Summary
Ceftolozane/tazobactam is a novel generation cephalosporin and β-lactamase inhibitor combination antibiotic. It was approved for the treatment of adults (18 years and older) with complicated intraabdominal infections used in combination with metronidazole and complicated urinary tract infections by the United States Food and Drug Administration. Its primary activity is against multidrug-resistant Pseudomonas aeruginosa and other aerobic Gram-negative bacteria. The main characteristic features of the antibiotic include: (1) a greater affinity for penicillin-binding proteins produced by P. aeruginosa; (2) better outer membrane permeability that displays resistance mechanisms against upregulation of efflux pumps, and (3) effectiveness against pathogens producing AmpC β-lactamases, primitive b-lactamases (TEM-1, TEM-2, SHV-1, and OXA-1), and extended spectrum β-lactamases. However, it is not effective against pathogens producing metallo-β-lactamases and Klebsiella pneumoniae carbapenemases. Ceftolozane/tazobactam is promising for difficult-to-treat infections caused by multidrug-resistant Gram-negative bacteria. Herein, the features of ceftolozane/tazobactam, including its pharmacokinetics, antimicrobial spectrum, and data from recent clinical studies are reviewed.
Introduction
Antibiotic resistance in clinically important Gram-negative bacteria (GNB) is one of the most serious global health concerns. The rate of infection-related mortality due to multidrug-resistant (MDR) bacteria has been reported as 33-38%[1, 2]. Treatment options are limited for difficult-to-treat infections caused by MDR Pseudomonas aeruginosa, especially strains that produce carbapenemases (KPC) and/or extended-spectrum β-lactamases (ESBL)[3].
Ceftolozane/tazobactam is a new antibiotic that is effective against P. aeruginosa and other common Gram-negative pathogens, including those with antibiotic resistance[2]. In this paper, the pharmacological properties, antimicrobial spectrum, and data from current studies of this antibiotic, which is not yet available in Turkey are reviewed.
Ceftolozane/tazobactam is a new-generation cephalosporin/ β-lactamase inhibitor that combines a new semi-synthetic cephalosporin, ceftolozane, and the β-lactamase inhibitor tazobactam, at a ratio of 2:1 (2 units ceftolozane, 1 unit tazobactam)[4]. Ceftolozane is an oximino-aminothiazolyl cephalosporin in which the pyridium at position 3 in ceftazidime is replaced by the heavier pyrazole[5]. It binds to penicillin-binding proteins and inhibits cell wall synthesis.
Ceftolozane has several characteristic properties: (1) it has higher affinity than ceftazidime to various penicillin-binding proteins in P. aeruginosa; (2) it has more efficient outer membrane permeability and is therefore less affected by efflux pump activity; (3) it shows greater resistance to AmpC β-lactamase than ceftazidime; (4) it is not affected by primitive β-lactamases (TEM-1, TEM-2, SHV-1 and OXA-1); and (5) it is hydrolyzed by ESBLs, but is resistant to these enzymes when combined with tazobactam[4-6]. These properties enhance its effectiveness against GNB, including P. aeruginosa strains[5]. However, ceftolozane/tazobactam is hydrolyzed by metallo-β- lactamases and Klebsiella pneumoniae KPC enzymes[7].
Maximum plasma concentration is reached approximately one hour after initiating antibiotic infusion. Its plasma half-life is short at 2.7 hours on average. Therefore, a repeat dose is required every eight hours. Ceftolozane is minimally metabolized in the kidneys and excreted unaltered in the urine[8]. The steady-state volume of distribution of ceftolozane is 12.9 l, which is close to the mean extracellular volume. Volume of distribution was found to increase in obese patients and patients with infection[9]. These properties indicate that the antibiotic will reach an adequate therapeutic concentration in areas of extracellular infection. No antagonism has been observed when used in vitro with other antibiotics. Ceftolozane/tazobactam is contraindicated in patients with history of severe hypersensitivity reactions to any β-lactam antibiotic, especially piperacillin/tazobactam. Ceftolozane/tazobactam is classified as pregnancy category B. The drug is excreted unaltered in the urine, and dosage adjustment is required for patients with kidney disease. The recommended dose based on creatinine clearance of 30-50 ml/ min is ceftolozane 500 mg/tazobactam 250 mg every 8 hours; for 15-29 ml/min, ceftolozane 250 mg/tazobactam 125 mg every 8 hours. In end-stage kidney disease requiring hemodialysis, the initial dose is ceftolozane 500 mg/tazobactam 250 mg, followed by a maintenance dose of ceftolozane 100 mg/tazobactam 50 mg every eight hours. Dose adjustment is not needed for liver disease. The recommended dose and duration of the antibiotic is 1 g administered intravenously every eight hours for seven days for complicated urinary system infections (UTI), while a duration of 4-14 days is recommended for complicated intra-abdominal infections depending on their severity. Its safety and effectiveness have not been determined in pediatric patients[10].
