DRUG EVALUATION For reprint orders, please contact: [email protected]
Ceftolozane/tazobactam for the treatment of complicated urinary tract and intra-abdominal infections
Matteo Bassetti*,1,2 & Elda Righi1
ABSTRACT High rates of morbidity and mortality have been linked to the emergence of antimicrobial-resistant Gram-negative pathogens, especially in the hospital setting. Infections due to extended-spectrum-β-lactamase producing Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae) and multidrug-resistant Pseudomonas aeruginosa pose a major health threat and dramatically reduce the therapeutic options to achieve an appropriate treatment. There is a need for novel antimicrobials that could provide clinical efficacy toward multidrug-resistant Gram-negative pathogens, including extended-spectrum-β-lactamase and carbapenemase producers. Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin associated with a well-established β-lactamase inhibitor currently in clinical development for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia. Phase II and III trials have shown high efficacy and good tolerability in complicated urinary and intra-abdominal infections compared with standard therapy. A study for the treatment of nosocomial pneumonia is planned. The dramatic rise in resistance of Gram-negative pathogens is currently a great concern due to increased morbidity and mortality associated with these infections, particularly in the healthcare setting [1,2] . The emergence of multidrug resistant (MDR) strains of Pseudomonas aeruginosa and extended-spectrum-β-lactamases (ESBLs) producing Enterobacteriaceae showing multiple resistances to penicillins, cephalosporins and quinolones has narrowed the choices for an effective therapy [3,4] . The class of the carbapenems has often been used as the last resort for the treatment of life-threatening infections caused by resistant organisms [5] . As a consequence, their extensive use has led to an increase in the frequency of carbapenem-resistant isolates [5–7] . Despite this dramatic scenario, the number of antimicrobial products currently being developed to address these unmet medical needs appear to be limited [8] . Specifically, the need of new compounds toward P. aeruginosa is dictated by the fact that this pathogen has negated the effectiveness of the majority of agents, including carbapenems, and its resistance may be mediated by the development of resistance either through the selection of a mutant or through the transfer of resistance determinants from other pathogens [4,9] . Piperacillin-tazobactam, a β-lactam/β-lactamase inhibitor combination, has been frequently employed against Gram-negative pathogens due to its broad spectrum of activity. Nevertheless, increasing rates in P. aeruginosa resistance along with an alarming reduction in its in vitro potency against Enterobacteriaceae have been recently noted [10,11] . Colistin has re-emerged as a reasonable option for the treatment of infections
KEYWORDS
• ceftolozane/tazobactam • cephalosporins • Pseudomonas aeruginosa • resistant Gram-negative
bacteria
Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy *Author for correspondence: Tel.: +39 0432 559 353; Fax: +39 0432 559 370; [email protected] 1 2
10.2217/FMB.14.112 © 2015 Future Medicine Ltd
Future Microbiol. (2015) 10(2), 151–160
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Drug Evaluation Bassetti & Elda caused by MDR Gram-negative bacteria, but there is concern about its efficacy, safety and possible selection of resistances. Among carbapenems, doripenem shows an enhanced anti pseudomonal activity but displays cross-resistance with meropenem [8] . Other compounds are currently under investigation or in late development in the market, although the antibiotics with new mechanisms of action are few and most have some holes in their spectrums against MDR Gram-negative pathogens. Other compounds that have completed Phase II studies showing activity against resistant Enterobacteriaceae and P. aeruginosa include ceftazidime/avibactam (Astra-Zeneca, tested in association with metronidazole), that covers ESBL producers, KPC producers as well as AmpC overexpressing strains but is not active against efflux-mediated ceftazidime resistance in P. aeruginosa, metallo-lactamases, OX A ESBLs and NDM-1 producers; plazomicin (Achaogen, neoglycoside derived from sisomicin), showing some gaps of activity toward Providencia spp., Proteus spp. and NDM-1producing Enterobacteriaceae ; ceftaroline/ avibactam (Cerexa), showing limited activity toward metallo-lactamases and P. aeruginosa producing AmpC or with reduced outer membrane permeability [12] . Characteristics of ceftolozane/tazobactam Ceftolozane/tazobactam (formerly known as CXA-201) is a novel oxyimino-aminothia-zolyl antipseudomonal cephalosporin associated with a well-recognized β-lactamase inhibitor (2:1 ratio), produced by Cubist Pharmaceutics. The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity (Figure 1) . This new compound has been developed for the treatment of complicated urinary tract infections (cUTIs), complicated intraabdominal infections (cIAIs) and nosocomial pneumonia. Based on positive data from Phase III clinical trials in cUTIs and cIAIs that met the primary endpoints established by the US FDA and the European Medicines Agency (EMA) [13–16] , Cubist submitted a New Drug Application (NDA) in April 2014 for approval of ceftolozane/tazobactam for these two clinical indications. Also, a pivotal Phase III trial to assess the
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safety and efficacy of ceftolozane/tazobactam at a dose of 3 g every 8 h compared with meropenem for the treatment of nosocomial pneumonia is expected to be completed in 2018 [17] . Ceftolozane/tazobactam spectrum of activity includes difficult-to-treat Gram-negative pathogens. Specifically, activity against Escherichia coli and Klebsiella pneumoniae, including most ESBL strains, has been shown [18,19] . Furthermore, ceftolozane/tazobactam has demonstrated excellent activity against P. aeruginosa, including strains resistant to carbapenems, piperacillin/tazobactam, and other cephalosporins, as well as MDR strains [20] . Ceftolozane/tazobactam does not have activity against KPC or metallo-β-lactamase producing pathogens. A favorable safety profile was demonstrated in the Phase III cUTI and cIAI trials in which ceftolozane/tazobactam was administered intravenously as 1.5 g every 8 h. Chemistry Ceftolozane mechanism of action is similar to other β-lactams antibiotics. It exerts its bactericidal activity by inhibiting essential penicillinbinding proteins (PBPs), particularly PBP3 and PBP1b, blocking the cell wall synthesis and subsequently causing cell death [21] . Tazobactam is an inhibitor of most class A β-lactamases and some class C β-lactamases and binds to the active site of β-lactamase enzymes protecting ceftolozane from hydrolysis [22,23] . Against P. aeruginosa, ceftolozane appears to be stable toward the overexpression of the chromosomal cephalosporinase AmpC driven by PBP4 mutations, that represent the most common pathogen mutation conferring resistance [21] . Furthermore, ceftolozane is not a substrate of the efflux pumps or the carbapenem-specific porin OprD in P. aeruginosa [21] . Ceftolozane alone has shown in various studies a two to fourfold higher potency than ceftazidime in terms of MICs, killing kinetics and binding affinities to essential PBPs [18,21,24] . When the profile of ceftolozane PBP inhibition was compared with that of ceftazidime, over twofold higher affinity compared with ceftazidime was shown for PBP 1, 2 and 3; compared with imipenem, significantly higher affinity was demonstrated for PBP1b and lower affinity for PBP1c [21,25] . A summary of ceftolozane activity against PBPs compared with other antimicrobials that are commonly used in the clinical p ractice is reported in Table 1.
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections
O-
O S N H2N
O
O
N N
N
N
N H
H
O +
S
NH
NH
N
O
Drug Evaluation
NH2
NH2
OH
N
N
N
H O
O
Ceftolozane
N
O NaO O
S
CH3 O
Tazobactam sodium salt
Figure 1. Chemical structure of ceftolozane/tazobactam (formerly known as CXA-201), a novel oxyimino-aminothia-zolyl cephalosporin.
