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PubMed1982

Activity and synergy of ureido penicillins and aminoglycosides against Pseudomonas aeruginosa.

The in vitro activities of piperacillin, azlocillin, mezlocillin, sulbenicillin and ticarcillin were compared with those of carbenicillin using 88 clinical isolates of Pseudomonas aeruginosa. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) were determined by standard techniques. The MIC for 90% of the strains was 7.5 mg/l for piperacillin, 10.0 mg/l for azlocillin, 26.5 mg/l for mezlocillin, 48.4 mg/l for sulbenicillin, 50.0 mg/l for ticarcillin and more than 100 mg/l for carbenicillin. The MBC/MIC ratio was 1.3 for piperacillin, 1.9 for ticarcillin, 2.1 for sulbenicillin, 3.3 for mezlocillin and 4.5 for azlocillin. The susceptibilities of the same strains to four aminoglycosides were tested. The MIC for 90% of the strains was 0.3 mg/l for sisomicin and tobramycin, 1.5 mg/l for amikacin, and 2.2 mg/l for gentamicin. The effect of combining piperacillin, azlocillin and mezlocillin with gentamicin, tobramycin, sisomicin and amikacin was studied using checkerboard titration. The highest degrees of synergy were found with the combinations of piperacillin and an aminoglycoside. Strong potentiation was observed in 85% of the strains with piperacillin - sisomicin and in 50% with piperacillin - gentamicin. The synergistic effects of azlocillin and mezlocillin in combination with an aminoglycoside (observed in 30-65% of the strains) were for the most part moderate or slight. No antagonism was observed.

Aminoglycosides↗
PubMed1996

[Drug-resistance patterns of clinical isolates of Pseudomonas aeruginosa in regard to their lipopolysaccharide-chain sizes].

Pseudomonas aeruginosa strains isolated from patients with different types of the infections each consisted of LPSs different in chain sizes. The drug-susceptibility patterns of these strains of P. aeruginosa were investigated to clarify the relationship between the LPS-compositions and susceptibility to some kinds of anti-pseudomonal drugs. The susceptibilities of nineteen strains (seven long-LPS strains, four short-LPS strains and eight LPS-deficient strains) to piperacillin, ceftazidime, gentamicin, norfloxacin and polymyxin-B were determined and these strains were classified into six types (Types I-VI) according to their drug-resistance patterns. Six of the eight LPS-deficient strains were found to be highly resistant to gentamicin alone (Type IV). Four of the seven strains with the long-LPS and one strain with the short-LPS were resistant to three drugs such as piperacillin, ceftazidime and norfloxacin, and classified into Type I. These results indicated that the major part of the LPS-deficient strains and the considerable part of the long-chain LPS strains of P. aeruginosa tested had each characteristic profile in the drug resistance. The outer membrane proteins of thirteen strains, consisting of different types of LPS compositions, were analyzed by SDS-PAGE. The strains belonging to the same types of the drug-resistance patterns were found to have similar OMP-profiles, although a few exceptions were found. beta-lactamase and gentamicin-inactivating activities were determined for piperacillin-resistant and gentamicin-resistant strains, respectively. Of the piperacillin-resistant strains tested, the activity of beta-lactamase was high in one (No. 8) only, low in four and not found in four. The results showed that degrees of resistance of P. aeruginosa strains tested to piperacillin did not correlate to their producibility of beta-lactamase except one strain. Of the nine gentamicin-resistant strains tested, the gentamicin inactivating activity was high in one (No. 30) only, moderate in six and low in two. These results suggested that the significant levels of piperacillin- or gentamicin-resistance of P. aeruginosa isolated tested might be expressed each due to their decreased abilities for drug-permeabilities in addition to drug-inactivating activities such as beta-lactamase or gentamicin-modifying enzyme. In the case of some resistant strains, the resistance to piperacillin or gentamicin was not explained by the results of the present study. Therefore, we must investigate the possibility that other mechanisms participate in the resistance of these strains.

Drug Resistance, Microbial↗
PubMed1982

In vitro activity of apalcillin compared with that of other new penicillins and anti-Pseudomonas cephalosporins.