Ceftolozane/tazobactam is primarily effective against aerobic GNB. Major pathogens that it affects are P. aeruginosa, ESBL-positive Enterobacteriaceae, MDR Gram-negative bacilli, and various antibiotic-resistant phenotypes (e.g., certain carbapenem-resistant isolates, piperacillin-tazobactam and ceftazidime-resistant isolates)[10]. Ceftolozane is resistant to AmpC β-lactamase and unaffected by efflux pump activity and loss of OprD porin, making it a very effective antipseudomonal agent. However, it is not effective against Acinetobacter or Stenotrophomonas spp.[2, 11, 12]. It has activity against certain streptococci, minimal activity against staphylococci, and it is not effective against enterococci. Its effect against anaerobic bacteria is limited: it is effective against Fusobacterium and Propionibacterium spp., activity against Bacteroides spp. has not been documented, and it is ineffective against Clostridium spp.[13, 14].
eftolozane/tazobactam was introduced to the market in 2014 by Cubist Pharmaceuticals under the name Zerbaxa®. It was approved by the United States Food and Drug Administration (FDA) for use in the treatment of complicated UTI (pyelonephritis) and for the treatment of complicated intra-abdominal infections in adults aged 18 or older (in combination with metronidazole)[15]. Randomized studies that led to gaining FDA approval are presented in Table 1[10]. Studies performed during the licensing process for ceftolozane/tazobactam demonstrated efficacy against complicated UTI (pyelonephritis) caused by Escherichia coli, K. pneumoniae, Proteus mirabilis, and P. aeruginosa and complicated intra-abdominal infections caused by Enterobacter cloacae, E. coli, Klebsiella oxytoca, K. pneumoniae, P. mirabilis, P. aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius[15].
Enterobacteriaceae isolates with minimum inhibitory concentration (MIC) ≤1 mg/l are sensitive and those with >1 mg/l are resistant according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria, while strains with MIC ≤2 mg/l are sensitive and >2 mg/l are resistant according to the Clinical and Laboratory Standards Institute (CLSI) criteria. For P. aeruginosa isolates, the EUCAST and CLSI criteria are the same: those with MIC ≤4 mg/l are sensitive and >4 mg/l are resistant[16, 17]. The major in vitro studies evaluating the efficacy of ceftolozane/tazobactam against E. coli, K. pneumoniae, and P. aeruginosa are presented in Table 2[5, 16-21]. The antibiotic showed high activity, especially against P. aeruginosa, with a microbiological eradication rate of 84.4-99%. Among more resistant P. aeruginosa strains, the microbiological eradication rate was 77.7-94.5% for ceftazidime-resistant isolates, 70.3-92.8% for meropenem-resistant isolates, and 89.5-93.5% for colistin-resistant isolates.
The efficacy of ceftolozane/tazobactam against Enterobacteriaceae isolates varies depending on bacterium’s resistance patterns, and it is generally less effective than with P. aeruginosa isolates (Table 2). Its microbiological eradication rate in Enterobacteriaceae isolates was 89.2% overall and 79.1% in ESBL-positive isolates. Its microbiological eradication rate in E. coli isolates was 94.5-99.3% overall and 93.4-95.7% and 97.9-100% in ESBL- and CTX-M-15-positive isolates, respectively. It appears that ceftolozane/tazobactam efficacy is the least against K. pneumoniae. The microbiological eradication rate in K. pneumoniae isolates was 82.7-89.1% overall and 41.8-78.7% in ESBL-positive isolates. Its microbiological eradication rate in meropenem-resistant isolates is negligible (1.4-4%), which is mainly due to its ineffectiveness against KPC[16].
The results of various studies of the in vitro efficacy of ceftolozane/tazobactam against Gram-negative isolates compared to that of cefepime, ceftazidime, piperacillin/tazobactam, meropenem, and colistin are shown in Table 3. Its efficacy against P. aeruginosa isolates was found to be similar to colistin and higher than the other antibiotics. Although it was vastly superior to all of the other antibiotics except colistin against P. aeruginosa and PDR P. aeruginosa isolates in particular, it was slightly less effective compared to colistin. For Enterobacteriaceae isolates, it was superior to cefepime and ceftazidime, equivalent or superior to piperacillin/tazobactam, and far inferior to meropenem and colistin.
Ceftolozane/tazobactam was found to be much more effective than cefepime and ceftazidime and slightly more effective than piperacillin/tazobactam, while it was found less effective than meropenem and colistin against ESBL-positive Enterobacteriaceae isolates. At the species level, ceftolozane/tazobactam was superior to cefepime and ceftazidime and equivalent or superior compared to piperacillin/tazobactam for E. coli and K. pneumoniae isolates. In particular, its efficacy was found to be much higher than cefepime and ceftazidime against ESBL-positive isolates of these species. It was inferior to cefepime and superior to ceftazidime and piperacillin/tazobactam against Enterobacter strains. Ceftolozane/tazobactam was found to be less effective than meropenem and colistin against all Enterobacteriaceae.