Similar to other oxyimino-aminothiazolyl cephalosporins, ceftolozane activity can be adversely affected by bacterial production lactamases, thus potentially narrowing the spectrum against Enterobacteriaceae and some anaerobic species, such as Bacteroides spp. [18] . Thus, the association with tazobactam was valuable to broaden the ceftolozane spectrum, particularly to include most ESBL-producing Enterobacteriaceae [18] . Microbiology & spectrum of activity In vitro analyses have demonstrated that ceftolozane has superior activity compared with piperacillin-tazobactam and ceftazidime against certain resistant strains of Enterobacteriaceae (e.g., E. coli, K. pneumoniae) [19–20,24] . In a study encompassing Enterobacteriaceae strains with high resistance to ceftazidime (>90% according to the CLSI breakpoints), ceftolozane/tazobactam was eightfold more active than piperacillin/tazobactam (MIC50 of 32 μg/ml; 48.2% susceptibility) and showed good in vitro activity against ceftazidime-resistant E. coli and K. pneumoniae (Table 2) . Similar to ceftriaxone and cefepime, piperacillin/
tazobactam exhibited only limited activity (MIC50, 16–32 μg/ml; 45.2–59.4% susceptible) [25] . Tazobactam synergism was mostly evident among ESBL-producing organisms (e.g., E. coli, K. pneumoniae and P. mirabilis), and inhibitory activity was also observed with AmpC-producing Enterobacter and Citrobacter strains. Importantly, in vitro activity of cefto lozane/tazobactam against these pathogens was not adversely affected by resistance to the carbapenems. Ceftolozane displayed excellent activity toward P. aeruginosa with or without the addition of tazobactam, and was at least eightfold-times more active than ceftazidime, cefepime and doripenem [25] . Another study using EUCAST breakpoints [27] analyzed the activity of ceftolozane/tazobactam against ESBL-producing E. coli (n = 149) and K. pneumoniae (n = 20). Only 58% of the strains were susceptible to piperacillin/tazobactam compared with 96% of ceftolozane/tazobactam having MIC values ≤1/4 μg/ml for ceftolozane/tazobactam (breakpoints 2
0.12 ± 0.03 >2 >2 0.04 ± 0.01 1.23 ± 0.49 >2
0.13 ± 0.01 0.08 ± 0.005 0.08 ± 0.01 0.12 ± 0.2 0.02 ± 0.01 0.2 ± 0.09
IC50: 50% inhibitory concentration; PBP: Penicillin-binding protein; SD: Standard deviation.
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Drug Evaluation Bassetti & Elda Table 2. Ceftolozane/tazobactam MICs (μg/ml) against difficult-to-treat Gram-negative pathogens in comparison with commonly used antimicrobials. Organism (number of isolates)
Ceftolozane/TZ MIC50/90 (range)
Piperacillin/TZ MIC50/90 (range)
Ceftazidime MIC50/90 (range)
Imipenem MIC50/90 (range)
Klebsiellapneumoniae CAZ-R (186) Klebsiella pneumoniae KPC producer (53) Escherichia coli CAZ-R (224) Proteus mirabilis ESBL producer (68) Enterobacter spp. CAZ-R (90) Citrobacter spp. CAZ-R (108) Pseudomonas aeruginosa CAZ-R (39) Pseudomonas aeruginosa IMI-R (143) Pseudomonas aeruginosa CAZ-R/IMI-R (213)
4/>16 (≤0.12–>16)
32–>64 (1–>64)
64/>64 (32–>64)
≤0.5–≤0.5 (0.5–>8)
>16/>16 (16–>16)
>64–>64 (>64)
>64/>64 (64–>64) >8–>8 (4–>8)
1/16 (≤0.12–>16)
16–>64 (1–>64)
64/>64 (32–>64)
≤0.5–≤0.5 (0.5–>8)
1/8 (0.25–>16)
≤1–8 (0.5–>32)
≤4/>64 (≤4/>64)
2–4 (≤0.5–4)
16/>16 (0.25–>16)
64–>64 (2–>64)
>64/>64 (32–>64) ≤0.5–1 (≤0.5–>8)
16/>16 (0.25–>16)
64–>64 (1–>64)
>64/>64 (32–>64) ≤0.5–1 (≤0.5–8)
2–64 (0.5–>128)
64–>64 (16–>64)
0.5–1 (0.25–8)
16–64 (2–>64)
>64/>128 (16–>128) 8/8 (2–8)
2/16 (0.5–>128)
>64–>64 (8–>64) 64/>128 (16–>128) >8/>8 (8–>8)
1–4 (0.5–4) >8/>8 (8–>8)
CAZ: Ceftazidime; ESBL: Extended-spectrum-β-lactamase; IMI: Imipenem; KPC: Klebsiella pneumoniae-carbapenemase producing; R: Resistant; TZ: Tazobactam. CAZ R: MIC ≥32 μg/ml, ESBL-producing P. mirabilis: MIC ≥32 μg/ml for ceftazidime or ceftriaxone. IMI/CAZ resistance for Pseudomonas aeruginosa defined by the CLSI breakpoints [26]. Data taken from [25].
P. aeruginosa mutants selected both in vitro and after targeted treatment of intensive care unit (ICU) patients [9] . As anticipated by the low activity on PBP4, ceftolozane was not significantly affected by high levels of AmpC expression compared with all tested β-lactams (e.g., piperacillin-tazobactam, ceftazidime and cefepime), except carbapenems. Ceftolozane showed relatively low MICs in vitro (mean: 1–2 μg/ml and 2.5 μg/ml for pan-lactam-resistant strains) against drug-resistant isolates from ICU patients [9] . In summary, ceftolozane shows a Gramnegative profile that is noninferior to that of third-generation cephalosporins such as ceftazidime, and an antipseudomonal activity that is the most potent among new β-lactams, displaying the lowest MIC values among all systemically administered antipseudomonal antibiotics [24,28–29] . The retained activity against AmpDPBP4 mutants expressing efflux pumps makes this compound promising in treating MDR P. aeruginosa nosocomial infections, including the isolates that emerge during antipseudomonal treatments. Furthermore, ceftolozane has in vitro activity against MDR P. aeruginosa, including strains resistant to carbapenems,
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cephalosporins, fluoroquinolones and aminoglycosides [30,31] . Spectrum gaps include the lack of activity on key resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus spp. ●●Pharmacokinetics & pharmacodynamics
Ceftolozane is administered only through intrevenous infusion. Similar to other β-lactams, time-kill experiments and animal infection models have demonstrated that the pharmacokinetics (PK)/pharmacodynamics (PD) index that is best correlated with the in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the MIC of a given pathogen (%f T >MIC). In a Phase I study involving healthy subjects receiving single and multiple doses In part 1 of the study, ceftolozane was given as a 1-h infusion at ascending doses from 250 to 2000 mg. In part 2 of the study, three successive cohorts received multiple doses for 10 days; cohorts 1 and 2 received 500 and 1000 mg every 8 h, respectively; cohort 3 received 1500 mg every 12 h [32] . Ceftolozane exhibited dose-linear PK following a two-compartmental model with
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections linear elimination. Mean plasma half-life was independent of the dosing and averaged 2.3 h (range: 1.9–2.6) [32] . Following single doses, ceftolozane displayed a steady-state volume of distribution ranging from 13.1 to 17.6 l. Negligible drug accumulation occurred with the multiple-dose regimens, with only minimal changes in the AUC occurring after 10 days of repeated dosing. The large majority of ceftolozane (>93%) was excreted unchanged in the urine; renal clearance averaged 102.4 and 112.2 ml/min after single and multiple doses, respectively. Ceftolozane may require a 50% dose reduction in patients with a creatinine clearance between 30 and 50 ml/min. In fact, while minimal changes were observed in patients with mild renal impairment, increases in AUC and half-life were 2.6 and 2.1-fold for ceftolozane and 2.0 and 1.6-fold for tazobactam, respectively, in case of moderate renal impairment [33] . Ceftolozane exhibits modest protein binding in human plasma of approximately 20% and rapid tissue distribution, including excellent lung penetration. The probability of achieving 40% T > MIC in plasma and epithelial lining fluid was observed in >90% of the simulated nosocomial pneumonia population for P. aeruginosa, E. coli and K. pneumoniae [34] . Nevertheless, a difference in target attainment in the lungs was noticed according to the dose (e.g., >98% for 3 g every 8-h dose vs 71–93% for 1.5 g every 8 h) in models of renal hyperclearance (180–250 ml/min). Furthermore, a rabbit experimental model demonstrated significantly greater reduction in pulmonary bacterial load with a ceftolozane human-equivalent dose of 2 g every 8 h compared with 1 g every 8 h [35] . For these reasons, the Phase III nosocomial pneumonia study has been designed with higher ceftolozane doses compared with the other studies. In vivo animal models confirmed higher decreases in disease burden for ceftolozane compared with piperacillin-tazobactam toward Gram-negative isolates, and enhanced activity toward ESBL-producing organisms when associated with tazobactam [36] . A murine study in a neutropenic model of thigh infection using ESBL-producing E. coli and K. pneumoniae showed that the reduction of bacterial growth was dependent on the dosing interval of ceftolozane/tazobactam [37] . In a study evaluating bacterial killing, greater reduction (>2-log) at
