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Effects of sodium piperacillin on platelet function in normal volunteers.

Piperacillin is a new semisynthetic penicillin which is similar in structure to carbenicillin and ticarcillin. Since the latter antibiotics have been shown to cause abnormalities in hemostasis, we studied the effects of piperacillin on blood coagulation and platelet function. Fifteen healthy volunteers received the drug in doses of either 100, 200, or 300 mg/kg per day for a period of 7 days. Serial studies showed no abnormalities in blood coagulation in any subject. Decreased platelet aggregation responses to adenosine diphosphate, epinephrine, collagen, and achidonic acid were commonly noted, but prolongation of the bleeding time occurred in only 3 of 15 subjects after 7 days of piperacillin administration. These results suggest that although piperacillin also induces platelet dysfunction, these effects may be less than those caused by ticarcillin or carbenicillin at an equivalent dosage.

Blood Coagulation↗

Comparative pharmacokinetics of azlocillin and piperacillin in normal adults.

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.

Adult↗

In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa.

A total of 103 isolates of Pseudomonas aeruginosa were studied to compare the in vitro effectiveness of three beta-lactam antibiotics (piperacillin, ticarcillin, and mezlocillin) when used alone and in combination with four aminoglycosides (tobramycin, gentamicin, amikacin, and netilmicin). All drugs were tested as single agents against a standard inoculum (5 X 10(5) CFU/ml). The three antipseudomonal penicillins were also tested against the isolates at a higher inoculum concentration (10(7) CFU/ml). Synergy testing was performed by the two-dimensional checkerboard method and was defined by a fractional bactericidal index of less than or equal to 0.5 and bacterial killing accomplished at antibiotic concentrations no greater than those achievable in serum. All combinations were assessed for synergy. The degree of synergy was further analyzed by dividing the isolates into groups based on their susceptibility and resistance to the individual agents in the combination. The overall effectiveness of the various aminoglycoside-antipseudomonal penicillin combinations was assessed regarding their ability to kill the isolates either as single agents or through synergy. Piperacillin was the most active antipseudomonal penicillin, and tobramycin and amikacin were the most active aminoglycosides when used as single agents. When tested against isolates at a higher inoculum concentration, ticarcillin was significantly more active than the other beta-lactams. The highest degree of overall synergy was noted with gentamicin-ticarcillin (78.2% of strains) and amikacin-piperacillin (77% of strains). When assessed for overall effectiveness, all combinations containing amikacin were the most active. The combination of amikacin-piperacillin was the most effective, with activity against 96% of all isolates.

Aminoglycosides↗

Randomized trial comparing ciprofloxacin plus netilmicin versus piperacillin plus netilmicin for empiric treatment of fever in neutropenic patients.

To assess the efficacy of ciprofloxacin in neutropenic patients, we conducted a randomized prospective trial comparing the combination of ciprofloxacin and netilmicin against piperacillin plus netilmicin as an empiric treatment of fever in cancer patients with neutropenia. Of 214 evaluable episodes, 115 and 99 were randomly assigned to the ciprofloxacin and the piperacillin arms, respectively. The overall response rates were very similar (59 and 62% for the ciprofloxacin and piperacillin arms, respectively). The response for the gram-positive bacteremias was almost identical (around 40%); this low response was due in part to an outbreak of infection by a multiply resistant strain of Staphylococcus epidermidis (for which the ciprofloxacin MIC was greater than or equal to 128 micrograms/ml) which occurred during the second half of the trial. Among gram-negative bacteremias, 9 of 11 infections (82%) responded to the ciprofloxacin combination compared with 3 of 7 (43%) that responded to the piperacillin combination (P = 0.23). The incidences of persistent, profound neutropenia were comparable in both treatments, but the susceptibility of the gram-negative organism to ciprofloxacin and netilmicin was significantly higher than was susceptibility to the other combination. Ciprofloxacin was well tolerated, and patients were able to convert from intravenous to oral therapy in 64 of 115 episodes.

Administration, Oral↗

Antipseudomonal activity of simulated infusions of gentamicin alone or with piperacillin assessed by serum bactericidal rate and area under the killing curve.