Apalcillin, a naphthydridine derivative of ampicillin, was compared with ticarcillin, azlocillin, mezlocillin, piperacillin, cefotaxime, and cefoperazone against gram-negative and gram-positive bacterial isolates and with cefsulodin and tobramycin against Pseudomonas aeruginosa. The minimal concentrations of apalcillin at which 50 and 90% of hospital isolates of Escherichia coli were inhibited were similar to those of mezlocillin and piperacillin (1.6 and 100 micrograms/ml, respectively). Apalcillin had minimal inhibitory concentrations similar to those of piperacillin against Citrobacter freundii and Citrobacter diversus. Against Klebsiella, apalcillin inhibited 50% of organisms at a concentration of 6.3 micrograms/ml, similar to piperacillin. The activity of apalcillin against Enterobacter (E. aerogenes, E. cloacae, and E. agglomerans) was similar to that of mezlocillin and piperacillin and greater than that of ticarcillin. The activity of apalcillin against Proteus mirabilis was similar to that of the other agents, as was its activity against indole-positive Proteus and Providencia. Only 40% of Serratia were inhibited at an apalcillin concentration of 25 micrograms/ml. Apalcillin was as active as piperacillin but twofold less active than cefoxitin or moxalactam against Bacteroides fragilis. It was as active as piperacillin, cefoperazone, and cefsulodin against P. aeruginosa (apalcillin inhibited 90% of organisms at a concentration of 25 mg/ml). There was an inoculum effect and a difference in the minimal inhibitory concentration and minimal bactericidal concentration with beta-lactamase strains. Apalcillin was hydrolyzed by plasmid beta-lactamase but not as well by cephalosporinases.

Ampicillin↗
PubMed1998

Activities and time-kill studies of selected penicillins, beta-lactamase inhibitor combinations, and glycopeptides against Enterococcus faecalis.

The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, vancomycin, and teicoplanin were tested against 212 Enterococcus faecalis strains (9 beta-lactamase producers) by standard agar dilution MIC testing (10[4] CFU/spot). The MICs at which 50 and 90% of the isolates were inhibited (MIC50s and MIC90s, respectively) were as follows (microg/ml): piperacillin, 4 and 8; piperacillin-tazobactam, 4 and 8; ticarcillin, 64 and 128; ticarcillin-clavulanate, 64 and 128; ampicillin, 2 and 2; ampicillin-sulbactam, 1 and 2; vancomycin, 1 and 4; and teicoplanin, 0.5 and 1. Agar dilution MIC testing of the nine beta-lactamase-positive strains with an inoculum of 10(6) CFU/spot revealed higher beta-lactam MICs (piperacillin, 64 to >256 microg/ml; ticarcillin, 128 to >256 microg/ml; and ampicillin, 16 to 128 microg/ml); however, MICs with the addition of inhibitors were similar to those obtained with the lower inoculum. Time-kill studies of 15 strains showed that piperacillin-tazobactam was bactericidal (99.9% killing) for 14 strains after 24 h at four times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Ampicillin gave 99.9% killing of 14 beta-lactamase-negative strains after 24 h at eight times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Killing by ticarcillin-clavulanate was slower than that observed for piperacillin-tazobactam, relative to the MIC. For the one beta-lactamase-producing strain tested by time-kill analysis with a higher inoculum, addition of the three inhibitors (including sulbactam) to each of the beta-lactams resulted in bactericidal activity at 24 h at two times the MIC. For an enzyme-negative strain, addition of inhibitors did not influence kinetics. Kinetics of vancomycin and teicoplanin were significantly slower than those of the beta-lactams, with bactericidal activity against 6 strains after 24 h at eight times the MIC, with 90% killing of 12 and 14 strains, respectively, at four times the MIC. Slower-kill kinetics by both glycopeptides were observed at earlier periods.

Anti-Bacterial Agents↗
PubMed1997

[Pseudomonas aeruginosa: bactericidal activity on various beta-lactam resistance phenotypes of 8 antibiotics and 7 combinations].