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Drug Evaluation
24 h was observed when tazobactam was administered every 6 or every 8 h compared with administration every 12 or 24 h [38] . Overall, low potential for selection of ceftolozane/tazobactam-resistant strains has been shown [39] . PD studies to determine the exposure necessary to prevent drug-resistant bacterial subpopulation employed doses ranging from 125 to 1500 mg every 8 h [40] . While the intermediate dose regimens selected resistant subpopulations by day 5, the three most intensive regimens (750, 1000 and 1500 mg) not only prevented drug-resistance amplification but also sterilized the model system. Finally, in vitro studies identify a low potential for ceftolozane to interact with drugs metabolized by CYP1A2 and CYP3A4. A Phase I study investigating in vivo enzyme inhibition in 16 healthy adult subjects administered ceftolozane/tazobactam along with organic anion transporters, CYP1A2 and CYP3A4 substrates and confirmed minimal potential for clinically relevant drug interactions [41] . Clinical efficacy Clinical efficacy of ceftolozane/tazobactam has been recently demonstrated in Phase II and III trials in cUTIs and cIAIs and it is summarized in Table 3. A Phase II trial in cUTIs compared ceftolozane (administered intravenously 1.0 g every 8 h) with ceftazidime (1.0 g every 8 h) demonstrating similar microbiologic and clinical outcomes after 7–10 days of treatment [26] . The Phase III clinical trial in cUTIs demonstrated ceftolozane/tazobactam statistical superiority over levofloxacin [42] . The study included data from two multicenter, global, double-blind randomized studies assessing the activity of ceftolozane/tazobactam (1.5 g every 8 h) compared with levofloxacin (administered intravenously 750 mg once daily) in 1083 adult patients with cUTIs, including pyelonephritis. The primary endpoint was noninferiority in both microbiological eradication and clinical cure rate at the Test of Cure (TOC) visit (5–9 days after the end of therapy). Microbiological eradication rates per pathogen were 91 versus 80% for E. coli, 84 versus 61% for K. pneumoniae and 86 versus 58% toward P. aeruginosa for ceftolozane/tazobactam versus levofloxacin, respectively. The results of a prospective, double-blind, randomized, multicenter Phase II trial comparing
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Drug Evaluation Bassetti & Elda Table 3. Clinical results of Phase II and III trials. Study type Population Phase II†
Dose
cUTI n = 129
Phase III§
1.0 g every 8 h for 7–10 days cUTI n = 1083 1.5 g every 8 h for 7 days
Phase II
cIAI n = 122
Phase III
cIAI n = 993
1.5 g every 8 h for 4–7 days‡ 1.5 g every 8 h for 4–10 days‡
Comparator
Cure rates (%) MITT and ME
Ceftazidime 1 g every 8h Levofloxacin 750 every 12 h Meropenem 1 g every 8h Meropenem 1 g every 8h
83.1 vs 76.3 85.5 vs 96.2 76.9 vs 68.4 83.3 vs 75.4 83.6 vs 96.0 88.7 vs 95.8 83.0 vs 87.3 94.2 vs 94.7
Ref. [26] [42] [43] [44]
Ceftozolane alone. In association with metronidazole 500 mg every 8 h. § Results of two identical studies combined. † ‡
ceftolozane/tazobactam (1.5 g every 8 h) in association with metronidazole (500 mg every 8 h) versus meropenem (1 g every 8 h) for the treatment of cIAIs have been recently published [43] . A total of 121 patients with cIAIs requiring surgical intervention were treated for 4–7 days. Primary endpoints were the clinical cure at TOC in the microbiological modified intent-to-treat (mMITT) and in the microbiologically evaluable (ME) populations. Ceftolozane/tazobactam showed cure rates of 83.6 and 88.7% compared with 96.0 and 95.8% of meropenem in mMITT and ME populations, respectively. High rates of microbiological success were shown for ceftolozane/tazobactam toward E. coli, K. pneumoniae and P. aeruginosa (89.5, 100 and 100%, respectively). Given the encouraging clinical and microbiological results from this trial, a Phase III study was conducted comparing ceftolozane/ tazobactam in association with metronidazole versus meropenem in the treatment of cIAIs [44] . Primary endpoint of the Phase III study was noninferiority in the clinical cure rate at TOC visit (26–30 days after the end of the therapy). Both primary endpoints requested by the FDA and European Medicines Agency (EMA) were met; for the FDA, the primary analysis was conducted in the MITT population where the overall clinical cure rate was 83.0% for ceftolozane/tazobactam and 87.3% for meropenem. For the EMA, the primary analysis was conducted in the clinically evaluable (CE) population achieving a clinical cure rate of 94.1% for ceftolozane/tazobactam versus 94.0% for meropenem. Comparable microbiological eradication rates per pathogen between ceftolozane/tazobactam and meropenem were observed: Escherichia coli 96
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versus 95%, K. pneumoniae 100 versus 88%, P. aeruginosa 100% (both groups), respectively. Clinical cure rates in patients infected with ESBL-producing Enterobacteriaceae were 100 and 88.5% for ceftolozane/tazobactam and meropenem treatment groups, respectively. A pivotal Phase III trial has been initiated to evaluate the safety and efficacy of ceftolozane/ tazobactam at a dose of 3 g every 8 h compared with meropenem at a dose of 1 g every 8 h for the treatment of nosocomial pneumonia [17] . Tolerability & adverse effects Ge et al. studied the tolerability of ceftolozane administered IV as single and multiple doses in a Phase I study previously described [32] . Ceftolozane was administered as a 1-hour infusion in single doses up to 2000 mg/day and multiple doses up to 3000 mg/day to healthy subjects for a period of 10 days [32] . None of the patients withdrew from the study and drugrelated adverse events were mild and infrequent. Infusion site pain or erythema occurred during multiple-dose administration but also, at a lower frequency, with placebo infusions. No clinically significant changes in hematology, coagulation or urinalysis parameters were noted. Another Phase I study analyzed the safety of ceftolozane, alone and in combination with tazobactam, in single doses of up to 2000 and multiple doses of up to 3000 per day in healthy subjects confirming good tolerability [39] . Over 90% of adverse events were mild in severity; the most common adverse event in single doses was constipation, reported in 6/18 (33%) subjects. In multiple doses administration, 99% adverse events were mild in severity; 48 (51%) were related to the study drug, with mild infusion-related events being the most common (69%). Adverse events
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections
Drug Evaluation
EXECUTIVE SUMMARY ●●
The increase in multidrug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa and extended-
spectrum-β-lactamases producing Enterobacteriaceae has narrowed the choices for an appropriate antimicrobial treatment of nosocomial life-threatening infections. ●●
Despite these concerning data, a limited number of antimicrobial products is currently being developed.
Characteristics of ceftolozane/tazobactam ●●
Ceftolozane is a novel antipseudomonal cephalosporin associated with tazobactam, a β-lactamase inhibitor.
●●
This compound has been developed for the treatment of cUTI, cIAI and nosocomial pneumonia.
●●
Ceftolozane/tazobactam spectrum of activity comprises most extended-spectrum-β-lactamase-producing strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, including multidrug-resistant strains.
Chemistry ●●
Ceftolozane blocks the cell wall synthesis through inhibition of penicillin-binding proteins.
●●
Ceftolozane is not a substrate of the efflux pumps and porins that represent the most common mechanisms of resistance for P. aeruginosa.
●●
The association of ceftolozane with tazobactam contributes to broaden its spectrum to include most extendedspectrum-β-lactamases-producing Enterobacteriaceae.