The objectives of this study were to (i) determine which of three simulated dosing regimens (gentamicin alone, simultaneous infusions of gentamicin and piperacillin, or staggered infusions of gentamicin and piperacillin) produced the fastest killing rate of Pseudomonas aeruginosa in serum, using the serum bactericidal rate (SBR) assay; and (ii) describe an alternative method of analysis of killing curves, the area under the killing curve (AUKC). Gentamicin alone or combined with piperacillin was added to heat-inactivated human serum to approximate drug concentrations achieved after the above-mentioned types of infusion. By a microdilution technique, seven strains of P. aeruginosa were exposed to no drug (control) and gentamicin alone or with piperacillin; colony counts were determined at hourly intervals for 5 h, and log10 CFU per milliliter was plotted versus time. Linear regression was used to calculate the slope (SBR) of each timed killing curve for each drug concentration tested alone or in combination. In addition, the AUKC for each curve was calculated. To compare simulated infusion regimens further, the cumulative AUKC (the sum of AUKCs for specific time points along the serum concentration-time curve for each simulated regimen) was calculated. With the SBR assay or AUKC determination, there was a significant increase in the rate of killing of all test strains by the combination compared with gentamicin alone only at gentamicin concentrations which exceeded the MIC (8, 5, and 2.5 micrograms/ml). Mean cumulative AUKC of the simultaneous-infusion regimen was significantly less (indicating faster killing) than either the staggered-infusion regimen or the gentamicin infusion alone. Both the SBR and AUKC have the potential for integration of in vitro microbiologic effects and in vivo pharmacokinetics of antimicrobial agents.

Blood Bactericidal Activity↗

Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group.

Empiric therapy for febrile granulocytopenic patients is mandatory, but whether monotherapy is a safe alternative and whether fluoroquinolones are useful agents for this indication are still controversial issues. The use of monotherapy with intravenous ciprofloxacin (200 to 300 mg every 12 h) was evaluated against combined therapy with piperacillin plus amikacin in febrile granulocytopenic patients with solid tumor or lymphoma. The study was discontinued prematurely because patients treated with ciprofloxacin had a significantly lower overall success rate than patients treated with piperacillin plus amikacin (31 of 48 patients [65%] versus 48 of 53 patients [91%], P = 0.002). Patients with gram-positive coccal bacteremia had a particularly poor outcome: therapy failed for six of eight patients (75%) treated with ciprofloxacin, while therapy failed for none of four patients treated with piperacillin plus amikacin. Death from primary infection during initially randomized protocol therapy occurred in 7 of 48 patients (14.5%) treated with ciprofloxacin and in 3 of 53 (6%) treated with piperacillin plus amikacin. This study does not support the use of this dose of intravenous ciprofloxacin as empiric monotherapy for fever in granulocytopenic patients.

Adult↗

Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin Structure Study Group.

We compared the efficacy and safety of two beta-lactam-beta-lactamase inhibitor combinations, namely, piperacillin-tazobactam and ticarcillin-clavulanate, in the treatment of complicated bacterial infections of skin that required hospitalization. The study was a randomized, double-blind, comparative trial involving 20 centers. The infections were classified as (i) cellulitis with drainage, (ii) cutaneous abscess, (iii) diabetic or ischemic foot infection, and (iv) infected wounds and ulcers with drainage. The clinical response rates were comparable for the two treatment regimens (61% of the patients were cured with piperacillin-tazobactam and ticarcillin-clavulanate and improvement was seen in 15 and 16% of patients treated with piperacillin-tazobactam and ticarcillin-clavulanate, respectively). Both regimens were found to be safe and well tolerated. These data support the use of piperacillin-tazobactam for initial empiric therapy of hospitalized patients with complicated skin and skin structure infections.

Bacteroides Infections↗

Piperacillin and tazobactam exhibit linear pharmacokinetics after multiple standard clinical doses.

A population pharmacokinetic (PK) analysis was conducted to determine if piperacillin and tazobactam exhibited linear or nonlinear PKs and if incremental changes in the daily dosage of piperacillin affected tazobactam PKs. Four dosage groups were evaluated after multiple dosing regimens. Concentrations of drug in plasma and amounts in urine were best fitted by using a linear two-compartment PK model. No significant difference between dosing groups was seen for any piperacillin or tazobactam PK parameters. Both drugs exhibited linear PKs when given at usual clinical doses. Tazobactam PKs did not appear to be affected by the different dosing regimens of piperacillin.

Drug Therapy, Combination↗

Clinafloxacin versus piperacillin-tazobactam in treatment of patients with severe skin and soft tissue infections.