Bactericidal activities of 8 antibiotics (ticarcillin, piperacillin, piperacillin-tazobactam, ceftazidime, cefepime, imipenem, amikacin, ciprofloxacin) and of 7 combinations have been studied by time-killing curve technique for 16 Pseudomonas aeruginosa selected for their beta-lactams resistance phenotypes (3 wild strains, 5 penicillinases, 2 extended-spectrum beta-lactamases, 3 high level cephalosporinases and 3 non enzymatic resistance). Bactericidal activities of beta-lactams used alone were as follows: imipenem > cefepime > ceftazidime, piperacillin, piperacillin-tazobactam > ticarcillin. All the antibiotics combinations were synergistic or additive. However, only the combination of imipenem with amikacin was bactericidal for all strains. For the strains with penicillinases, piperacillin-tazobactam was not more effective than piperacillin. For the extended-spectrum beta-lactamases, we have observed a synergy with piperacillin-tazobactam and ciprofloxacin or amikacin.

Amikacin↗
PubMed2004

Safety and tolerability of ertapenem.

Ertapenem is a Group 1 carbapenem that was licensed in the USA in November 2001 and in Europe in April 2002. Its safety profile has been assessed in 240 healthy volunteers participating in 12 clinical pharmacology studies and in 2046 patients enrolled in five Phase IIa and eight Phase IIb/III clinical trials. The most common drug-related adverse events (AEs) reported in trials comparing ertapenem and piperacillin-tazobactam and in trials comparing ertapenem and ceftriaxone were: diarrhoea (ertapenem versus piperacillin-tazobactam 5.0% versus 7.0%; ertapenem versus ceftriaxone 5.6% versus 5.9%); infused vein complications (ertapenem versus piperacillin-tazobactam 4.5% versus 7.9%; ertapenem versus ceftriaxone 3.2% versus 4.6%); nausea (ertapenem versus piperacillin-tazobactam 2.5% versus 3.4%; ertapenem versus ceftriaxone 3.4% versus 3.3%); and elevations in alanine aminotransferase levels (ertapenem versus piperacillin-tazobactam 8.8% versus 7.3%; ertapenem versus ceftriaxone 8.3% versus 6.9%). Most ertapenem-related AEs were reported as mild-to-moderate in intensity. Ertapenem was not associated with prolongation of the QTc interval. Local reactions of moderate-to-severe intensity at the infusion site were infrequent and occurred with similar frequency in the ertapenem and comparator treatment groups. No overall differences in safety were observed between elderly (aged > or = 65 years and > or = 75 years) and younger patients. Ertapenem, 1 g once a day given by intravenous infusion or intramuscular injection, was generally well tolerated and had overall safety and tolerability profiles similar to those of piperacillin-tazobactam and ceftriaxone.

Adult↗
PubMed2005

Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection.

OBJECTIVES: We investigated the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam in hospitalized patients. PATIENTS AND METHODS: A multicentre, randomized clinical trial was conducted in hospitalized patients with complicated intra-abdominal infection. Patients received piperacillin/tazobactam administered by either continuous infusion (13.5 g over 24 h, n = 130) or intermittent infusion (3.375 g every 6 h, n = 132). NONMEM was used to perform population pharmacokinetic analysis in a subset of patients (n = 56) who had serum samples obtained at steady-state for drug concentration analyses. Classification and regression tree analysis was used to identify the breakpoints of piperacillin PK-PD indexes in 94 patients with causative pathogen's MIC. RESULTS: A one-compartment model was applied to fit the data. Creatinine clearance and body weight were the most significant variables to explain patient variability in piperacillin and tazobactam clearance and volume of distribution. The infusion method had no influence on PK parameters. For patients (n = 30) receiving intermittent infusion in the pharmacokinetic study, mean Cmax and half-life were 122.22 mg/L and 1.17 h for piperacillin, and 15.74 mg/L and 1.81 h for tazobactam. For patients (n = 26) receiving continuous infusion in the pharmacokinetic study, mean steady-state concentration was 35.31 +/- 12.15 mg/L for piperacillin and 7.29 +/- 3.28 mg/L for tazobactam. As a result of a low rate of failures (<11%) observed in the trial and the low MICs for infecting pathogens, no association could be established between clinical/microbiological outcome and drug exposure. CONCLUSIONS: Intermittent infusion and continuous infusion of piperacillin and tazobactam provided sufficient drug exposure to treat those pathogens commonly implicated in intra-abdominal infections.