Microbiology & spectrum of activity ●●
Ceftolozane is not significantly affected by high levels of AmpC expression compared with piperacillin/tazobactam, ceftazidime and cefepime.
●●
Ceftolozane/tazobactam shows noninferior profile compared with ceftazidime and piperacillin/tazobactam, and superior activity toward certain resistant strains of E. coli and K. pneumoniae.
●●
Its antipseudomonal activity is the most potent among new β-lactams.
●●
Ceftolozane/tazobactam does not have activity against KPC or metallo-β-lactamase-producing pathogens.
Pharmacokinetics & pharmacodynamics ●●
Ceftolozane is administered through intravenous infusion and has a mean plasma half-life of 2.3 h.
●●
Over 90% is excreted unchanged in the urine; dose adjustments are required in patients with a creatinine clearance between 30 and 50 ml/min.
●●
Ceftolozane exhibits modest protein binding in human plasma with rapid tissue distribution, including excellent lung penetration.
●●
Low potential for selection of ceftolozane/tazobactam-resistant strains has been shown for drugs metabolized by CYP1A2 and CYP3A4.
Clinical efficacy ●●
Clinical efficacy of ceftolozane/tazobactam administered at 1.5 g every 8 h has been demonstrated in Phase II studies and, more recently, in Phase III trials in cUTI and cIAI.
●●
A Phase III clinical trial in cUTI has demonstrated ceftolozane/tazobactam statistical superiority over levofloxacin (MITT cure rates of 76.9 vs 68.4%, respectively).
●●
A Phase III study comparing ceftolozane/tazobactam in association with metronidazole versus meropenem showed noninferiority (overall clinical cure of 83.0 vs 87.3%, respectively)
●●
Comparable microbiological eradication rates toward meropenem were observed against E. coli, K. pneumoniae and P. aeruginosa.
●●
A pivotal Phase III trial has been initiated at a dose of 3 g every 8 h compared with meropenem for the treatment of nosocomial pneumonia.
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Drug Evaluation Bassetti & Elda EXECUTIVE SUMMARY (CONT.) Tolerability & adverse effects ●●
Phase I studies demonstrated good tolerability of ceftolozane administered intravenously as single and multiple doses up to 3000 mg/day.
●●
Adverse events were not dose related, and no dose-limiting toxicity was identified.
●●
Data from Phase III study in the treatment of cIAI showed drug-related adverse events similar to other cephalosporins and comparable to meropenem.
were not dose related, and no dose-limiting toxicity was identified. In patients with cUTI, ceftolozane/tazobactam and levofloxacin showed drug-related adverse events in 10.3 and 12.0% of the cases, respectively [26] . Consistent with that seen with ceftolozane in the prior Phase II trial in cUTI, the most commonly reported adverse events for ceftolozane/tazobactam were headache (5.8%), constipation (3.9%), hypertension (3%), nausea (2.8%) and diarrhea (1.9%). The ceftolozane/ tazobactam group registered one nontreatment-related death (due to bladder cancer) and two drug-related serious adverse events (both Clostridium difficile associated infection, subsequently resolved) [42] . The Phase II trial in cIAI showed a similar adverse event rate for ceftolozane/tazobactam and meropenem [43] . In the Phase III study in cIAI, drug-related adverse events were consistent with that seen with other cephalosporin antibiotics and were again comparable to meropenem. The most commonly reported adverse events for ceftolozane/tazobactam in combination with metronidazole were nausea (7.9%), diarrhea (6.2%) and fever (5.2%). In this trial, other adverse events for ceftolozane/tazobactam included insomnia (3.5%) and vomiting (3.3%) [44] . Conclusion & future perspective Ceftolozane is a novel cephalosporin currently being developed in association with the β-lactamase inhibitor tazobactam for the treatment of cUTIs, cIAIs and nosocomial pneumonia. Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases such as TEM-1 and SHV-1. Similar to other cephalosporins, such as ceftazidime and ceftriaxone, ESBL and carbapenemases may compromise its activity. The addition of tazobactam expands its spectrum and allows activity against ESBLproducing bacteria and Bacteroides spp. Thanks
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to its ability to escape various resistance mechanisms, ceftolozane offers unique activity versus P. aeruginosa, including carbapenem, piperacillin/tazobactam, ceftazidime-resistant and MDR isolates. Similar to other cephalosporins, various Phase I, II and III studies have reported ceftolozane/tazobactam to possess a good safety and tolerability profile. Additionally, overall efficacy including superiority to levofloxacin in cUTIs and comparable efficacy to meropenem in cIAI have been recently demonstrated in Phase III trials. Considering the lack of new compounds addressing the threat of Gramnegative pathogens in severe nosocomial infections, the availability of this novel compound appears of major interest for the future and this agent is expected to be a useful addition to the current antimicrobial arsenal. Potential roles for ceftolozane/tazobactam include empiric therapy where infections due to resistant Gram-negative organisms are suspected or as an alternative therapy to third-generation cephalosporins in case of treatment failure. Its increased activity versus P. aeruginosa, including MDR strains, makes this agent suitable for carbapenem-sparing regimens toward suspected and documented P. aeruginosa infections, thus reducing the selection of carbapenem-resistant strains. Financial & competing interests disclosure M Bassetti serves on scientific advisory boards for Cubist, Pfizer, Inc., Merck, Novartis and Astellas Pharma, Inc.; and has received funding for travel or speaker honoraria from Cubist, Inc., Merck, Novartis, GlaxoSmithKline, Gilead Sciences, Inc., Sanofi-Aventis, Teva, Bayer, Janssen, Astellas Pharma Inc. and Ranbaxy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
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Drug Evaluation
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A. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 54, 3933–3937 (2010). •
Summary of the escape mechanisms of ceftolozane towards P. aeruginosa PBPs.
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AM, Anderson VE. Inactivation of CMY-2 beta-lactamase by tazobactam: initial mass spectroscopic characterization. Biochim. Biophys. Acta 1547, 196–205 (2001). 23 Bush K, Macalintal C, Rasmussen BA, Lee
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resistance response triggered by inactivation of a nonessential penicillin-binding protein. PLoS Pathog. 5, e1000353 (2009). 26 Umeh O, Cebrik D, Friedland I. A double-
blind, randomized, Phase 2 study to compare the safety and efficacy of intravenous CXA-101 (CXA) and intravenous ceftazidime (CTZ) in complicated urinary tract infection (cUTI). Presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA, USA, 12–15 September 2010. 27 European Committee on Antimicrobial
Susceptibility Testing, Breakpoint tables for interpretation of MICs and zone diameters, Version 3.1, 2013. www.eucast.org/clinical_breakpoints 28 Brown NP, Pillar CM, Sahm DF, Ge Y.
Activity profile of CXA-101 and CXA-101/ tazobactam against target Gram-positive and Gram-negative pathogens. Presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, USA, 12–15 September 2009. 29 Livermore DM, Mushtaq S, Ge Y, Warner M.
Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates. Int. J. Antimicrob. Agents 34, 402–406 (2009).
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has high activity against clinical isolates of Pseudomonas aeruginosa including ceftazidime-resistant isolates. Presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, USA, 12–15 September 2009. 31 Riera E, Macia MD, Mena A et al. Activity of
the new cephalosporin CXA-101 against biofilms of relevant P. aeruginosa (PA) phenotypes in cystic fibrosis chronic respiratory infection: mucoid and hypermutable strains. Presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, USA, 12–15 September 2009. 32 Ge Y, Whitehouse MJ, Friedland I, Talbot
GH. Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intravenous infusions. Antimicrob. Agents Chemother. 54, 3427–3431 (2010). 33 Miller B, Hershberger E, Benziger D, Trinh
M, Friedland I. Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses. Antimicrob. Agents Chemother. 56, 3086–3091 (2012). 34 Hong MC, Hsu DI, Bounthavong M.
Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination 6, Infect. Drug Resist. 6, 215–223 (2013). •
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et al. In vivo activity of CXA- 101 against Pseudomonas aeruginosa (PA) in a rabbit experimental model of pneumonia: comparison with ceftazidime (CAZ), piperacillin/tazobactam (TZP), and imipenem (IMP). Presented at: 51st Interscience Conference on Antimicrobial Agents
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van Mil A, Lagarde C, Mouton JV. Pharmacodynamics of ceftolozane combined with tazobactam in a neutropenic mouse thigh model. Presented at: 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Denver, CO, USA, 10–13 September 2013. 38 Van Scoy B, Mendes RE, Nicasio AM et al.
Pharmacokinetics–pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob. Agents Chemother. 57, 2809–2814 (2013). 39 Cabot G, Bruchmann S, Mulet X et al.
Pseudomonas aeruginosa ceftolozane/ tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Presented at: 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Denver, CO, USA, 10–13 September 2013. 40 Van Scoy BD, Mendes RE, Castanheira M
et al. Relationship between ceftolozane/ tazobactam (TOL/TAZ) exposure and E. coli resistance amplification prevention in a hollow fiber infection model (HFIM). Presented at: 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Denver, CO, USA, 10–13 September 2013.
CYP1A2 or CYP3A4 or transported by OAT1 and OAT3. Presented at: 24th European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Barcelona, Spain, 10–13 May 2014. 42 Wagenlehner F, Umeh O, Huntington J et al.
Efficacy and safety of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (CUTI)/ pyelonephritis in hospitalised adults: results from the Phase 3 aspect-CUTI trial. Presented at: 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Barcelona, Spain, 10–13 May 2014. •• Presents the results of the Phase III trials in cUTIs comparing ceftolozane/tazobactam versus levofloxacin. 43 Lucasti C, Hershberger E, Miller B et al. A
multicenter, double-blind, randomized, Phase II trial to assess the safety and efficacy of ceftolozane/tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob. Agents Chemother. doi:10.1002/ jcph.395 (2014) (Epub ahead of print). •• Presents the results of the Phase II trials in cIAIs comparing ceftolozane/tazobactam versus meropenem. 44 Eckmann C. Hershberger E. Miller B et al.
Efficacy and safety of ceftolozane/tazobactam versus meropenem in the treatment of complicated intra-abdominal infections (cIAI) in hospitalised adults: results from the Phase 3 aspect-cIAI trial. Presented at: 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Barcelona, Spain, 10–13 May 2014. •• Presents the results of the Phase III trials in cIAIs comparing ceftolozane/tazobactam versus meropenem.
41 Wooley M. Bernardo P. Miller B. Hershberger
E. Krishna G. Evaluation of the potential for drug–drug interactions between ceftolozane/ tazobactam and drugs metabolised by
Future Microbiol. (2015) 10(2)
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Ceftolozane/tazobactam for the treatment of complicated urinary tract and intra-abdominal infections
Matteo Bassetti*,1,2 & Elda Righi1
ABSTRACT High rates of morbidity and mortality have been linked to the emergence of antimicrobial-resistant Gram-negative pathogens, especially in the hospital setting. Infections due to extended-spectrum-β-lactamase producing Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae) and multidrug-resistant Pseudomonas aeruginosa pose a major health threat and dramatically reduce the therapeutic options to achieve an appropriate treatment. There is a need for novel antimicrobials that could provide clinical efficacy toward multidrug-resistant Gram-negative pathogens, including extended-spectrum-β-lactamase and carbapenemase producers. Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin associated with a well-established β-lactamase inhibitor currently in clinical development for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia. Phase II and III trials have shown high efficacy and good tolerability in complicated urinary and intra-abdominal infections compared with standard therapy. A study for the treatment of nosocomial pneumonia is planned. The dramatic rise in resistance of Gram-negative pathogens is currently a great concern due to increased morbidity and mortality associated with these infections, particularly in the healthcare setting [1,2] . The emergence of multidrug resistant (MDR) strains of Pseudomonas aeruginosa and extended-spectrum-β-lactamases (ESBLs) producing Enterobacteriaceae showing multiple resistances to penicillins, cephalosporins and quinolones has narrowed the choices for an effective therapy [3,4] . The class of the carbapenems has often been used as the last resort for the treatment of life-threatening infections caused by resistant organisms [5] . As a consequence, their extensive use has led to an increase in the frequency of carbapenem-resistant isolates [5–7] . Despite this dramatic scenario, the number of antimicrobial products currently being developed to address these unmet medical needs appear to be limited [8] . Specifically, the need of new compounds toward P. aeruginosa is dictated by the fact that this pathogen has negated the effectiveness of the majority of agents, including carbapenems, and its resistance may be mediated by the development of resistance either through the selection of a mutant or through the transfer of resistance determinants from other pathogens [4,9] . Piperacillin-tazobactam, a β-lactam/β-lactamase inhibitor combination, has been frequently employed against Gram-negative pathogens due to its broad spectrum of activity. Nevertheless, increasing rates in P. aeruginosa resistance along with an alarming reduction in its in vitro potency against Enterobacteriaceae have been recently noted [10,11] . Colistin has re-emerged as a reasonable option for the treatment of infections
KEYWORDS
• ceftolozane/tazobactam • cephalosporins • Pseudomonas aeruginosa • resistant Gram-negative
bacteria
Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy *Author for correspondence: Tel.: +39 0432 559 353; Fax: +39 0432 559 370; [email protected] 1 2
10.2217/FMB.14.112 © 2015 Future Medicine Ltd
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Drug Evaluation Bassetti & Elda caused by MDR Gram-negative bacteria, but there is concern about its efficacy, safety and possible selection of resistances. Among carbapenems, doripenem shows an enhanced anti pseudomonal activity but displays cross-resistance with meropenem [8] . Other compounds are currently under investigation or in late development in the market, although the antibiotics with new mechanisms of action are few and most have some holes in their spectrums against MDR Gram-negative pathogens. Other compounds that have completed Phase II studies showing activity against resistant Enterobacteriaceae and P. aeruginosa include ceftazidime/avibactam (Astra-Zeneca, tested in association with metronidazole), that covers ESBL producers, KPC producers as well as AmpC overexpressing strains but is not active against efflux-mediated ceftazidime resistance in P. aeruginosa, metallo-lactamases, OX A ESBLs and NDM-1 producers; plazomicin (Achaogen, neoglycoside derived from sisomicin), showing some gaps of activity toward Providencia spp., Proteus spp. and NDM-1producing Enterobacteriaceae ; ceftaroline/ avibactam (Cerexa), showing limited activity toward metallo-lactamases and P. aeruginosa producing AmpC or with reduced outer membrane permeability [12] . Characteristics of ceftolozane/tazobactam Ceftolozane/tazobactam (formerly known as CXA-201) is a novel oxyimino-aminothia-zolyl antipseudomonal cephalosporin associated with a well-recognized β-lactamase inhibitor (2:1 ratio), produced by Cubist Pharmaceutics. The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity (Figure 1) . This new compound has been developed for the treatment of complicated urinary tract infections (cUTIs), complicated intraabdominal infections (cIAIs) and nosocomial pneumonia. Based on positive data from Phase III clinical trials in cUTIs and cIAIs that met the primary endpoints established by the US FDA and the European Medicines Agency (EMA) [13–16] , Cubist submitted a New Drug Application (NDA) in April 2014 for approval of ceftolozane/tazobactam for these two clinical indications. Also, a pivotal Phase III trial to assess the
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safety and efficacy of ceftolozane/tazobactam at a dose of 3 g every 8 h compared with meropenem for the treatment of nosocomial pneumonia is expected to be completed in 2018 [17] . Ceftolozane/tazobactam spectrum of activity includes difficult-to-treat Gram-negative pathogens. Specifically, activity against Escherichia coli and Klebsiella pneumoniae, including most ESBL strains, has been shown [18,19] . Furthermore, ceftolozane/tazobactam has demonstrated excellent activity against P. aeruginosa, including strains resistant to carbapenems, piperacillin/tazobactam, and other cephalosporins, as well as MDR strains [20] . Ceftolozane/tazobactam does not have activity against KPC or metallo-β-lactamase producing pathogens. A favorable safety profile was demonstrated in the Phase III cUTI and cIAI trials in which ceftolozane/tazobactam was administered intravenously as 1.5 g every 8 h. Chemistry Ceftolozane mechanism of action is similar to other β-lactams antibiotics. It exerts its bactericidal activity by inhibiting essential penicillinbinding proteins (PBPs), particularly PBP3 and PBP1b, blocking the cell wall synthesis and subsequently causing cell death [21] . Tazobactam is an inhibitor of most class A β-lactamases and some class C β-lactamases and binds to the active site of β-lactamase enzymes protecting ceftolozane from hydrolysis [22,23] . Against P. aeruginosa, ceftolozane appears to be stable toward the overexpression of the chromosomal cephalosporinase AmpC driven by PBP4 mutations, that represent the most common pathogen mutation conferring resistance [21] . Furthermore, ceftolozane is not a substrate of the efflux pumps or the carbapenem-specific porin OprD in P. aeruginosa [21] . Ceftolozane alone has shown in various studies a two to fourfold higher potency than ceftazidime in terms of MICs, killing kinetics and binding affinities to essential PBPs [18,21,24] . When the profile of ceftolozane PBP inhibition was compared with that of ceftazidime, over twofold higher affinity compared with ceftazidime was shown for PBP 1, 2 and 3; compared with imipenem, significantly higher affinity was demonstrated for PBP1b and lower affinity for PBP1c [21,25] . A summary of ceftolozane activity against PBPs compared with other antimicrobials that are commonly used in the clinical p ractice is reported in Table 1.