Patients (n = 409) with severe skin and soft tissue infections (SSTIs) were randomized to receive clinafloxacin or piperacillin-tazobactam (plus optional vancomycin for methicillin-resistant cocci), administered intravenously, with the option to switch to oral medication. Most patients had cellulitis, wound infections, or diabetic foot infections. Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa were the most common baseline pathogens. Fewer baseline pathogens were resistant to clinafloxacin (1.8%) than to piperacillin-tazobactam (6.2%) (P = 0.001). The clinafloxacin and piperacillin-tazobactam groups did not differ significantly in clinical cure rates (68.8 and 65.2%, respectively) or microbiologic eradication rates (61.5 and 57.2%). Clinafloxacin yielded higher eradication rates for all three of the most common pathogenic species, although no differences were statistically significant. Within the power of this study, the overall frequency of adverse events was similar (P = 0.577) in the two treatment groups. Drug-associated adverse events (P = 0.050) and treatment discontinuations (P = 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin. Although most cases of phototoxicity were mild to moderate, four cases were reported as severe. In summary, clinafloxacin monotherapy was equivalent in effectiveness to therapy with piperacillin-tazobactam plus optional vancomycin in the treatment of hospitalized patients with severe SSTIs.

Adolescent↗

Penetration of piperacillin into bronchial mucosa and sputum.

Bronchial mucosal biopsies were obtained during fibreoptic bronchoscopy in 12 patients receiving a new semisynthetic penicillin, piperacillin. The piperacillin levels estimated in bronchial mucosa exceeded those required to eradicate organisms associated with acute bronchitis, Haemophilus influenzae and Streptococcus pneumoniae, and compared favourably with those required for activity against a wide variety of anaerobic and Gram-negative organisms including Pseudomonas aeruginosa. Sputum and serum piperacillin levels were obtained from eight patients with bronchial disease receiving a five to seven day course (8 to 16 g/day). Sputum/serum level ratios were constant for the two dosages (10.7% for 8 g/day; 14.3% for 16 g/day) suggesting a diffusion transfer process, although the presence of pus in the sputum appeared to facilitate penetration. Seven patients achieved sputum levels exceeding those required for activity against Haemophilus influenzae and Streptococcus influenzae, and four for Pseudomonas aeruginosa. This study provides pharmacolinetic support of the use of piperacillin in bronchopulmonary infection.

Aged↗

Adverse reactions to piperacillin in adults with cystic fibrosis.

Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin (59 courses in all) during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic. The fever resolved shortly after the piperacillin treatment was stopped, as did the widespread rashes in the two patients who developed them. Three of four patients who had probable reactions to azlocillin may have been sensitised by piperacillin. As piperacillin does not appear to be any more effective than other antipseudomonal penicillins in cystic fibrosis, it is no longer used at the hospital for treating bronchopulmonary exacerbations in such patients.

Adult↗

Elimination of piperacillin and tazobactam by renal replacement therapies with AN69 and polysulfone hemofilters: evaluation of the sieving coefficient.

BACKGROUND/AIM: Piperacillin-tazobactam is commonly used to treat infections in ICU patients. Controversial data have been published about the sieving/saturation coefficient (Sc/Sa) of piperacillin during continuous renal replacement therapies (CRRT). The objective was to evaluate the Sc/Sa of piperacillin-tazobactam during continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) using AN69 and polysulfone. METHODS: Ringer lactate, BSA-containing Ringer lactate and plasma were circulated at 150 ml/min. The ultrafiltrate/dialysis flow was kept at 1,500 ml/min. A bolus was injected and samples were taken. Drugs were measured using HPLC. Sc/Sa was calculated according to standard formula. RESULTS: Free passage of drugs through the membranes was reported with protein free solutions. In the presence of proteins the Sc/Sa lowered and correlated to protein free fraction. Polysulfone had a significantly higher permeability than AN69 during CVVH. CONCLUSION: Drug binding to albumin contributes to the decrease of the Sc/Sa of piperacillin but it does not completely justify the in vivo value obtained by some authors.

Acrylic Resins↗

Clinical evaluation of piperacillin.

28 patients with aerobic (7), anaerobic (7), and mixed (14) infections were treated with intravenous piperacillin for an average duration of 14 days. All bacterial isolates tested in this study were susceptible to piperacillin less than or equal to 128 micrograms/ml. 27 patients were treated with 20 g of piperacillin/day in four divided doses. 1 patient with renal failure received only 8 g/day. 26 patients were treated with piperacillin and two with Staphylococcus aureus infection received gentamicin in addition. The peak serum levels were 266 micrograms/ml at 1 h and the trough 16 micrograms/ml at 5 h. In all, 26 patients (93%) were 'cured', one had 'recurrence', and one 'failed'. Adverse effects were pruitus in two patients, transient elevation of LDH in one, and transient eosinophilia in another. In our preliminary study, piperacillin was found to be safe and effective in the treatment of clinical infections.

Adult↗

Combination effect of piperacillin with four aminoglycosides on nonfermenting gram-negative bacteria.