There are no clinical studies from Turkey on ceftolozane/tazobactam. Although clinical studies are in progress, it is believed that ceftolozane/tazobactam will be especially useful in the treatment of infections caused by MDR Pseudomonas spp. and MDR Enterobacteriaceae isolates[6, 23]. Small case series reported in the literature support the effectiveness of ceftolozane/tazobactam against P. aeruginosa infections, including MDR isolates (Table 4). In these case series, ceftolozane/tazobactam was mostly used in the treatment of severe PDR and MDR P. aeruginosa infections in patients who had malignancy, organ transplantation, serious underlying diseases such as HIV, and in immunosuppressed patients either alone or in combination with other antibiotics (mostly colistin and amikacin) and had relatively high success rate (54/74, 72.97%). It was effective even in the presence of bacteremia and septic shock (8/12, 66.6%). Ceftolozane/tazobactam was also found to be effective in off-label use such as pneumonia, bone and joint infections, meningitis, and skin and soft tissue infections caused by MDR P. aeruginosa (Table 4).
Studies evaluating the efficacy of ceftolozane/tazobactam against infections caused by enteric bacteria are ongoing. In a meta-analysis of phase 3 studies investigating its efficacy against infections caused by ESBL-positive E. coli and K. pneumoniae, it was compared with levofloxacin (750 mg/day) in UTIs, and combined with metronidazole (1500 mg/day) for comparison with meropenem (3 g/day) in intra-abdominal infections[29]. According to US FDA/EUCAST threshold values, 81.8% / 72.3% of 150 ESBL-positive isolates (95% / 88.1% E. coli, 56.7% / 36.7% K. pneumoniae) were sensitive to ceftolozane/tazobactam, while 25.3% / 24.1% were sensitive to levofloxacin and 98.3% / 98.3% were sensitive to meropenem. Clinical cure rates were found to be 97.4% (76/78) in the ceftolozane/tazobactam group [98% (49/50) for E. coli, 94.4% (17/18) for K. pneumoniae], 82.6% (38/46) in the levofloxacin group, and 88.5% (23/26) in the meropenem group. These results indicate that ceftolozane/tazobactam is effective against UTI and intra-abdominal infections caused by ESBL-positive enteric bacteria. A double-blind, randomized phase 2 study performed at 35 centers in five countries by Lucasti et al.[30] compared ceftolozane/tazobactam (1.5 g every eight hours, 4-7 days) (alone or in combination with metronidazole) with meropenem (3 g/day) for complicated intra-abdominal infections. Ceftolozane/tazobactam was administered to 82 patients and meropenem to 39 patients. The clinical cure rates were 83.6% and 96%, respectively. The most commonly isolated pathogen in both groups was E. coli [67.2% (41/61) in the ceftolozane/tazobactam group and 76% (19/25) in the meropenem group]. Success rates for infections caused by E. coli were 89.5% (34/38) in the ceftolozane/tazobactam group and 94.7% (18/19) in the meropenem group. In another phase 3 study comparing meropenem with ceftolozane/tazobactam (1.5 g/day) combined with metronidazole (500 mg every eight hours) for complicated intra-abdominal infections, similar clinical cure rates were reported in both groups (83% for ceftolozane/tazobactam and 87.3% for meropenem)[31]. In patients with infections caused by ESBL-positive Enterobacteriaceae isolates, clinical cure rates were 95.8% (23/24) in the ceftolozane/tazobactam group and 88.5% (23/26) in the meropenem group. In patients with CTX-M-ESBL-producer bacterial infections, the clinical cure rate was 100% (13/13) in the ceftolozane/tazobactam group and 88.5% (23/26) in the meropenem group.
These results indicate that ceftolozane/tazobactam is effective against intra-abdominal and UTI caused by Enterobacteriaceae species including ESBL-positive isolates.
Studies evaluating the efficacy of ceftolozane/tazobactam in nosocomial pneumonia caused by P. aeruginosa are ongoing, and initial results are promising[23]. Favorable outcomes have been reported in pneumonia caused by PDR and MDR P. aeruginosa in patients with severe underlying conditions such as kidney disease, malignancy, neutropenia, and solid organ transplantation (Table 4).
Conclusion
In summary, the cephalosporin/b-lactamase combination ceftolozane/tazobactam shows remarkable efficacy against GNB. Although it is not effective against carbapenemase-positive pathogens, it is effective against Enterobacteriaceae isolates, including those that are ESBL-positive. Its efficacy against P. aeruginosa isolates, especially MDR and PDR isolates, is noteworthy. With these properties, ceftolozane/tazobactam has the potential to improve treatment success in patients with infections caused by difficult-to-treat MDR and PDR GNB. The antibiotic is FDA-approved for the treatment of complicated UTI and intra-abdominal infections, and was also found to be effective in the treatment of other off-label infections. Determining the efficacy of this antibiotic in Turkey against MDR and PDR Gram-negative isolates in particular may give an idea of its role in the treatment of our patients.
Ethics
Peer-review: Externally and internally peer-reviewed.
Financial Disclosure: The author declared that this study received no financial support.