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections
O-
O S N H2N
O
O
N N
N
N
N H
H
O +
S
NH
NH
N
O
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NH2
NH2
OH
N
N
N
H O
O
Ceftolozane
N
O NaO O
S
CH3 O
Tazobactam sodium salt
Figure 1. Chemical structure of ceftolozane/tazobactam (formerly known as CXA-201), a novel oxyimino-aminothia-zolyl cephalosporin.
Similar to other oxyimino-aminothiazolyl cephalosporins, ceftolozane activity can be adversely affected by bacterial production lactamases, thus potentially narrowing the spectrum against Enterobacteriaceae and some anaerobic species, such as Bacteroides spp. [18] . Thus, the association with tazobactam was valuable to broaden the ceftolozane spectrum, particularly to include most ESBL-producing Enterobacteriaceae [18] . Microbiology & spectrum of activity In vitro analyses have demonstrated that ceftolozane has superior activity compared with piperacillin-tazobactam and ceftazidime against certain resistant strains of Enterobacteriaceae (e.g., E. coli, K. pneumoniae) [19–20,24] . In a study encompassing Enterobacteriaceae strains with high resistance to ceftazidime (>90% according to the CLSI breakpoints), ceftolozane/tazobactam was eightfold more active than piperacillin/tazobactam (MIC50 of 32 μg/ml; 48.2% susceptibility) and showed good in vitro activity against ceftazidime-resistant E. coli and K. pneumoniae (Table 2) . Similar to ceftriaxone and cefepime, piperacillin/
tazobactam exhibited only limited activity (MIC50, 16–32 μg/ml; 45.2–59.4% susceptible) [25] . Tazobactam synergism was mostly evident among ESBL-producing organisms (e.g., E. coli, K. pneumoniae and P. mirabilis), and inhibitory activity was also observed with AmpC-producing Enterobacter and Citrobacter strains. Importantly, in vitro activity of cefto lozane/tazobactam against these pathogens was not adversely affected by resistance to the carbapenems. Ceftolozane displayed excellent activity toward P. aeruginosa with or without the addition of tazobactam, and was at least eightfold-times more active than ceftazidime, cefepime and doripenem [25] . Another study using EUCAST breakpoints [27] analyzed the activity of ceftolozane/tazobactam against ESBL-producing E. coli (n = 149) and K. pneumoniae (n = 20). Only 58% of the strains were susceptible to piperacillin/tazobactam compared with 96% of ceftolozane/tazobactam having MIC values ≤1/4 μg/ml for ceftolozane/tazobactam (breakpoints 2
0.12 ± 0.03 >2 >2 0.04 ± 0.01 1.23 ± 0.49 >2
0.13 ± 0.01 0.08 ± 0.005 0.08 ± 0.01 0.12 ± 0.2 0.02 ± 0.01 0.2 ± 0.09
IC50: 50% inhibitory concentration; PBP: Penicillin-binding protein; SD: Standard deviation.
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Drug Evaluation Bassetti & Elda Table 2. Ceftolozane/tazobactam MICs (μg/ml) against difficult-to-treat Gram-negative pathogens in comparison with commonly used antimicrobials. Organism (number of isolates)
Ceftolozane/TZ MIC50/90 (range)
Piperacillin/TZ MIC50/90 (range)
Ceftazidime MIC50/90 (range)
Imipenem MIC50/90 (range)
Klebsiellapneumoniae CAZ-R (186) Klebsiella pneumoniae KPC producer (53) Escherichia coli CAZ-R (224) Proteus mirabilis ESBL producer (68) Enterobacter spp. CAZ-R (90) Citrobacter spp. CAZ-R (108) Pseudomonas aeruginosa CAZ-R (39) Pseudomonas aeruginosa IMI-R (143) Pseudomonas aeruginosa CAZ-R/IMI-R (213)
4/>16 (≤0.12–>16)
32–>64 (1–>64)
64/>64 (32–>64)
≤0.5–≤0.5 (0.5–>8)
>16/>16 (16–>16)
>64–>64 (>64)
>64/>64 (64–>64) >8–>8 (4–>8)
1/16 (≤0.12–>16)
16–>64 (1–>64)
64/>64 (32–>64)
≤0.5–≤0.5 (0.5–>8)
1/8 (0.25–>16)
≤1–8 (0.5–>32)
≤4/>64 (≤4/>64)
2–4 (≤0.5–4)
16/>16 (0.25–>16)
64–>64 (2–>64)
>64/>64 (32–>64) ≤0.5–1 (≤0.5–>8)
16/>16 (0.25–>16)
64–>64 (1–>64)
>64/>64 (32–>64) ≤0.5–1 (≤0.5–8)
2–64 (0.5–>128)
64–>64 (16–>64)
0.5–1 (0.25–8)
16–64 (2–>64)
>64/>128 (16–>128) 8/8 (2–8)
2/16 (0.5–>128)
>64–>64 (8–>64) 64/>128 (16–>128) >8/>8 (8–>8)
1–4 (0.5–4) >8/>8 (8–>8)
CAZ: Ceftazidime; ESBL: Extended-spectrum-β-lactamase; IMI: Imipenem; KPC: Klebsiella pneumoniae-carbapenemase producing; R: Resistant; TZ: Tazobactam. CAZ R: MIC ≥32 μg/ml, ESBL-producing P. mirabilis: MIC ≥32 μg/ml for ceftazidime or ceftriaxone. IMI/CAZ resistance for Pseudomonas aeruginosa defined by the CLSI breakpoints [26]. Data taken from [25].
