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Piperacillin/Tazobactam

1999; Adis, Springer Healthcare; Volume: 57; Issue: 5 Linguagem: Inglês

10.2165/00003495-199957050-00017

1179-1950

Caroline M. Perry, Anthony Markham,

Pneumocystis jirovecii pneumonia detection and treatment

Piperacillin/tazobactam is a β-lactam/β-lactamase inhibitor combination with a broad spectrum of antibacterial activity encompassing most Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria, including many pathogens producing β-lactamases. Evidence from clinical trials in adults has shown that piperacillin/tazobactam, administered in an 8: 1 ratio, is an effective treatment for patients with lower respiratory tract, intra-abdominal, urinary tract, gynaecological and skin/soft tissue infections, and for fever in patients with neutropenia. Combination regimens of piperacillin/tazobactam plus an aminoglycoside are used to treat patients with severe nosocomial (hospital-acquired) infections. In clinical trials, piperacillin/tazobactam was significantly more effective than ticarcillin/clavulanic acid in terms of clinical and microbiological outcome in patients with community-acquired pneumonia. In patients with intra-abdominal infections, clinical and bacteriological response rates were significantly higher with piperacillin/tazobactam than with imipenem/cilastatin (administered at a dosage lower than is recommended in countries outside Scandinavia). Piperacillin/tazobactam in combination with amikacin was at least as effective as ceftazidime plus amikacin in the treatment of ventilator-associated pneumonia and was significantly more effective than ceftazidime plus amikacin in the empirical treatment of febrile episodes in patients with neutropenia or granulocytopenia. In other trials, the efficacy of piperacillin/tazobactam was similar to that of standard aminoglycoside-containing and other treatment regimens in patients with intra-abdominal, skin/soft tissue or gynaecological infections. Piperacillin/tazobactam is generally well tolerated. The most frequent adverse events are gastrointestinal symptoms (most commonly diarrhoea) and skin reactions. The incidence of adverse events with piperacillin/tazobactam is higher when the combination is given in combination with an aminoglycoside than when given as monotherapy. Conclusion: Because of the broad spectrum of antibacterial activity provided by piperacillin/tazobactam, it is useful for the treatment of patients with polymicrobial infections caused by aerobic or anaerobic β-lactamase-producing bacteria. Piperacillin/tazobactam appears to have a particularly useful role in the treatment of patients with intra-abdominal infections and, in combination with amikacin, in the treatment of patients with febrile neutropenia, especially given the current prevalence of Gram-positive infections in this group. Although piperacillin has a broad spectrum of antibacterial activity, the increased prevalence of β-lactamase-producing bacteria over recent years has led to an increase in resistance to this agent, and has compromised its activity in the clinical setting. When coadministered with piperacillin, tazobactam, a β-lactamase inhibitor, restores and extends the antibacterial cover provided by piperacillin and thus enhances its clinical potential. Tazobactam shows good inhibitory activity against plasmid-mediated β-lactamases, staphylococcal penicillinase and chromosomal 2e β-lactamases. However, it is less inhibitory against group 1 β-lactamase subtypes and against group 3 metallo-β-lactamases. Tazobactam has a minimal ability to induce chromosomally mediated class I β-lactamases, whereas clavulanic acid is a moderate to strong inducer of these enzymes and thus has the potential to compromise the antibacterial activity of coadministered β-lactam agents. Piperacillin/tazobactam has good in vitro activity against methicillin-sensitive Staphylococcus aureus and coagulase-negative staphylococci. Piperacillin/tazobactam is also active against Streptococcus pyogenes and penicillin-sensitive strains of S. pneumoniae. Most strains of Enterococcus faecalis are also susceptible to the combination. Methicillin-resistant strains of S. aureus and many methicillin-resistant coagulase-negative staphylococci are resistant to piperacillin/tazobactam. Strains of E. faecium were resistant to piperacillin/tazobactam in 2 in vitro studies. Many Enterobacteriaceae, including Escherichia coli, Klebsiella spp. and Enterobacter spp. are susceptible to piperacillin/tazobactam. The combination exhibits excellent activity against Haemophilus influenzae and Moraxella catarrhalis and is active against Pseudomonas aeruginosa. Although there has been a change in susceptibility patterns of P. aeruginosa over recent years, with a general trend towards an increase in resistance to various antibacterial