Abdomen↗
PubMed2003

Antiendotoxin activity of antimicrobial peptides and glycopeptides.

An animal study was performed to investigate the efficacy of two glycopeptides and two cationic peptides in the prevention of lethality in a septic shock rat model. Adult Wistar rats were given an intraperitoneal injection of 2x10(10) CFU of Escherichia coli ATCC 25922, with the exception of an uninfected control group (C0). Animals were randomized to receive, immediately after bacterial challenge, intraperitoneally isotonic sodium chloride solution (control group C1), 3 mg/Kg teicoplanin (group 1), 7 mg/Kg vancomycin (group 2), 1 mg/Kg colistin (group 3), 1 mg/Kg buforin II (group 4), or 60 mg/Kg piperacillin (group C(PIP)). In addition, four groups (1a, 2a, 3a, and 4a) received the above mentioned drugs in combination with piperacillin. All compounds and combinations significantly reduced the lethality and the number of E. coli in abdominal fluid compared with C1 group, with the exception of the glycopeptides. Colistin and buforin II combined with piperacillin significantly decreased the lethality compared with piperacillin alone. Finally, colistin, buforin II, and teicoplanin significantly reduced plasma endotoxin concentration in comparison with piperacillin and saline treatment. Antimicrobial peptides and teicoplanin act as antiendotoxin agents and enhance the efficacy of piperacillin.

Animals↗
PubMed2000

Beta-lactamase inhibitor combinations with extended-spectrum penicillins: factors influencing antibacterial activity against enterobacteriaceae and Pseudomonas aeruginosa.

Production of beta-lactamases is the most common mechanism by which gram-negative bacteria express resistance to beta-lactam antibiotics. One successful method of circumventing the threat of plasmid-encoded beta-lactamases is to combine inhibitors of these enzymes with a penicillin. Currently, four inhibitor-penicillin combinations are in clinical use: ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-clavulanate, and piperacillin-tazobactam. Of these, ticarcillin-clavulanate and piperacillin-tazobactam have the broadest spectra of activity that includes Pseudomonas aeruginosa. Many factors influence the activity and pharmacodynamics of these combinations, including potency of both agents, pharmacokinetics of the inhibitor, type and quantity of beta-lactamase produced by the target bacterium, and potential for the inhibitor to induce expression of chromosomal cephalosporinases in the target bacterium. Although ticarcillin-clavulanate and piperacillin-tazobactam have similar spectra of activity, they have many differences. Most notable are increased potency of piperacillin against Enterobacteriaceae and P aeruginosa, increased activity of piperacillin-tazobactam against gram-negative pathogens producing penicillin-sensitive enzyme (PSE)-class beta-lactamase or hyperproducing other plasmid-encoded beta-lactamases, and the more favorable pharmacokinetics of tazobactam. In the treatment of P. aeruginosa infections, the potential for clavulanate to induce expression of chromosomal cephalosporinase and antagonize antibacterial activity of ticarcillin is a concern, especially in patients who lack protective host defenses. These are not concerns with piperacillin-tazobactam.

Clavulanic Acid↗
PubMed1989

[Susceptibility of clinically-isolated problem pathogenic bacteria to broad spectrum antibiotics].

The action of broad-spectrum antibiotics investigated by disc diffusion method on 636 problem bacteria such as S. aureus, Enterobacter, Klebsiella, Pseudomonas, E. coli, Proteus that isolated from various clinical specimens. The highest and lowest ratio of susceptibility were as follows: S. aureus were found sensitive 90% to Netilmicin, 27% to Piperacillin, Enterobacter species 78% to Netilmicin, 25% to Piperacillin, Klebsiella 69% to Amikacin, 20% to Piperacillin, Pseudomonas 66% to Amikacin, 5% to Amoxicillin-Clavulanic acid, E.coli 68% to Netilmicin and Ceftriaxone, 32% to Piperacillin, Proteus 70% to Netilmicin, 43% to Piperacillin, S.epidermidis 90% to Amoxicillin-Clavulanic acid, 60% to Piperacillin.

Amikacin↗
PubMed2001

Evaluation of the VITEK 2 system for the identification and susceptibility testing of three species of nonfermenting gram-negative rods frequently isolated from clinical samples.

VITEK 2 is a new automatic system for the identification and susceptibility testing of the most clinically important bacteria. In the present study 198 clinical isolates, including Pseudomonas aeruginosa (n = 146), Acinetobacter baumannii (n = 25), and Stenotrophomonas maltophilia (n = 27) were evaluated. Reference susceptibility testing of cefepime, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, piperacillin, tobramycin, levofloxacin (only for P. aeruginosa), co-trimoxazole (only for S. maltophilia), and ampicillin-sulbactam and tetracycline (only for A. baumannii) was performed by microdilution (NCCLS guidelines). The VITEK 2 system correctly identified 91.6, 100, and 76% of P. aeruginosa, S. maltophilia, and A. baumannii isolates, respectively, within 3 h. The respective percentages of essential agreement (to within 1 twofold dilution) for P. aeruginosa and A. baumannii were 89.0 and 88.0% (cefepime), 91.1 and 100% (cefotaxime), 95.2 and 96.0% (ceftazidime), 98.6 and 100% (ciprofloxacin), 88.4 and 100% (gentamicin), 87.0 and 92.0% (imipenem), 85.0 and 88.0% (meropenem), 84.2 and 96.0% (piperacillin), and 97.3 and 80% (tobramycin). The essential agreement for levofloxacin against P. aeruginosa was 86.3%. The percentages of essential agreement for ampicillin-sulbactam and tetracycline against A. baumannii were 88.0 and 100%, respectively. Very major errors for P. aeruginosa (resistant by the reference method, susceptible with the VITEK 2 system [resistant to susceptible]) were noted for cefepime (0.7%), cefotaxime (0.7%), gentamicin (0.7%), imipenem (1.4%), levofloxacin (2.7%), and piperacillin (2.7%) and, for one strain of A. baumannii, for imipenem. Major errors (susceptible to resistant) were noted only for P. aeruginosa and cefepime (2.0%), ceftazidime (0.7%), and piperacillin (3.4%). Minor errors ranged from 0.0% for piperacillin to 22.6% for cefotaxime against P. aeruginosa and from 0.0% for piperacillin and ciprofloxacin to 20.0% for cefepime against A. baumannii. The VITEK 2 system provided co-trimoxazole MICs only for S. maltophilia; no very major or major errors were obtained for co-trimoxazole against this species. It is concluded that the VITEK 2 system allows the rapid identification of S. maltophilia and most P. aeruginosa and A. baumannii isolates. The VITEK 2 system can perform reliable susceptibility testing of many of the antimicrobial agents used against P. aeruginosa and A. baumannii. It would be desirable if new versions of the VITEK 2 software were able to determine MICs and the corresponding clinical categories of agents active against S. maltophilia.

Acinetobacter↗
PubMed2003

Clinical and microbiologic analysis of a hospital's extended-spectrum beta-lactamase-producing isolates over a 2-year period.

