Piperacillin/Tazobactam

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Abstract
Piperacillin/tazobactam is a β-lactam/β-lactamase inhibitor combination with a broad spectrum of antibacterial activity against most Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria. Piperacillin/tazobactam is effective and well-tolerated in patients with lower respiratory tract infections (LRTI), intra-abdominal infections, skin and soft tissue infections, and febrile neutropenia. In comparative clinical trials against various other antibacterial regimens, piperacillin/tazobactam has shown higher clinical success rates, particularly in the treatment of patients with intra-abdominal infections and febrile neutropenia. Cost analyses of piperacillin/tazobactam have been variable, in part, because of differences in specific costs included. Three US cost analyses found that piperacillin/tazobactam had lower total medical costs than clindamycin plus gentamicin or imipenem/cilastatin in intra-abdominal infections, and ticarcillin/clavulanic acid in community-acquired pneumonia. Piperacillin/tazobactam plus amikacin had lower total costs than ceftazidime plus amikacin in another cost analysis of patients with febrile neutropenic episodes modelled in nine European countries. However, piperacillin/tazobactam plus tobramycin was more costly than ceftazidime plus tobramycin in hospital-acquired pneumonia in a US cost analysis. In cost-effectiveness analyses, all studies of intra-abdominal infections, pneumonia and febrile neutropenic episodes consistently reported lower costs per unit of effectiveness versus comparators. Piperacillin/tazobactam was dominant (greater efficacy and lower costs) versus imipenem/cilastatin in intra-abdominal infections and ceftriaxone, ciprofloxacin or meropenem in pneumonia. Piperacillin/tazobactam plus amikacin was dominant over ceftazidime plus amikacin in the treatment of febrile neutropenic episodes. In a cost-effectiveness analysis of skin and soft tissue infection, piperacillin/tazobactam had lower costs per successfully treated patient than ceftriaxone or cefotaxime, but a slightly higher cost-effectiveness ratio than amoxicillin/clavulanic acid. All cost-effectiveness analyses were based on decision-analytical models. Conclusions: Piperacillin/tazobactam is likely to reduce overall treatment costs of moderate to severe bacterial infections by increasing initial treatment success, thereby reducing the length of hospital stay and the use of additional antibacterials. Piperacillin/tazobactam has shown clinical and economic advantages over standard antibacterial regimens in the treatment of intra-abdominal infections, LRTIs, febrile episodes in patients with neutropenia, and skin and soft tissue infections, although more complete published data are needed to confirm these results. Present data regarding clinical efficacy, bacterial resistance and costs would support the use of piperacillin/tazobactam as an empirical first-line option in moderate to severe bacterial infections. Costs associated with antibacterial treatment of moderate to severe infections include drug acquisition costs, preparation and administration, monitoring, hospitalisation, adverse effects, laboratory tests, treatment failure and the development of antibacterial resistance. Drug acquisition costs, the use of consumable materials in administration, and the time required to administer treatment regimens and monitor therapy can vary across different antibacterial treatment regimens. However, these costs are only a small part (7 to 12%) of total costs of treatment. Infection with antibacterial-resistant pathogens is associated with markedly worse outcomes and higher costs, as newer, more expensive antibacterials are required to eradicate resistant organisms. Nosocomial infection acquired during inpatient treatment is also associatedwith increased length of hospital stay, higher antibacterial failure rates and higher costs. Nosocomial infections commonly involve antibacterial-resistant organisms. Strict hygiene measures, antibacterial policies and epidemiological surveillance of bacterial organisms and resistance patterns are required to limit antibacterial resistance and nosocomial infection rates. Piperacillin/tazobactam has a broad spectrum of antibacterial activity against the majority of Gram-positive bacteria, Gram-negative bacteria, and anaerobes, notably Bacteroides fragilis and Clostridium spp. Resistant strains include methicillin-resistant Staphylococcus aureus, strains of Enterococcus faecium, Stenotrophomonas maltophilia, some Citrobacter spp. and some Pseudomonas spp. In noncomparative trials and randomised comparative double-blind trials, bacterial eradication and clinical success rates for piperacillin/tazobactam in the treatment of intra-abdominal infections, lower respiratory tract infections (LRTIs), febrile neutropenic episodes and skin and soft tissue infections are similar to those with other standard regimens for these indications. In particular, there have been several comparative trials of piperacillin/tazobactam versus imipenem/cilastatin in intra-abdominal infections, and piperacillin/tazobactam plus an aminoglycoside versus ceftazidime plus an aminoglycoside in febrile neutropenic episodes and pneumonia. In these trials, bacterial eradication rates and clinical response rates for piperacillin/tazobactam have been equivalent to those for imipenem/cilastatin. Clinical success rates for piperacillin/tazobactam plus an aminoglycoside were statistically higher than those for ceftazidime plus an aminoglycoside in most studies. Data from clinical trials and a postmarketing surveillance study indicate that piperacillin/tazobactam is well tolerated. When given as monotherapy, adverse effects have been reported in 1.5 to 9.1% of patients, with gastrointestinal symptoms (most commonly diarrhoea) and skin reactions being most frequently reported. The incidence of adverse events increases by more than two-fold when an aminoglycoside is added to piperacillin/tazobactam therapy. Several publications have suggested that reducing widespread use of thirdgeneration cephalosporins in favour of piperacillin/tazobactam and other β-lactam/β-lactamase inhibitor combinations reduces the incidence of bacterial resistance. In