agents, piperacillin/tazobactam has maintained its activity against this pathogen: results of several recent surveys showed that 91 to 95% of isolates of P. aeruginosa were susceptible to piperacillin/tazobactam. Stenotrophomonas (Xanthomonas) maltophilia strains are resistant to the combination. Piperacillin/tazobactam is highly active against anaerobes, including Bacteroides spp., notably B. fragilis. It is also highly active against Clostridium spp. The combination demonstrated good efficacy in murine models of intra-abdominal infection or pneumonia caused by extended spectrum β-lactamase-producing strains of K. pneumoniae. After single intravenous 4/0.5g doses of piperacillin/tazobactam, mean maximum plasma concentrations (Cmax) of piperacillin and tazobactam were 264.4 to 368 and 29.1 to 39 mg/L, respectively, in healthy adult volunteers. There was no evidence of accumulation of either agent after multiple doses in healthy adult volunteers or in adult patients with infection. The ratio of piperacillin Cmax to tazobactam Cmax was about 8: 1 in healthy volunteers or in patients with intra-abdominal infections after multiple doses of 4/0.5g 6- or 8-hourly. However, mean piperacillin area under the plasma concentration-time curve (AUC) values were >2-fold higher in patients with burns than in healthy volunteers or in patients with intra-abdominal infections. At steady-state, the volume of distribution of piperacillin ranged from 15 to 21L in healthy volunteers and patients with infection; the corresponding range for tazobactam was 18 to 34.6L. Both agents are rapidly and widely distributed in various body tissues and fluids. About 50 to 60% of an administered dose of piperacillin/tazobactam is excreted via the renal route; biliary excretion accounts for the elimination of <2% of the dose. In healthy volunteers or patients with intra-abdominal infection, piperacillin and tazobactam each have a plasma elimination half-life of 0.8 to 1 hour. Dosage reduction is required for patients with moderate renal impairment [creatinine clearance <1.2 L/h (<20 ml/min)]. As haemodialysis removes up to 50% of piperacillin/tazobactam over 4 hours, an additional 2/0.25g dose should be given after each dialysis session. The pharmacokinetics of piperacillin/ tazobactam are not markedly affected in patients with hepatic impairment. In children with infection, mean Cmax and AUC values of piperacillin and tazobactam increase in a dose-dependent manner. The pharmacokinetics of piperacillin and tazobactam are not markedly altered when it is coadministered with vancomycin, tobramycin, ondansetron or ranitidine. Clinical cure or improvement was achieved in 85 to 94% of patients with community-acquired lower respiratory tract infections treated with various dosages of piperacillin/tazobactam. At a dosage of 3/0.375g 6-hourly, piperacillin/ tazobactam was significantly more effective than ticarcillin/clavulanic acid 3/0. 1g 4 times daily in patients with community-acquired pneumonia. Evaluations at the trial end-point (generally 10 to 14 days after discontinuation of treatment) showed favourable clinical responses in 84 and 64% of piperacillin/ tazobactam and ticarcillin/clavulanic acid recipients, respectively (p < 0.01). Piperacillin/tazobactam also achieved a significantly higher rate of bacterial eradication than ticarcillin/clavulanic acid at the end of treatment (91 vs 68%; p < 0.01) and 10 to 14 days later (91 vs 83%; p = 0.02). In patients with nosocomial pneumonia associated with mechanical ventilation in the intensive care unit, piperacillin/tazobactam 4/0.5g 4 times daily plus amikacin 7.5 mg/kg twice daily was at least as effective as ceftazidime 1g 4 times daily plus amikacin 7.5 mg/kg twice daily, with successful clinical and bacteriological outcomes documented in 51 and 36% of piperacillin/tazobactam- and ceftazidime-treated patients 6 to 8 days after the end of treatment. The efficacy of piperacillin/tazobactam was similar to that of imipenem/cilastatin in patients with nosocomial pneumonia. In patients with hospital-acquired acute purulent bronchitis or acute bacterial pneumonia, piperacillin/tazobactam 3/0.375g every 4 hours (plus tobramycin or amikacin) was significantly more effective than ceftazidime 2g every 8 hours (plus tobramycin or amikacin); clinical responses at the study end-point were achieved in 75 and 50% of patients (p < 0.01). Rates of bacterial eradication ranged from 76 to 100% in patients with intra-abdominal infections treated with piperacillin/tazobactam. The clinical efficacy of piperacillin/tazobactam was similar to that of clindamycin plus gentamicin and in 1 study was significantly better than that of imipenem/cilastatin 0.5g 8-hourly (a dosage lower than is recommended in countries outside Scandinavia). Piperacillin/tazobactam (80/10 mg/kg 8-hourly) was also beneficial in the treatment of children with appendicitis or peritonitis, with 91% of patients experiencing cure or improvement. Clinical success rates of 41 to 83% were reported in patients with febrile neutropenia or granulocytopenia who received empirical treatment with piperacillin/tazobactam 12–16/1.5–2 g/day (in divided doses) in combination with an aminoglycoside. 