STUDY OBJECTIVE: To evaluate the microbiologic and clinical outcomes of patients with extended-spectrum beta-lactamase (ESBL)-producing isolates over a 2-year period. DESIGN: Retrospective analysis. SETTING: Tertiary care teaching hospital. PATIENTS: Twenty-one patients with cultures of confirmed ESBL-producing Escherichia coli, Klebsiella pneumoniae, or Klebsiella oxytoca. MEASUREMENTS AND MAIN RESULTS: Antimicrobial susceptibilities of piperacillin-tazobactam, cefotetan, carbapenems, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, and nitrofurantoin (nitrofurantoin for urinary isolates only) of confirmed ESBL producers at our institution were determined, as well as clinical outcomes of patients with ESBL-producing isolates. Microbiologic and medical records were reviewed for patient sex and age, antimicrobial susceptibilities, antimicrobial therapy, and clinical and microbiologic outcomes. From January 2000-December 2001, 31 isolates were confirmed as ESBL producers (6 E. coli, 11 K. pneumoniae, and 14 K. oxytoca). A statistically significant increase occurred over the 2-year period from 9 (0.6%) of 1414 isolates in 2000 to 22 (1.8%) of 1218 isolates in 2001 (p = 0.0055). All isolates were susceptible to carbapenems, and more than 88% were susceptible to amikacin, cefotetan, or nitrofurantoin. Less than 70% of isolates were susceptible to gentamicin, fluoroquinolones, piperacillin-tazobactam, or trimethoprim-sulfamethoxazole. All patients treated with a carbapenem experienced clinical cure. Piperacillin-tazobactam alone and in combination resulted in an overall clinical cure rate of 55%, with a 50% cure rate for isolates susceptible to piperacillin-tazobactam. All patients in whom antibiotic therapy failed had been treated with piperacillin-tazobactam or cefepime, either alone or in combination with a fluoroquinolone. CONCLUSION: Carbapenems remain the treatment of choice for ESBL-producing pathogens. Piperacillin-tazobactam and cefepime should not be routinely administered for the treatment of these organisms.

Anti-Bacterial Agents↗
PubMed2006

[Antimicrobial susceptibility pattern of nosocomial gram negative pathogens: results from MYSTIC study in Hacettepe University Adult Hospital (2000-2004)].

Antimicrobial susceptibility patterns of Gram negative pathogens (n: 699) isolated from nosocomial infections in Hacettepe University Adult Hospital included in MYSTIC programme between 2000-2004 were determined by Etest (AB BIODISK, Solna, Sweden) using CLSI criteria. Of the total Escherichia coli (n: 179), Klebsiella pneumoniae (n: 168), Pseudomonas aeruginosa (n: 179) and Acinetobacter baumannii (n: 173) isolates, 55% were from patients in inpatient clinics and 45% were from patients in intensive care units. The extended-spectrum beta-lactamase (ESBL) production rate of E. coli and K. pneumoniae isolates were 28% and 47%, respectively. All E. coli and K. pneumoniae isolates were found susceptible to carbapenems. The susceptibility of ESBL positive E. coli isolates to piperacillin+tazobactam was 76% and 65% to cefepime, 63% to ceftazidime, 56% to tobramycin, 24% to ciprofloxacin. For ESBL negative E. coli isolates, the susceptibility rates were found 95%, 92%, 84% and 58% for ceftazidime and tobramycin, cefepime, piperacillin+tazobactam and ciprofloxacin, respectively. The susceptibility rates of ESBL positive K. pneumoniae isolates to piperacillin+tazobactam was 55% and 51% to cefepime, 49% to ciprofloxacin, 45% to tobramycin, 42% to ceftazidime. For ESBL negative K. pneumoniae isolates, the susceptibility rates were determined as follows; 92% for cefepime, 87% for tobramycin, 70% for piperacillin+tazobactam, 62% for ceftazidime and 60% for ciprofloxacin. Of the P. aeruginosa isolates, 77% were multi-drug resistant with susceptibility rates to piperacillin+tazobactam, ciprofloxacin, meropenem and imipenem as 55%, 53%, 51% and 49%, respectively. The susceptibilities of P. aeruginosa isolates were 48% to ceftazidime, 41% to cefepime and 35% to tobramycin. Of the A.baumannii isolates, 67% were multi-drug resistant with higher susceptibility rates to meropenem (53%), imipenem (48%) and tobramycin (44%) compared to other antimicrobials cefepime (37%), ciprofloxacin (29%), piperacillin+tazobactam (26%) and ceftazidime (22%).