various hospitals in the US and the UK, antibacterial policy changes that replaced cephalosporins with piperacillin/tazobactam as first-line treatment led to a recovery of Klebsiella pneumoniae susceptibility and a reduction in the incidence of glycopeptide-resistant Enterococcus species. The effect of piperacillin/tazobactam on healthcare resources and costs has been assessed in 20 studies. In these studies, piperacillin/tazobactam therapy is compared with standard antibacterial regimens for the treatment of intra-abdominal infections, community- or hospital-acquired pneumonia, febrile neutropenic episodes, skin and soft tissue infections and other serious infections. Thirteen studies are cost analyses while seven are cost-effectiveness analyses; only five studies are published in full. Although confirmation is required from more complete published studies, present pharmacoeconomic data indicate that piperacillin/tazobactam is likely to reduce overall treatment costs in moderate to severe bacterial infections. Cost analyses. Three cost analyses evaluated only the costs related to the antibacterial regimens under study (drug acquisition, administration and preparation, consumables, monitoring of plasma drug concentrations and waste). In these analyses, piperacillin/tazobactamis reported to have lower costs than standard antibacterial regimens for pneumonia and intra-abdominal infections, including cefotaxime plus metronidazole with or without aminoglycosides. In the treatment of fever in patients with neutropenia, piperacillin/tazobactam plus amikacin was associated with lower antibacterial costs than ceftazidime plus amikacin. In a German cost analysis of patients with febrile neutropenic episodes, piperacillin/tazobactam was more costly than ceftriaxone plus gentamicin. However, when the costs of secondary antibacterials (for patients with treatment failure) were also included, total antibacterial costs were lower for patients receiving piperacillin/tazobactam [445 euros (EUR)] than ceftriaxone plus gentamicin (EUR1129).However, all of the above cost analyses failed to consider hospitalisation costs, which are the largest component of total medical costs in treating moderate to severe infections, and should be the focus of pharmacoeconomic analysis of antibacterial treatments. Other cost analyses have included total direct medical costs. Three US cost analyses found that piperacillin/tazobactam had lower total medical costs per patient than clindamycin plus gentamicin (cost savings of $US284; 1993 values) or imipenem/cilastatin (cost savings of $US718; 1999 values) in intra-abdominal infections and ticarcillin/clavulanic acid (adjusted cost savings of $US2981; 1993 values) in community-acquired pneumonia. Piperacillin/tazobactam plus amikacin was also reported to have lower total medical costs than ceftazidime plus amikacin in another cost analysis of patients with febrile neutropenic episodes modelled in nine European countries. One UK cost analysis reported that piperacillin/tazobactam and the combination of penicillin, gentamicin and metronidazole were cost equivalent in the treatment of intra-abdominal infections in paediatric patients. Piperacillin/tazobactam treatment was found to be more costly than treatment with imipenem/cilastatin in a Canadian cost analysis of serious infections and a US cost analysis of intra-abdominal infections. Additional costs of 979 Canadian dollars (1996 values) and $US2190 (1994 values) per patient per treatment regimen were reported. In both these studies the cost of treatment failures was higher in piperacillin/tazobactam recipients. Piperacillin/tazobactam plus tobramycin was shown to be more costly than ceftazidime plus tobramycin in hospital-acquired LRTI in a US cost analysis (additional adjusted cost of $US702 per patient per treatment regimen; 1993 values). A German cost analysis found that total direct medical costs were lower for patients with febrile neutropenia receiving piperacillin/tazobactam than for those receiving ceftazidime plus amikacin, but when indirect costs were also considered, piperacillin/tazobactam was slightly more costly ($US79 per patient per treatment regimen; 1998 values). Cost-effectiveness analyses. Cost-effectiveness analyses largely support the use of piperacillin/tazobactam, rather than other standard antibacterial regimens, for intra-abdominal infections, pneumonia, febrile neutropenic episodes and skin and soft tissue infections. However, only one analysis (of intra-abdominal infections) is reported in full. In analyses of intra-abdominal infections, treatment with piperacillin/tazobactam dominated treatment with imipenem/cilastatin in three studies (two from Germany and one from Spain). Incremental cost-effectiveness ratios suggest that cost savings of 1995 Deutschmarks (DM) [year of cost not given] to DM15 828 [1998 values] or between 265 736 and 2 401 275 pesetas (1995 values) would result for every additional patient successfully treated with piperacillin/tazobactam rather than imipenem/cilastatin. In the treatment of pneumonia, the cost per successfully treated patient was lower with piperacillin/tazobactam (DM6538) than ceftriaxone (DM11 942), ciprofloxacin (DM13 352) or meropenem (DM7720) [year of costs not given]. Piperacillin/tazobactam was more cost effective than cefotaxime or ceftriaxone in a German analysis of skin and soft tissue infections, but less cost effective than amoxicillin/clavulanic acid. The costs per successfully treated patient were DM3355, DM3638, DM4221 and DM6474 for amoxicillin/clavulanic acid, piperacillin/ tazobactam, ceftriaxone and cefotaxime, respectively (year of costs not given). Piperacillin/tazobactam plus amikacin had lower (i.e. more favourable) cost-effectiveness ratios than ceftazidime plus amikacin in two analyses in patients with fever and neutropenia conducted in Germany and Spain. In the Spanish study the cost per unit of effectiveness was reported to be $US5250 for piperacillin/tazobactam plus amikacin and $US5850 for ceftazidime plus amikacin (year of costs not given). The costs per successfully treated patient reported in the German study were DM16 616 and DM20 828 for piperacillin/tazobactam plus amikacin and ceftazidime plus amikacin, respectively (year of costs not given).