P. aeruginosa mutants selected both in vitro and after targeted treatment of intensive care unit (ICU) patients [9] . As anticipated by the low activity on PBP4, ceftolozane was not significantly affected by high levels of AmpC expression compared with all tested β-lactams (e.g., piperacillin-tazobactam, ceftazidime and cefepime), except carbapenems. Ceftolozane showed relatively low MICs in vitro (mean: 1–2 μg/ml and 2.5 μg/ml for pan-lactam-resistant strains) against drug-resistant isolates from ICU patients [9] . In summary, ceftolozane shows a Gramnegative profile that is noninferior to that of third-generation cephalosporins such as ceftazidime, and an antipseudomonal activity that is the most potent among new β-lactams, displaying the lowest MIC values among all systemically administered antipseudomonal antibiotics [24,28–29] . The retained activity against AmpDPBP4 mutants expressing efflux pumps makes this compound promising in treating MDR P. aeruginosa nosocomial infections, including the isolates that emerge during antipseudomonal treatments. Furthermore, ceftolozane has in vitro activity against MDR P. aeruginosa, including strains resistant to carbapenems,
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cephalosporins, fluoroquinolones and aminoglycosides [30,31] . Spectrum gaps include the lack of activity on key resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus spp. ●●Pharmacokinetics & pharmacodynamics
Ceftolozane is administered only through intrevenous infusion. Similar to other β-lactams, time-kill experiments and animal infection models have demonstrated that the pharmacokinetics (PK)/pharmacodynamics (PD) index that is best correlated with the in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the MIC of a given pathogen (%f T >MIC). In a Phase I study involving healthy subjects receiving single and multiple doses In part 1 of the study, ceftolozane was given as a 1-h infusion at ascending doses from 250 to 2000 mg. In part 2 of the study, three successive cohorts received multiple doses for 10 days; cohorts 1 and 2 received 500 and 1000 mg every 8 h, respectively; cohort 3 received 1500 mg every 12 h [32] . Ceftolozane exhibited dose-linear PK following a two-compartmental model with
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections linear elimination. Mean plasma half-life was independent of the dosing and averaged 2.3 h (range: 1.9–2.6) [32] . Following single doses, ceftolozane displayed a steady-state volume of distribution ranging from 13.1 to 17.6 l. Negligible drug accumulation occurred with the multiple-dose regimens, with only minimal changes in the AUC occurring after 10 days of repeated dosing. The large majority of ceftolozane (>93%) was excreted unchanged in the urine; renal clearance averaged 102.4 and 112.2 ml/min after single and multiple doses, respectively. Ceftolozane may require a 50% dose reduction in patients with a creatinine clearance between 30 and 50 ml/min. In fact, while minimal changes were observed in patients with mild renal impairment, increases in AUC and half-life were 2.6 and 2.1-fold for ceftolozane and 2.0 and 1.6-fold for tazobactam, respectively, in case of moderate renal impairment [33] . Ceftolozane exhibits modest protein binding in human plasma of approximately 20% and rapid tissue distribution, including excellent lung penetration. The probability of achieving 40% T > MIC in plasma and epithelial lining fluid was observed in >90% of the simulated nosocomial pneumonia population for P. aeruginosa, E. coli and K. pneumoniae [34] . Nevertheless, a difference in target attainment in the lungs was noticed according to the dose (e.g., >98% for 3 g every 8-h dose vs 71–93% for 1.5 g every 8 h) in models of renal hyperclearance (180–250 ml/min). Furthermore, a rabbit experimental model demonstrated significantly greater reduction in pulmonary bacterial load with a ceftolozane human-equivalent dose of 2 g every 8 h compared with 1 g every 8 h [35] . For these reasons, the Phase III nosocomial pneumonia study has been designed with higher ceftolozane doses compared with the other studies. In vivo animal models confirmed higher decreases in disease burden for ceftolozane compared with piperacillin-tazobactam toward Gram-negative isolates, and enhanced activity toward ESBL-producing organisms when associated with tazobactam [36] . A murine study in a neutropenic model of thigh infection using ESBL-producing E. coli and K. pneumoniae showed that the reduction of bacterial growth was dependent on the dosing interval of ceftolozane/tazobactam [37] . In a study evaluating bacterial killing, greater reduction (>2-log) at
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Drug Evaluation
24 h was observed when tazobactam was administered every 6 or every 8 h compared with administration every 12 or 24 h [38] . Overall, low potential for selection of ceftolozane/tazobactam-resistant strains has been shown [39] . PD studies to determine the exposure necessary to prevent drug-resistant bacterial subpopulation employed doses ranging from 125 to 1500 mg every 8 h [40] . While the intermediate dose regimens selected resistant subpopulations by day 5, the three most intensive regimens (750, 1000 and 1500 mg) not only prevented drug-resistance amplification but also sterilized the model system. Finally, in vitro studies identify a low potential for ceftolozane to interact with drugs metabolized by CYP1A2 and CYP3A4. A Phase I study investigating in vivo enzyme inhibition in 16 healthy adult subjects administered ceftolozane/tazobactam along with organic anion transporters, CYP1A2 and CYP3A4 substrates and confirmed minimal potential for clinically relevant drug interactions [41] . Clinical efficacy Clinical efficacy of ceftolozane/tazobactam has been recently demonstrated in Phase II and III trials in cUTIs and cIAIs and it is summarized in Table 3. A Phase II trial in cUTIs compared ceftolozane (administered intravenously 1.0 g every 8 h) with ceftazidime (1.0 g every 8 h) demonstrating similar microbiologic and clinical outcomes after 7–10 days of treatment [26] . The Phase III clinical trial in cUTIs demonstrated ceftolozane/tazobactam statistical superiority over levofloxacin [42] . The study included data from two multicenter, global, double-blind randomized studies assessing the activity of ceftolozane/tazobactam (1.5 g every 8 h) compared with levofloxacin (administered intravenously 750 mg once daily) in 1083 adult patients with cUTIs, including pyelonephritis. The primary endpoint was noninferiority in both microbiological eradication and clinical cure rate at the Test of Cure (TOC) visit (5–9 days after the end of therapy). Microbiological eradication rates per pathogen were 91 versus 80% for E. coli, 84 versus 61% for K. pneumoniae and 86 versus 58% toward P. aeruginosa for ceftolozane/tazobactam versus levofloxacin, respectively. The results of a prospective, double-blind, randomized, multicenter Phase II trial comparing
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Drug Evaluation Bassetti & Elda Table 3. Clinical results of Phase II and III trials. Study type Population Phase II†
Dose
cUTI n = 129
Phase III§
1.0 g every 8 h for 7–10 days cUTI n = 1083 1.5 g every 8 h for 7 days
Phase II
cIAI n = 122
Phase III
cIAI n = 993
1.5 g every 8 h for 4–7 days‡ 1.5 g every 8 h for 4–10 days‡
Comparator
Cure rates (%) MITT and ME
Ceftazidime 1 g every 8h Levofloxacin 750 every 12 h Meropenem 1 g every 8h Meropenem 1 g every 8h
83.1 vs 76.3 85.5 vs 96.2 76.9 vs 68.4 83.3 vs 75.4 83.6 vs 96.0 88.7 vs 95.8 83.0 vs 87.3 94.2 vs 94.7
Ref. [26] [42] [43] [44]
Ceftozolane alone. In association with metronidazole 500 mg every 8 h. § Results of two identical studies combined. † ‡
ceftolozane/tazobactam (1.5 g every 8 h) in association with metronidazole (500 mg every 8 h) versus meropenem (1 g every 8 h) for the treatment of cIAIs have been recently published [43] . A total of 121 patients with cIAIs requiring surgical intervention were treated for 4–7 days. Primary endpoints were the clinical cure at TOC in the microbiological modified intent-to-treat (mMITT) and in the microbiologically evaluable (ME) populations. Ceftolozane/tazobactam showed cure rates of 83.6 and 88.7% compared with 96.0 and 95.8% of meropenem in mMITT and ME populations, respectively. High rates of microbiological success were shown for ceftolozane/tazobactam toward E. coli, K. pneumoniae and P. aeruginosa (89.5, 100 and 100%, respectively). Given the encouraging clinical and microbiological results from this trial, a Phase III study was conducted comparing ceftolozane/ tazobactam in association with metronidazole versus meropenem in the treatment of cIAIs [44] . Primary endpoint of the Phase III study was noninferiority in the clinical cure rate at TOC visit (26–30 days after the end of the therapy). Both primary endpoints requested by the FDA and European Medicines Agency (EMA) were met; for the FDA, the primary analysis was conducted in the MITT population where the overall clinical cure rate was 83.0% for ceftolozane/tazobactam and 87.3% for meropenem. For the EMA, the primary analysis was conducted in the clinically evaluable (CE) population achieving a clinical cure rate of 94.1% for ceftolozane/tazobactam versus 94.0% for meropenem. Comparable microbiological eradication rates per pathogen between ceftolozane/tazobactam and meropenem were observed: Escherichia coli 96
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versus 95%, K. pneumoniae 100 versus 88%, P. aeruginosa 100% (both groups), respectively. Clinical cure rates in patients infected with ESBL-producing Enterobacteriaceae were 100 and 88.5% for ceftolozane/tazobactam and meropenem treatment groups, respectively. A pivotal Phase III trial has been initiated to evaluate the safety and efficacy of ceftolozane/ tazobactam at a dose of 3 g every 8 h compared with meropenem at a dose of 1 g every 8 h for the treatment of nosocomial pneumonia [17] . Tolerability & adverse effects Ge et al. studied the tolerability of ceftolozane administered IV as single and multiple doses in a Phase I study previously described [32] . Ceftolozane was administered as a 1-hour infusion in single doses up to 2000 mg/day and multiple doses up to 3000 mg/day to healthy subjects for a period of 10 days [32] . None of the patients withdrew from the study and drugrelated adverse events were mild and infrequent. Infusion site pain or erythema occurred during multiple-dose administration but also, at a lower frequency, with placebo infusions. No clinically significant changes in hematology, coagulation or urinalysis parameters were noted. Another Phase I study analyzed the safety of ceftolozane, alone and in combination with tazobactam, in single doses of up to 2000 and multiple doses of up to 3000 per day in healthy subjects confirming good tolerability [39] . Over 90% of adverse events were mild in severity; the most common adverse event in single doses was constipation, reported in 6/18 (33%) subjects. In multiple doses administration, 99% adverse events were mild in severity; 48 (51%) were related to the study drug, with mild infusion-related events being the most common (69%). Adverse events
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Ceftolozane/tazobactam for urinary tract & intra-abdominal infections
Drug Evaluation
EXECUTIVE SUMMARY ●●
The increase in multidrug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa and extended-
spectrum-β-lactamases producing Enterobacteriaceae has narrowed the choices for an appropriate antimicrobial treatment of nosocomial life-threatening infections. ●●
Despite these concerning data, a limited number of antimicrobial products is currently being developed.
Characteristics of ceftolozane/tazobactam ●●
Ceftolozane is a novel antipseudomonal cephalosporin associated with tazobactam, a β-lactamase inhibitor.
●●
This compound has been developed for the treatment of cUTI, cIAI and nosocomial pneumonia.
●●
Ceftolozane/tazobactam spectrum of activity comprises most extended-spectrum-β-lactamase-producing strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, including multidrug-resistant strains.
Chemistry ●●
Ceftolozane blocks the cell wall synthesis through inhibition of penicillin-binding proteins.
●●
Ceftolozane is not a substrate of the efflux pumps and porins that represent the most common mechanisms of resistance for P. aeruginosa.
●●
The association of ceftolozane with tazobactam contributes to broaden its spectrum to include most extendedspectrum-β-lactamases-producing Enterobacteriaceae.
Microbiology & spectrum of activity ●●
Ceftolozane is not significantly affected by high levels of AmpC expression compared with piperacillin/tazobactam, ceftazidime and cefepime.
●●
Ceftolozane/tazobactam shows noninferior profile compared with ceftazidime and piperacillin/tazobactam, and superior activity toward certain resistant strains of E. coli and K. pneumoniae.
●●
Its antipseudomonal activity is the most potent among new β-lactams.
●●
Ceftolozane/tazobactam does not have activity against KPC or metallo-β-lactamase-producing pathogens.
Pharmacokinetics & pharmacodynamics ●●
Ceftolozane is administered through intravenous infusion and has a mean plasma half-life of 2.3 h.
●●
Over 90% is excreted unchanged in the urine; dose adjustments are required in patients with a creatinine clearance between 30 and 50 ml/min.
●●
Ceftolozane exhibits modest protein binding in human plasma with rapid tissue distribution, including excellent lung penetration.
●●
Low potential for selection of ceftolozane/tazobactam-resistant strains has been shown for drugs metabolized by CYP1A2 and CYP3A4.
Clinical efficacy ●●
Clinical efficacy of ceftolozane/tazobactam administered at 1.5 g every 8 h has been demonstrated in Phase II studies and, more recently, in Phase III trials in cUTI and cIAI.
●●
A Phase III clinical trial in cUTI has demonstrated ceftolozane/tazobactam statistical superiority over levofloxacin (MITT cure rates of 76.9 vs 68.4%, respectively).
●●
A Phase III study comparing ceftolozane/tazobactam in association with metronidazole versus meropenem showed noninferiority (overall clinical cure of 83.0 vs 87.3%, respectively)
●●
Comparable microbiological eradication rates toward meropenem were observed against E. coli, K. pneumoniae and P. aeruginosa.
●●
A pivotal Phase III trial has been initiated at a dose of 3 g every 8 h compared with meropenem for the treatment of nosocomial pneumonia.
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Drug Evaluation Bassetti & Elda EXECUTIVE SUMMARY (CONT.) Tolerability & adverse effects ●●
Phase I studies demonstrated good tolerability of ceftolozane administered intravenously as single and multiple doses up to 3000 mg/day.
●●
Adverse events were not dose related, and no dose-limiting toxicity was identified.
●●
Data from Phase III study in the treatment of cIAI showed drug-related adverse events similar to other cephalosporins and comparable to meropenem.
were not dose related, and no dose-limiting toxicity was identified. In patients with cUTI, ceftolozane/tazobactam and levofloxacin showed drug-related adverse events in 10.3 and 12.0% of the cases, respectively [26] . Consistent with that seen with ceftolozane in the prior Phase II trial in cUTI, the most commonly reported adverse events for ceftolozane/tazobactam were headache (5.8%), constipation (3.9%), hypertension (3%), nausea (2.8%) and diarrhea (1.9%). The ceftolozane/ tazobactam group registered one nontreatment-related death (due to bladder cancer) and two drug-related serious adverse events (both Clostridium difficile associated infection, subsequently resolved) [42] . The Phase II trial in cIAI showed a similar adverse event rate for ceftolozane/tazobactam and meropenem [43] . In the Phase III study in cIAI, drug-related adverse events were consistent with that seen with other cephalosporin antibiotics and were again comparable to meropenem. The most commonly reported adverse events for ceftolozane/tazobactam in combination with metronidazole were nausea (7.9%), diarrhea (6.2%) and fever (5.2%). In this trial, other adverse events for ceftolozane/tazobactam included insomnia (3.5%) and vomiting (3.3%) [44] . Conclusion & future perspective Ceftolozane is a novel cephalosporin currently being developed in association with the β-lactamase inhibitor tazobactam for the treatment of cUTIs, cIAIs and nosocomial pneumonia. Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases such as TEM-1 and SHV-1. Similar to other cephalosporins, such as ceftazidime and ceftriaxone, ESBL and carbapenemases may compromise its activity. The addition of tazobactam expands its spectrum and allows activity against ESBLproducing bacteria and Bacteroides spp. Thanks
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to its ability to escape various resistance mechanisms, ceftolozane offers unique activity versus P. aeruginosa, including carbapenem, piperacillin/tazobactam, ceftazidime-resistant and MDR isolates. Similar to other cephalosporins, various Phase I, II and III studies have reported ceftolozane/tazobactam to possess a good safety and tolerability profile. Additionally, overall efficacy including superiority to levofloxacin in cUTIs and comparable efficacy to meropenem in cIAI have been recently demonstrated in Phase III trials. Considering the lack of new compounds addressing the threat of Gramnegative pathogens in severe nosocomial infections, the availability of this novel compound appears of major interest for the future and this agent is expected to be a useful addition to the current antimicrobial arsenal. Potential roles for ceftolozane/tazobactam include empiric therapy where infections due to resistant Gram-negative organisms are suspected or as an alternative therapy to third-generation cephalosporins in case of treatment failure. Its increased activity versus P. aeruginosa, including MDR strains, makes this agent suitable for carbapenem-sparing regimens toward suspected and documented P. aeruginosa infections, thus reducing the selection of carbapenem-resistant strains. Financial & competing interests disclosure M Bassetti serves on scientific advisory boards for Cubist, Pfizer, Inc., Merck, Novartis and Astellas Pharma, Inc.; and has received funding for travel or speaker honoraria from Cubist, Inc., Merck, Novartis, GlaxoSmithKline, Gilead Sciences, Inc., Sanofi-Aventis, Teva, Bayer, Janssen, Astellas Pharma Inc. and Ranbaxy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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