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Ceftolozane/tazobactam (CXA 201) for the treatment of intra-abdominal infections Expert Rev. Anti Infect. Ther. 12(11), 1311–1324 (2014)

Emilio Maseda*1, Lorenzo Aguilar2, Maria-Jose Gimenez2 and Fernando Gilsanz1 1 Department of Anesthesiology and Surgical Critical Care, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain 2 PRISM-AG, Madrid, Spain *Author for correspondence: Tel.: +34 629 01 86 89 [email protected]

During the mid-nineties, 95–97% of intra-abdominal infection (IAI)- associated microbes were susceptible to commonly used antibiotics. Nowadays, in Gram-negative bacilli, b-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of IAIs, especially for complicated IAIs and for those of nosocomial origin in severely ill patients. In this setting, this article reviews the place in the therapeutic armamentarium of ceftolozane/tazobactam, a new cephalosporin/b-lactamase inhibitor with good activity against extended spectrum b-lactamase producing Enterobacteriaceae, with stability to AmpC b-lactamases and good anti-pseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa. A profound review of its in vitro activity, in vivo efficacy in animal models, pharmacodynamics, pharmacokinetics, clinical efficacy in clinical trials in complicated IAIs and safety data is performed. KEYWORDS: AmpC • ceftolozane/tazobactam • complicated intra-abdominal infections • enterobacteriaceae • extended-spectrum b-lactamases • Pseudomonas aeruginosa

The clinical spectrum of intra-abdominal infections (IAIs) ranges from acute appendicitis to generalized peritonitis. The terms ‘uncomplicated’ and ‘complicated’ IAI have been classically used to differentiate clinical situations and are the basis for categorization of the severity of infections for treatment recommendations [1]. However, it has been recommended to avoid using these terms [2], at least in clinical studies, since they lead to a mixture of very different entities [3]. Uncomplicated IAIs exist in single-organ processes and are typically managed by surgical resection without antimicrobial therapy. Complicated IAIs (cIAIs) are localized or generalized peritoneal inflammation with abscess formation warranting prolonged course of antimicrobial therapy after surgical intervention. The approach to the management of cIAI depends on the patient’s characteristics (comorbidities, previous antibiotic treatment), local resistance data, setting (intensive care unit (ICU), hospital ward) and origin of infection (community-acquired, healthcare-associated or nosocomial). Healthcare-associated infections suggest a higher likelihood of involvement of

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10.1586/14787210.2014.950230

resistant pathogens, and in critically ill patients IAIs are more associated with acute kidney injury and septic shock [4]. In this sense, national and international databases show that one in four cases of severe sepsis or septic shock is caused by IAI [3]. During the mid-1990s, 95–97% of all IAIassociated microbes were susceptible against commonly used antibiotics [5]. However, resistance phenotypes in target bacteria have emerged and diffused over time worldwide. Core microorganisms of IAI are enterobacteriaceae (Escherichia coli or Klebsiella pneumoniae), and Bacteroides spp. (primarily Bacteroides fragilis) in infections in patients with less than 5 days of hospitalization. With respect to Gram-positives, methicillin-resistant Staphylococcus aureus is not a common pathogen in secondary peritonitis [2], being very rare in immunocompetent patients [3]. The role of Enterococcus spp. in secondary peritonitis is controversial with one study showing a minor role for this pathogen [6], others concluding that it increases the rate of morbidity but not of mortality [7,8] and one study showing that its involvement increases mortality [9]. Enterococci