The in vitro efficacy of piperacillin in combination with gentamicin, tobramycin, amikacin and netilmicin against 57 nonfermenting gram-negative bacterial strains was compared by use of the checkerboard agar dilution technique. On average 34% of all nonfermenting strains were inhibited by additive, 13% by synergistic piperacillin-amino-glycoside combinations. Great variation occurred between the different bacterial species. Piperacillin-aminoglycoside combinations were most active on Pseudomonas aeruginosa and least potent on Pseudomonas cepacia. Piperacillin was highly active against P. aeruginosa, P. cepacia, Pseudomonas fluorescens-putida and Acinetobacter species.

Aminoglycosides↗

Agar (disk) diffusion test susceptibility of clinical isolates of Pseudomonas aeruginosa to azlocillin, cefotaxime, cefsulodin, lamoxactam, mezlocillin, and piperacillin.

The standardized Bauer-Kirby agar diffusion test served to examine 100 clinical isolates of Pseudomonas aeruginosa against various recently introduced broad-spectrum penicillins and cephalosporins. Neither cefotaxime nor lamoxactam displayed significant activity against this microorganism. Azlocillin, cefsulodin, and piperacillin were significantly more effective (p less than 0.0001) than mezlocillin against the majority of isolates. When compared individually, azlocillin and piperacillin displayed comparable in vitro activity; the same was true for cefsulodin compared with piperacillin. On the other hand, cefsulodin was somewhat more active than azlocillin (p less than 0.05, greater than 0.01) against P. aeruginosa. These data should enable diagnostic laboratories to curtail the number of antimicrobial drugs routinely utilized to examine clinical isolates of P. aeruginosa for antibiotic susceptibility, i.e., piperacillin exclusively.

Azlocillin↗

Clinical evaluation of combination of cefmetazole and piperacillin in the treatment of infections in patients with acute leukemia.

27 episodes of infection in patients with acute leukemia were treated with combination of cefmetazole and piperacillin. Causative bacteria were isolated in each infection. The patients were treated with 6 g cefmetazole and 15 g piperacillin per day in three divided doses. Among the episodes of infection, 21 (78%) of 27 responded to cefmetazole and piperacillin. Adverse reactions were skin rash in 2 patients, transient elevation of serum glutamic-pyruvic transaminase in 3 patients and elevation of creatinine in 1 patient. Cefmetazole and piperacillin appear to be an effective combination, with acceptable adverse reactions, for the empiric therapy of infection in patients with acute leukemia.

Acute Disease↗

Piperacillin tazobactam compared with co-amoxiclav, ampicillin plus sulbactam and timentin against beta-lactamase-producing clinical isolates of Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca.

A total of 266 enterobacterial isolates (Escherichia coli = 190, Klebsiella pneumoniae = 49, K. oxytoca = 27) were tested for susceptibility (Bauer-Kirby agar disk diffusion test and agar dilution procedure) to ampicillin, ampicillin in 10 micrograms/ml of sulbactam, amoxicillin in 4 micrograms/ml of clavulanic acid, piperacillin, piperacillin plus tazobactam (8:1 ratio), ticarcillin and timentin (ticarcillin in 4 micrograms/ml of clavulanic acid). Discrepant results between the two methods of susceptibility testing were categorized as follows: category I = very major [minimal inhibitory concentration (MIC) = resistant, disk diffusion = susceptible] category II = major (MIC = susceptible, disk diffusion = resistant), category III = minor (MIC = intermediate susceptibility, disk diffusion = susceptible), category IV = slight (MIC = resistant, disk diffusion = intermediate), category V = minimal (MIC = susceptible, disk diffusion = intermediate) and category VI = negligible (MIC = intermediate, disk diffusion = resistant). The antibiotics, or combinations with beta-lactamase inhibitors, yielded the following discrepant results: ampicillin (II = 2, V = 1 and VI = 3), co-amoxiclav (I = 5, III = 25, IV = 1 and V = 3), ampicillin plus sulbactam (I = 5, II = 3, III = 1, V = 19 and VI = 1), piperacillin (II = 15, III = 1, V = 15 and VI = 85), piperacillin plus tazobactam (III = 16, IV = 2, V = 1 and VI = 5) and timentin (I = 2, III = 48 and IV = 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗

Prolonged elimination of piperacillin in a patient with renal and liver failure.

A 22-year-old female with acute leukemia was admitted to the oncology center for evaluation and treatment. Piperacillin was used during her admission for treatment of Pseudomonal sepsis. The patient's renal and liver function deteriorated during the hospital course, requiring large dose adjustments of piperacillin. The elimination half-life of piperacillin was estimated to be 32 hours. Patients with both liver and renal disease require only small doses of piperacillin to achieve therapeutic plasma concentration.

Adult↗