2 values for clavulanic acid were 0.75, 0.9, 2.0, 2.5 and 4.8 h in the same groups. The area under concentration-time curve (AUC) for ticarcillin increased from 787 to 2839 mg/l/h and for clavulanic acid from 12.8 to 29 mg/l/h when group mean values from patients with mild and severe renal insufficiency were compared. The plasma clearance (Clpl) of clavulanic acid was in all groups greater than that of ticarcillin i.e. 166 and 100 ml/min vs. 79.2 and 25.0 ml/min when comparing mean values from groups with mild and severe renal insufficiency respectively. The plasma clearance ratio clavulanic acid/ticarcillin increased proportionally to the degree of renal insufficiency from a value of 1.5 in normal subjects to between 3.3 and 3.8 in more advanced cases.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of ticarcillin and clavulanic acid (Timentin) was assessed in a regimen combined with tobramycin in febrile episodes in neutropenic patients. After randomization, 151 patients were assessable following treatment with either Timentin and tobramycin or piperacillin and tobramycin. The overall success rate was 70% in the Timentin and tobramycin group and 71% when piperacillin and tobramycin were given: when no infection could be demonstrated efficacy was 73% in the Timentin group, 65% when only clinical or radiological evidence of infection was present and 63% with conclusive microbiology. The figures in the groups treated with the piperacillin-containing regimen were 83%, 79%, and 50% respectively. There was no significant difference between the treatment groups. In septicaemic patients, the Timentin regimen was effective in 55% of cases, while the piperacillin group was successful in 40%. Timentin is a useful addition to the agents suitable for the treatment of febrile neutropenic patients.

The efficacy and safety of Timentin (ticarcillin plus potassium clavulanate) and piperacillin were compared in a clinical trial of 78 hospitalized patients with urinary tract infections. There were 37 evaluable patients in the Timentin-treated group and 39 in the piperacillin-treated group. The 43 infection sites in each group were primarily complicated pyelonephritis or complicated cystitis; six patients in the Timentin-treated group and four in the piperacillin-treated group also had septicaemia. Both ticarcillin (3 g) plus potassium clavulanate (200 mg) and piperacillin (125-200 mg/kg per day) were administered intravenously. The 43 most common pathogens in each treatment group were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from the urinary tract and E. coli from the blood. Nine pathogens in the Timentin-treated group and 11 in the piperacillin-treated group were resistant to ticarcillin in vitro. Eradication was achieved for 39 of the 43 (91%) pathogens in the Timentin group, including all six organisms isolated from the blood, and eight (89%) of the ticarcillin-resistant pathogens. In the piperacillin-treated group, 33 of the 43 (77%) pathogens were eradicated, including three of the four blood isolates, but only eight (73%) of the ticarcillin-resistant pathogens. Clinical cure or improvement occurred in 97% of the patients in each group. Mild and transient increases in levels of liver enzymes or eosinophils were reported for 11 patients in the Timentin group and seven in the piperacillin group. In one patient in the Timentin group, a drug-related rash and nausea developed, and treatment was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

The penetration of ticarcillin and clavulanate into cartilage was investigated in 20 subjects undergoing funnel chest correction. Cartilage samples, obtained 120 or 180 min after administration of ticarcillin/clavulanate (mean dose: ticarcillin 70.0 mg/kg, clavulanate 4.7 mg/kg), were divided into core samples and outer covering portions. After 120 min, the mean ticarcillin in the outer portion was 11.0 mg/kg and that in the core sample was 0.81 mg/kg; at 180 min the mean concentration in the outer portion was 6.47 mg/kg and ticarcillin was undetectable in all but two core samples. Clavulanate was shown to decline with time in spiked cartilage preparations and the results in this investigation may underestimate penetration. Clavulanate was undetectable in most core samples. In the outer portion the mean concentration was 1.30 mg/kg at 120 min and 0.62 mg/kg at 180 min. The penetration gradient requires further elucidation and should be considered when chemotherapy for infection in cartilage is discussed.

A combination of ticarcillin and clavulanic acid (ratio 15:1) was given prophylactically to 24 newborn infants at risk of infection. Serum and urine concentrations of ticarcillin and clavulanic acid were measured after the first parenteral dose. Fifteen of 22 organisms isolated from the infants were sensitive to the drug. The pharmacokinetic profile was satisfactory and the combination was well tolerated.

Concern has been expressed that clavulanate can antagonize ticarcillin against enterobacteria and pseudomonads that have inducible expression of chromosomal 'Class I' beta-lactamases. It is suggested that clavulanate-induced enzyme inactivates ticarcillin, which itself is a feeble inducer. We confirmed that this mechanism applied, showing that antagonism was abolished in beta-lactamase-basal mutants of inducible strains. Antagonism has been reported in double disc tests with strains of Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, Serratia spp. and indole-positive Proteeae. Only with some strains of Ent. cloacae and Morganella morganii, however, did the presence of 1-32 mg/l clavulanate elevate the MIC of ticarcillin by more than one or two dilutions in chequerboard studies. Clavulanate was synergistic with ticarcillin against Proteus vulgaris strains, being a potent inhibitor of the unusual Class I enzyme of this species. Induction-determined antagonism was not reduced in Ent. cloacae transconjugants that produced the plasmid-mediated TEM-1 beta-lactamase, despite the ability of this enzyme to bind clavulanate. Our results suggest that Ent. cloacae and M. morganii strains should be confirmed not to be more sensitive to ticarcillin alone than to ticarcillin/clavulanate, before the latter combination is used clinically. Otherwise, it appears that beta-lactamase induction is unlikely to cause significant antagonism. It is emphasized that induction is reversible, causing, at worst, a transient resistance. It should not be confused with the selection of stably-derepressed mutants that can occur, for example, in the clinical use of newer cephalosporins.

Twenty-eight patients with bacteraemia were treated with Timentin, a combination of ticarcillin and clavulanic acid, and tobramycin. According to a simple physiological classification scheme 20 patients were moderately and eight severely ill. Clinical cure was achieved in 15 of 20 moderately ill and in four of eight severely ill patients. The nine therapeutic failures were due to non-removable foreign material (2 cases), abscesses that were not effectively evacuated (5 cases), urolithiasis (1 case), and decubitus ulcer (1 case). One of these cases was complicated by infection with a Klebsiella strain with Timentin and tobramycin MICs of 64 mg/l. Thirteen of 31 bacterial isolates from blood were resistant to greater than or equal to 128 mg/l of ticarcillin of which 11 were susceptible to less than or equal to 64 mg/l of Timentin. The addition of Timentin to tobramycin offered a better coverage in vitro than ticarcillin combined with tobramycin against the strains isolated from the blood of the patients included in this study.

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin. Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate. The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium.