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PubMed1979

Piperacillin dosage.

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Bacterial Infections↗
PubMed1986

Effect of 5-fluorouracil, mitoxantrone, methotrexate, and vincristine on the antibacterial activity of ceftriaxone, ceftazidime, cefotiam, piperacillin, and netilmicin.

Using the checkerboard agar dilution technique, antibacterial activity and in vitro interactions of 4 antineoplastic agents and 5 antimicrobial drugs were examined against 56 strains of 7 bacterial species. 5-fluorouracil was found to inhibit all strains of Staphylococcus aureus and of Staphylococcus epidermidis at a concentration of 0.8 micrograms/ml or less. 84% of all gram-negative strains were inhibited synergistically when 5-fluorouracil was combined with beta-lactam antibiotics. Methotrexate and cefotiam were antagonistic in 42% of all combinations, especially when tested against Escherichia coli and Klebsiella pneumoniae.

Anti-Bacterial Agents↗
PubMed1977

[Excretion in bile and clinical study of T-1220 (piperacillin) in biliary tract diseases (author's transl)].

The excretion of T-1220 in bile was evaluated in 4 patients with biliary tract diseases. The bile was collected for 6 hours after intravenous injection of T-1220. The maximal concentration in bile was 1,600 mcg/ml at 0.5 approximately 1 hour after administration of 1 g of T-1220 to 1 case. In 3 cases treated with 2 g, the maximal concentration was 155 approximately 1,115 mcg/ml at 2 approximately 3 hours after administration. Total excretion rates in bile after 0 approximately 6 hours were 0.5 approximately 7.2%. T-1220 was applied clinically to 3 patients with biliary tract infections. Clinical results obtained were good in all cases. No side effect was observed in all cases.

Aged↗
PubMed2002

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing.

BACKGROUND: Although intermittent bolus dosing is currently the standard of practice for many antimicrobial agents, beta-lactams exhibit time-dependent bacterial killing. Maximizing the time above the minimum inhibitory concentration (MIC) for a pathogen is the best pharmacodynamic predictor of efficacy. Use of a continuous infusion has been advocated for maximizing the time above the MIC compared with intermittent bolus dosing. OBJECTIVE: This study compared the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered as an intermittent bolus versus a continuous infusion against clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae. METHODS: Healthy volunteers were randomly assigned to receive piperacillin 3 g/ tazobactam 0.375 g q6h for 24 hours, piperacillin 6 g/tazobactam 0.75 g continuous infusion over 24 hours, and piperacillin 12 g/tazobactam 1.5 g continuous infusion over 24 hours. Five clinical isolates each of P aeruginosa and K pneumoniae were used for pharmacodynamic analyses. RESULTS: Eleven healthy subjects (7 men, 4 women; mean +/- SD age, 28 +/- 4.7 years) were enrolled. Mean steady-state serum concentrations of piperacillin were 16.0 +/- 5.0 and 37.2 +/- 6.8 microg/mL with piperacillin 6 and 12 g, respectively. Piperacillin/tazobactam 13.5 g continuous infusion (piperacillin 12 g/tazobactam 1.5 g) was significantly more likely to produce a serum inhibitory titer > or = 1:2 against P aeruginosa at 24 hours than either the 6.75 g continuous infusion (piperacillin 6 g/tazobactam 0.75 g) or 3.375 g q6h (piperacillin 3 g/ tazobactam 0.375 g). There were no statistical differences against K pneumoniae between regimens. The median area under the inhibitory activity-time curve (AUIC) for the 13.5 g continuous infusion was higher than that for 3.375 g q6h and the 6.75 g continuous infusion against both P aeruginosa and Kpneumoniae (P < or = 0.007, 13.5 g continuous infusion and 3.375 g q6h vs 6.75 g continuous infusion against K pneumoniae). The percentage of subjects with an AUIC > or = 125 was higher with both 3.375 g q6h and the 13.5 g continuous infusion than with the 6.75 g continuous infusion against P aeruginosa and K pneumoniae (both, P < 0.001 vs 6.75 g continuous infusion against K pneumoniae). CONCLUSIONS: Piperacillin 12 g/tazobactam 1.5 g continuous infusion consistently resulted in serum concentrations above the breakpoint for Enterobacteriaceae and many of the susceptible strains of P aeruginosa in this study in 11 healthy subjects. Randomized controlled clinical trials are warranted to determine the appropriate dose of piperacillin/tazobactam.

Adult↗
PubMed2004

In vitro activities of antibiotic combinations against clincal isolates of Pseudomonas aeruginosa.

Combination therapy has been recommended to treat Pseudomonas aeruginosa infections worldwide. The purpose of the present study was to determine the in vitro activities of piperacillin, cefepime, aztreonam, amikacin, and ciprofloxacin alone and in combination against 100 clinical isolates of P. aeruginosa from one medical center in southern Taiwan. The combination susceptibility assay was performed using the checkerboard technique. The percentage of resistance of P. aeruginosa to single agents in our study was relatively high for the Asia-Pacific area, except to aztreonam. Piperacillin plus amikacin exhibited the highest potential for synergy (59/100) in this study. Moreover, a high percentage of synergism was also noted with amikacin combined with cefepime (7/100) or aztreonam (16/100). The combination of two beta-lactams, such as cefepime with piperacillin, and aztreonam with cefepime or piperacillin, showed synergistic effects against some P. aeruginosa isolates. Although ciprofloxacin is a good anti-pseudomonal agent, a very low potential for synergy with other antibiotics was demonstrated in this study. No antagonism was exhibited by any combination in our study. Among piperacillin-resistant strains, there was synergy with a beta-lactam plus amikacin, including the combination of piperacillin and amikacin. However, the combination of two beta-lactams, such as piperacillin and cefepime or aztreonam, did not have any synergistic activity against these strains. In summary, the combinations of amikacin with the tested beta-lactams (piperacillin, aztreonam, cefepime) had a greater synergistic effect against P. aeruginosa, even piperacillin-resistant strains, than other combinations. Understanding the synergistic effect on clinical strains may help clinicians choose better empirical therapy in an area with high prevalence of multidrug-resistant P. aeruginosa.

Amikacin↗
PubMed1978

In vitro studies of piperacilin, a new semisynthetic penicillin.

Piperacillin, a new semisynthetic penicillin, was compared with other semisynthetic penicillins, cephalosporins, and aminoglycosides by the agar dilution method against 3,600 isolates of facultative gram-negative bacilli, Bacteroides fragilis, and enterococci. At 64 mug/ml, piperacillin inhibited 90% of the isolates in each group of organisms tested except for Escherichia coli (83% inhibited by 64 mug/ml). Compared with carbenicillin, piperacillin had a 16-fold increase in activity by weight against Pseudomonas aeruginosa and the enterococcus, an 8-fold increase against Serratia marcescens, and a 4-fold increase against B. fragilis and Enterobacter species. Piperacillin was highly active against carbenicillin-resistant Klebsiella pneumoniae and inhibited many aminoglycoside-resistant organisms. Except for P. aeruginosa, the minimum bactericidal concentration of piperacillin was usually within one tube dilution of the minimum inhibitory concentration. Approximately one-third of the gram-negative bacilli were inhibited synergistically by piperacillin plus amikacin, but no synergy could be demonstrated against enterococci. Piperacillin's in vitro activity against gram-negative bacilli was similar to gentamicin's except that it also included B. fragilis, and piperacillin was decidedly superior to presently available penicillins against K. pneumoniae.

Amikacin↗
PubMed1985

[6R-[(R)-2-[3-[2-(p-Aminosulfonyl)anilino-4-hydroxy-5- pyrimidinyl]ureido]-2-(4-hydroxyphenyl)acetamido]-penicillanic acid, sodium salt (VX-VC 43), a new broad-spectrum beta-lactam antibiotic. In vitro and in vivo antibiotic activity].

6R-[(R)-2-[3-[2-(p-Aminosulfonyl) anilino-4-hydroxy-5-pyrimidinyl] ureido]-2-(4-hydroxyphenyl)acetamido]-penicillanic acid, sodium salt (VX-VC 43), a pyrimidinylureidopenicillin, is a broad-spectrum antibiotic. In vitro it is more active than piperacillin, apalcillin and mezlocillin especially against the following strains; E. coli, Ps. aeruginosa, Ps. stutzeri, K. pneumoniae, Eb. cloacae, Ser. marcescens, Proteus, Sh. flexneri, Y. enterocolitica, Cb. freundii, Acb. calcoaceticus, Bacteroides and Sc. faecalis. The minimal inhibitory concentration (MIC, micrograms/ml), for VX-VC 43 lies between 0.06 and 4 for piperacillin between 0.25 and 16, for apalcillin between 0.25 and 8, and for mezlocillin between 0.5 and 32. The action of VX-VC 43 is bactericidal. In tests against patient-isolates of E. coli (n = 50), Ps. aeruginosa (n = 50), K. pneumoniae (n = 46) and Eb. cloacae (n = 50) VX-VC 43 is clearly more active than Piperacillin. In the case of Ps. aeruginosa 2 micrograms/ml VX-VC 43 inhibits 43.9% of the bacteria and 8.5% with piperacillin; for E. coli 0.25 micrograms/ml inhibits 43.9% with VX-VC 43 and 0% with piperacillin; for K. pneumoniae 4 micrograms/ml inhibits 43.7% with VX-VC 43 and 28% for piperacillin; with Eb. cloacae 2 micrograms/ml inhibits 78% with VX-VC 43 and 4% with piperacillin. Addition of 50% human serum, or a change in culture medium pH (from 6 to 8) has little or no effect on the MIC of VX-VC 43 or piperacillin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Interactions of tazobactam and clavulanate with inducibly- and constitutively-expressed Class I beta-lactamases.

Clavulanate and tazobactam (YTR 830) were tested as inhibitors and inducers of the AmpC-type Class I beta-lactamases of Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii and the Ic beta-lactamase of Proteus vulgaris. Both clavulanate and tazobactam inhibited the Pr. vulgaris Class Ic beta-lactamase and potentiated ticarcillin and piperacillin against beta-lactamase derepressed variants of this species. Tazobactam, but not clavulanate, also had some ability to inhibit the AmpC Class I enzymes of M. morganii, C. freundii, Ps. aeruginosa, E. cloacae and S. marcescens. The piperacillin + tazobactam combination, unlike ticarcillin + clavulanate, showed some degree of synergy against most derepressed strains of these species. This behaviour partly depended upon the greater inhibitory activity of tazobactam for the enzymes, but also on piperacillin being easier to potentiate than ticarcillin. The synergy between piperacillin and tazobactam was greatest for M. morganii and C. freundii, least for Ps. aeruginosa and E. cloacae. Unfortunately, it is in the last two species that these enzymes pose the greatest resistance threat. Tazobactam caused little or no antagonism of piperacillin against beta-lactamase inducible species, whereas clavulanate antagonized ticarcillin against beta-lactamase inducible strains of E. cloacae and M. morganii (not other species). The antagonism of ticarcillin was attributable to beta-lactamase induction. The lack of antagonism with the tazobactam+piperacillin combination was related to tazobactam being a weaker inducer than clavulanate, not to piperacillin being less susceptible to antagonism than ticarcillin.

Bacteria↗
PubMed2001

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Adipose Tissue↗
PubMed1996

Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.

Animals↗
PubMed2004

In vitro and in vivo activities of novel 6-methylidene penems as beta-lactamase inhibitors.

Novel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as beta-lactamase inhibitors. The concentrations of these molecules that resulted in 50% inhibition of enzyme activity were 0.4 to 3.1 nM for the TEM-1 enzyme, 7.8 to 72 nM for Imi-1, 1.5 to 4.8 nM for AmpC, and 14 to 260 nM for a CcrA metalloenzyme. All the inhibitors were more stable than imipenem against hydrolysis by hog and human dehydropeptidases. Piperacillin was combined with a constant 4-microg/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2- to 32-fold for extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae strains. The MICs for piperacillin-resistant (MIC of piperacillin, >64 microg/ml) strains of Enterobacter spp., Citrobacter spp., and Serratia spp. were reduced to the level of susceptibility (MIC of piperacillin, < or =16 microg/ml) when the drug was combined with 4, 2, or 1 microg of these penem inhibitors/ml. Protection against acute lethal bacterial infections with class A and C beta-lactamase- and ESBL-producing organisms in mice was also demonstrated with piperacillin plus inhibitor. Median effective doses were reduced by approximately two- to eightfold compared to those of piperacillin alone when the drug was combined with the various inhibitors at a 4:1 ratio. Pharmacokinetic analysis after intravenous administration of the various inhibitors showed mean residence times of 0.1 to 0.5 h, clearance rates of 15 to 81 ml/min/kg, and volumes of distribution between 0.4 and 2.5 liters/kg. The novel methylidene penem molecules inhibit both class A and class C enzymes and warrant further investigation for potential as therapeutic agents when used in combination with a beta-lactam antibiotic.

Animals↗
PubMed1999

[Biliary diffusion of tazocillin in man].

The objective of this study was to determine the extent of biliary excretion of tazocillin, a combination of piperacillin and tazobactam administered as an intravenous infusion in a dose of 4 g of piperacillin and 0.5 g of tazobactam. In 10 patients, piperacillin and tazobactam levels were determined in serum, main bile duct bile, gallbladder bile, and gallbladder wall specimens harvested during a cholecystectomy procedure 1 h after completion of a tazocillin infusion. In five other patients, piperacillin and tazobactam levels were determined in bile collected from a main bile duct T-tube during 12 h following a tazocillin infusion given seven days after cholecystectomy. HPLC was used to assay both compounds. Piperacillin and tazobactam levels in the intraoperative specimens were as follows: 69.1 +/- 13.8 and 9.9 +/- 1.7 micrograms/ml, respectively, in the serum; 630 +/- 133 and 11.9 +/- 2.2 micrograms/ml, respectively, in the main bile duct bile; 342 +/- 114 and 7.7 +/- 2.3 micrograms/ml, respectively, in the gallbladder bile; and 49.3 +/- 20.2 and 2.9 +/- 0.6 micrograms/g, respectively, in the gallbladder wall. In the T-tube bile specimens, peak piperacillin and tazobactam levels were 358 +/- 281 and 9.9 +/- 3.3 micrograms/ml, respectively, after 1 h; total biliary excretion over 12 hours was 28.3 +/- 18.0 mg and 1.0 +/- 0.5 mg, i.e., 0.7 +/- 0.4% and 0.2 +/- 0.1% of the dose, respectively. The levels of piperacillin and tazobactam found in bile and gallbladder wall specimens in this study suggest that tazocillin may prove valuable for the prevention and treatment of biliary infections.

Bile↗
PubMed1986

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Adult↗