 2014 Informa UK Ltd

ISSN 1478-7210

1311

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Drug Profile

Maseda, Aguilar, Gimenez & Gilsanz

are more frequently isolated in IAI of nosocomial origin than in those community acquired [10]. In a published study on secondary bacterial peritonitis, higher rates of isolation were associated with nosocomial onset of the disease, higher values of Charlson and APACHE II scores, rapidly fatal disease and admission to the ICU [8]. In the majority of IAIs (including communityacquired and early secondary peritonitis), coverage of enterococci, including vancomycin-resistant enterococci, in the empirical regimen is not needed [2]. In this sense, randomized studies have shown clinical response and microbiological eradication in noncritically ill patients with positive cultures treated with antibiotics without antienterococcal activity [10]. Although routine coverage is not recommended, it has been advocated in particular clinical conditions such as the presence of septic shock in patients previously receiving prolonged treatment with cephalosporins, immunosuppressed patients at risk for bacteremia, the presence of valvular heart disease or prosthetic intravascular materials and recurrent intra-abdominal infection accompanied by severe sepsis [1,2,11,12]. In these cases, it should be considered the local prevalence of vancomycin resistance in Enterococcus faecium, which may be high in some geographical areas [13]. The B. fragilis group consists of species of obligate anaerobic bacteria that inhabit the human gut. They are among the leading pathogens isolated from IAIs and thus should always be covered. Coverage for obligate anaerobic bacilli should be provided for distal small bowel, appendiceal and colon-derived infections, and for more proximal gastrointestinal perforations in the presence of obstruction or paralytic ileus [1]. There are data indicating higher failure rates if these organisms are treated with an inactive agent [1]. Although isolated cases of resistance to single agents have been reported, multidrug-resistant (MDR) B. fragilis strains are exceptionally rare [14,15]. In Europe, resistance to imipenem/cilastin or metronidazole has been reported in only 1–2% of isolates [15]. When the onset of the infection occurs in patients with >5 days of hospitalization, the risk for infection by multidrugresistant bacteria among Gram-negatives (main target bacteria in IAIs) should be taken into account. In addition to core microorganisms, extended spectrum b-lactamase (ESBL)-producing E. coli and K. pneumoniae, AmpC-producing enterobacteria of the ESCPM group (Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Providencia rettgeri and Morganella morganii) and Pseudomonas aeruginosa (that may produce carbapenemases) should be suspected. In a recent Dutch multicenter study, the second most frequent source of bacteremia caused by ESBL-producing bacteria was IAI (after urinary tract infection [UTI]) [16]. In the multicenter SMART study, ESBL-producing isolates represented from 8.5 to 11.2% of all enterobacterial isolates worldwide [17–19]. These b-lactamases confer resistance to first-, second- and thirdgeneration cephalosporins and aztreonam (but not to cephamycins and carbapenems), with ESBL-producing strains exhibiting co-resistance to aminoglycosides and quinolones [20]. Risk factors for ESBLs include antibiotic pressure derived from the use of third-generation cephalosporins, aminoglycosides and quinolones 1312

(but not b-lactam/b-lactam inhibitor combinations or carbapenems), previous hospitalization, advanced age, diabetes and use of catheters in ICU patients [20,21]. All isolates belonging to species of the ESCPM group have the potential to produce AmpC inducible b-lactamases upon exposure to inducible agents as b-lactams [22,23]. AmpC genes have been mobilized to plasmids and expressed worldwide [24], with reports of prevalence in E. coli and Klebsiella ranging from 0.64 to 2.9% [25–27]. In addition, ESBLs have been increasingly described in AmpC producers, and high rates of resistance to penicillins including piperacillin/tazobactam and cephalosporins (included cefepime) described [28]. Emergence of organisms with chromosomically encoded inducible AmpC has been associated with the use of third-generation cephalosporins [29] and derepressed overproduction described in 20% infections of ESCPM isolates during third-generation cephalosporin treatment [24]. The heavy use of carbapenems after dissemination of multidrug-resistant bacteria (ESBL- and/or AmpC- producers) raises the fear of selection and diffusion of carbapenemaseproducing strains. Resistance to carbapenems can arise not only by carbapenemase production but also by permeability alterations (efflux pumps and/or porin deficit) plus AmpC or ESBL enzymes. Although carbapenemase prevalence remains low, the spectrum of activity of these enzymes encompasses all known b-lactams (from penicillins to carbapenems) and currently there are not available inhibitors to block their action [30]. Among enterobacteria the prevalence of carbapenemase-producing strains is relatively low, with lower rates in E. coli than in K. pneumoniae (8.3%), and with differences between countries [31]. Reported percentages of carbapenemase production among enterobacterial isolates from IAIs are lower [17,18]. P. aeruginosa is the third (far away from E. coli) Gramnegative isolated in IAIs, with a prevalence ranging from 8 to 13% [3,10], anecdotal in community-acquired infections (3%) [32], but more frequent (16%) in postoperative nosocomial peritonitis [33]. P. aeruginosa represented around 6% of all Gram-negative bacilli isolated from shock septic patients in the ICU in a series of ICU patients where around 30% of them presented IAI [34]. Factors associated with its presence in peritoneal fluid are high APACHE score and respiratory failure [33] and, as in other infectious settings, it is associated with higher mortality, which in this case is related to more severe peritonitis [33]. Since it is not infrequent the association of pulmonary foci infection with IAI in ICU patients, in these cases and in those patients with IAI and shock septic criteria, the consequences of treatment failure are greater and thus widening of coverage to less common pathogens, as P. aeruginosa, is recommended [1,10]. To adequately cover P. aeruginosa, one has to assume the presence of multidrug resistance. In the ICU, risks factors for multidrug resistance in P. aeruginosa are previous exposure to third-generation cephalosporins, acylureidopenicillins or carbapenems [35]. Pan-resistance in P. aeruginosa results from concomitant multiple resistance mechanisms: lower outer membrane permeability, efflux pumps, AmpC b-lactamases and much less often to production of b-lactamases [36,37]. Although Expert Rev. Anti Infect. Ther. 12(11), (2014)