Acinetobacter baumannii↗
PubMed2006

[Efficacies of ceftazidime and cefepime in rats with experimental pneumonia caused by extended-spectrum beta-lactamase-producing strain of Klebsiella pneumonia].

OBJECTIVE: To investigate the in vivo activities of ceftazidime and cefepime with susceptibility in vitro in rats with experimental pneumonia caused by extended-spectrum beta-lactamase-producing strain of Klebsiella pneumonia. METHODS: With intratracheal instillation method, 3 Klebsiella pneumonia strains isolated from this hospital were used to produce 3 groups of experimental model of pneumonia in rats. All the 3 strains showed resistant to cefotaxime and susceptible to piperacillin-tazobactam in vitro. To ceftazidime and cefepime, strain 1 was both susceptible. Strain 2 was susceptible to ceftazidime and resistant to cefepime. Strain 3 was resistant to ceftazidime and susceptible to cefepime. The three groups of rats were randomly assigned to one of the following five groups: one control group and four treatment groups. The efficacies were evaluated 96 hours later by the survival rate and the viable bacterial counts of the lungs (lg CFU/g). RESULTS: Group 1: piperacillin-tazobactam, ceftazidime and cefepime significantly improved the survival rate (75.0%, 76.9%, 80.0%) and reduced the bacterial counts [(10.8 +/- 2.8), (11.1 +/- 3.2), (11.0 +/- 3.7) lg CFU/g] compared with cefotaxime and the control group [36.0%, 32.0%; (15.7 +/- 5.6), (16.0 +/- 5.5) lg CFU/g; P < 0.05]. Group 2: piperacillin-tazobactam, ceftazidime significantly improved the survival rate (79.2%, 73.1%) and reduced the bacterial counts [(10.7 +/- 2.3), (11.0 +/- 2.7) lg CFU/g] compared with cefotaxime and the control groups [42.3%, 33.3%; (15.5 +/- 5.4), (15.8 +/- 4.6) lg CFU/g; P < 0.05]. Group 3: the survival rate in piperacillin-tazobactam and cefepime groups (80.8%, 75.0%) were significantly higher and the bacterial counts in piperacillin-tazobactam [(10.4 +/- 2.4) lg CFU/g] were significantly lower compared with the cefotaxime and the control groups [37.5%, 34.6%; (14.2 +/- 5.6), (15.3 +/- 4.9) lg CFU/g; P < 0.05]. CONCLUSION: Cefepime and ceftazidime can reduce the mortality and the number of viable bacteria in rat pneumonia caused by some ESBL-producing Klebsiella pneumonia strains susceptible to either of them and their efficacies were similar to piperacillin-tazobactam.

Animals↗
PubMed1999

Treatment of experimental pneumonia in rats caused by a PER-1 extended-spectrum beta-lactamase-producing strain of Pseudomonas aeruginosa.

The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum beta-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 +/- 0.4 log10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the beta-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats' lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three beta-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum beta-lactamase-possessing strain would be imipenem plus amikacin.

Amikacin↗
PubMed2003

Variable susceptibility to piperacillin/tazobactam amongst Klebsiella spp. with extended-spectrum beta-lactamases.

MICs of piperacillin/tazobactam are conventionally determined by varying the concentration of piperacillin in the presence of a fixed 4 mg/L tazobactam. When tested in this way, the MIC distribution for Klebsiella isolates with extended-spectrum beta-lactamases (ESBLs) is strongly bimodal, such that many producers are inhibited at 16 + 4 mg/L whilst others require MICs of > or =512 + 4 mg/L. When, however, piperacillin/tazobactam was tested as a fixed 8:1 ratio, the MIC distribution became unimodal. If clavulanate 4 mg/L was combined with piperacillin, a unimodal MIC distribution was seen for ESBL-producing Klebsiella spp. but a bimodal distribution arose if the clavulanate concentration was reduced to 0.25 mg/L. These data for alternative combinations suggested that the bimodal MIC distribution seen for piperacillin + tazobactam 4 mg/L was a titration effect, not a reflection of some ESBLs being resistant to tazobactam. Even within single strains, as defined by serotype and DNA fingerprints, there was considerable variation in susceptibility to piperacillin + tazobactam 4 mg/L, with some representatives highly susceptible and others highly resistant. Some of the more resistant representatives produced more of their ESBL, or had a greater number of beta-lactamase types, but these associations were not universal. Elevated resistance to piperacillin + tazobactam was not associated with porin change in any ESBL producer examined, but has been found by others.