72 hours after the initiation of treatment, clinical response rates were significantly higher in patients treated with piperacillin/tazobactam plus amikacin than in ceftazidime plus amikacin-treated patients (61% vs 45 or 54%; p ≤ 0.05). In similar patients, piperacillin/tazobactam in combination with gentamicin was significantly more effective than piperacillin/gentamicin; clinical response rates of 83 and 48% (p < 0.001) were reported at 72 hours. The efficacy of piperacillin/tazobactam monotherapy was similar to that of ceftazidime plus amikacin in patients with febrile neutropenia with 81 and 83% of febrile episodes resolved in patients treated with piperacillin/tazobactam and ceftazidime plus amikacin; median times to fever defervescence were also similar in the 2 treatment groups (3.3 vs 2.9 days). The piperacillin/tazobactam combination also showed good clinical and bacteriological efficacy in patients with bacteraemia and in patients with skin and soft tissue, gynaecological or bone and joint infections. Piperacillin/tazobactam is also an effective treatment for patients with complicated urinary tract infections, achieving cure or improvement in 88 and 90.4% of patients 5 to 9 days after the end of treatment and in ≥80% of patients after 4 to 6 weeks of follow-up. Bacterial eradication rates after the same period of follow-up were 79.6 and 73%; E. coli, K. pneumoniae and P. aeruginosa were identified as common persistent pathogens. In a US economic evaluation, piperacillin/tazobactam was estimated to be less costly than comparator therapies in patients with community-acquired lower respiratory tract or intra-abdominal infection. Direct costs of therapy with piperacillin/tazobactam 3/0.375g 6-hourly were $US2981 per patient lower than with ticarcillin/clavulanic acid 3/0.1g 6-hourly in patients with community-acquired pneumonia. In patients with intra-abdominal infections, direct costs of piperacillin/tazobactam treatment were $US284 per patient lower than costs of treatment with clindamycin plus gentamicin. A UK study showed that direct costs of treatment of patients with intra-abdominal infections were lower for piperacillin/tazobactam than for ceftazidime plus metronidazole alone or in combination with either gentamicin or netilmicin. Costs of acquisition, preparation, administration and waste disposal were included in this analysis. However, although the acquisition cost of piperacillin/tazobactam is lower than that of imipenem/cilastatin, a comparative cost analysis showed a cost advantage for the latter combination when the number of days spent in hospital was included in the economic model. Results of a Canadian study that included patients with various serious infections showed that direct per patient costs of piperacillin/tazobactam and imipenem/cilastatin were broadly similar ($Can696 vs $Can762). A pharmacoeconomic study, based on data from a trial conducted in patients with febrile neutropenia, showed that piperacillin/tazobactam plus amikacin was more cost effective than ceftazidime plus amikacin: estimated costs per successfully treated patient were DM16 616 and DM20 828 for piperacillin/tazobactam plus amikacin and ceftazidime plus amikacin, respectively. Both direct and indirect costs of treatment were incorporated in this model. Pooled data from numerous clinical trials indicate that piperacillin/tazobactam, given in dosages of up to 4/0.5g 6-hourly, is generally well tolerated in patients with mild, moderate or severe infections. The most frequently reported adverse events are gastrointestinal symptoms (most commonly diarrhoea) and skin reactions. Adverse events are typically mild or moderate in severity and rarely necessitate the discontinuation of treatment. Incidences of these types of events increase markedly in patients receiving piperacillin/tazobactam in combination with an aminoglycoside. Other adverse events reported in patients receiving piperacillin/tazobactam include minor changes in laboratory test values (e.g. increases in alanine amino-transferase and in total bilirubin). Pseudomembranous colitis, bleeding manifestations and anaphylactic reactions have been reported in patients receiving penicillins, including piperacillin. Piperacillin/tazobactam is given intravenously as a bolus injection over 3 to 5 minutes or by infusion over 20 to 30 minutes. Recommended dosages range from 2/0.25g every 6 to 12 hours (for the treatment of patients with relatively mild infections) to 4/0.5g every 6 or 8 hours for the treatment of more severe infections.