Bacterial Outer Membrane Proteins↗
PubMed1994

Pharmacokinetic characteristics of piperacillin/tazobactam.

Piperacillin/tazobactam is a new combination of a broad-spectrum penicillin and a beta-lactamase inhibitor. In studies in healthy volunteers, the pharmacokinetics of piperacillin combined with tazobactam were similar to those of piperacillin alone. In contrast, tazobactam administered with piperacillin achieved higher plasma concentrations and had a longer half-life than tazobactam administered alone. Intravenous infusion of 4.0 g piperacillin with 0.5 g tazobactam over 5 min resulted in mean maximum plasma concentrations of 380 micrograms piperacillin/ml and 35.3 micrograms tazobactam/ml; half-lives were 1.14 h for piperacillin and 0.92 h for tazobactam. Within 30 min of infusion, piperacillin/tazobactam achieves 16-85% of plasma concentrations in skin, muscle, lung, gallbladder, and intestinal mucosa. Plasma and tissue levels remain above the MIC90s of major pathogens for 2 h post administration. These findings show that piperacillin/tazobactam is truly synergistic combination which can be expected to be effective in treating a wide variety of infections in the clinical setting.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

In-vitro activity of piperacillin/tazobactam relative to other antibiotics against blood culture isolates.

Resistance of bacteria to antibiotics is an increasing problem in many countries. Accurate locally relevant information is essential for detection and control of emerging resistance and to facilitate choice of empirical antibiotic therapy in the immediate management of seriously ill patients. We have determined the minimum inhibitory concentration of piperacillin/tazobactam for 97 strains of bacteria (55 Enterobacteriaceae, 13 non-fermentative Gram-negative bacilli, 22 Staphylococcus aureus, 6 Enterococcus faecalis and 1 Bacillus cereus) isolated from blood cultures and compared its activity to that of amoxycillin, co-amoxiclav, cephalothin, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, piperacillin, cefotaxime. The strains were consecutive non-fastidious isolates with the following qualifications: coagulase negative staphylococci and diphtheroids were excluded and the number of Staphylococcus aureus isolates was limited to 12 methicillin-resistant and 10 methicillin-sensitive strains. Multiple isolates of the same species from individual patients were not included. The minimum inhibition concentrations of methicillin, penicillin, teichoplanin and vancomycin were also determined for specific groups of organisms. MICs were determined by the Etest method (AB Biodisk, Solna, Sweden) on Mueller Hinton agar. The MICs of appropriate American Type Culture Collection control strains were determined. Based on the interpretative criteria of the National Committee for Clinical Laboratory Standards (USA), 87 per cent of Gram-negative bacilli were susceptible to piperacillin/tazobactam compared with amoxycillin 26 per cent, cephalothin 35 per cent, co-amoxiclav 54 per cent, piperacillin 56 per cent, cefotaxime 69 per cent, ceftazidime 84 per cent, gentamicin 85 per cent and ciprofloxacin 91 per cent. Of all isolates 75 per cent were sensitive to piperacillin/tazobactam, compared with amoxycillin 22 per cent, cephalothin 35 per cent, piperacillin 41 per cent, co-amoxiclav 52 per cent, cefotaxime 59 per cent, ceftazidime 60 per cent, gentamicin 74 per cent and ciprofloxacin 77 per cent. Two isolates (1 E. coli and 1 Klebsiella pneumoniae) with antibiograms consistent with the relatively new resistance phenomenon of extended spectrum beta-lactamase production were identified. The spectrum of activity of piperacillin-tazobactam for empirical antibiotic therapy is significantly greater than that of piperacillin alone and is similar to that of ciprofloxacin and gentamicin.

Anti-Bacterial Agents↗