Ceftolozane/tazobactam (CXA 201) for the treatment of IAIs

Aminothiadiazole ring enhances activity against gram-negative bacilli

2-aminothylureido group has the optimal balance of activity against AmpC β-lactamase-producing P. aeruginosa and weakest convulsion-inducing potential (pks = 7.95)

H2N

Dimethylacetic acid moiety enhances antipseudomonal activity

2-methylpyrazole group was found to have the best activity against P. aeruginosa

S N

Drug Profile

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N H 3C NH2

O H3C O

H2N

N OH

NH

S 1

N 5

4

7

H3C 2

NH

N

O 8

Oxime confers β-lactamase stability

6

O

N+

NH

3

O

O

O–

Pyrazole ring provides stability against AmpC β-lactamase-ovarproducing P. aeruginosa

Figure 1. Ceftolozane structure–activity relationships. Reproduced with permission from [46]  Springer (2014).

multidrug resistance, including around 20% nonsusceptibility to carbapenems, is a common feature [38], carbapenemases are not a prevalent resistance mechanism, being permeability alterations and/or AmpC production far more frequent and present in nearly all isolates [39]. In infections caused by multidrug-resistant bacteria, it is of paramount importance to anticipate the spectrum of bacteria when initiating antimicrobial therapy. Primary inadequate empirical antibiotic regimens result in longer hospitalization, higher hospital charges and a higher mortality rate [40]. Because of the polymicrobial nature of IAIs, appropriate empiric therapy invariably requires combination therapy to achieve the necessary coverage for both common and more unusual organisms. As commented, in Gram-negative bacilli, b-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of IAIs, especially for cIAIs and for those of nosocomial origin. One strategy to deal with this raise in resistance is to turn once again to combinations of b-lactam antibiotics and b-lactamase inhibitors [41]. Ceftolozane/tazobactam

Ceftolozane/tazobactam (Cubist Pharmaceuticals, Inc.), formerly known as CXA-201, is a novel b-lactam/b-lactamase inhibitor in development with the potential to meet the challenges of infections caused by multidrug resistant strains of P. aeruginosa and other resistant Gram-negative bacteria. Ceftolozane has demonstrated increased stability to AmpC informahealthcare.com

b-lactamases [42,43] and is less affected by permeability alterations (changes in porins or efflux pumps) [42]. It is active against carbapenem- and cephalosporin-resistant P. aeruginosa by avoiding the efflux pumps (so common in this pathogen) and by its resistance to chromosomal AmpC b-lactamase of this species [41]. However, it is very susceptible to ESBLs, and this is the reason for its combination with tazobactam. Tazobactam is an inhibitor of most class A (ESBLs) and some class C b-lactamases by binding to the active site of these enzymes and protects ceftolozane from hydrolysis, broadening its coverage to include most ESBL-producing enterobacteria as well as some anaerobes such as Bacteroides spp. [43–45]. Chemistry & mechanism of action

Ceftolozane is a novel oxyimino-aminothiazolyl cephalosporin, with a structure similar to ceftazidime, but with new pyrazole rings in the 3-position side chain that confer stability against AmpC b-lactamases. FIGURE 1 shows the structure–activity relationship for ceftolozane [46]. As all b-lactams, ceftolozane exerts its bactericidal activity by inhibiting penicillin-binding proteins (PBPs), resulting in inhibition of cell-wall synthesis and subsequent cell death. As antipseudomonal-designed drug, its mechanism of action has been mainly investigated in P. aeruginosa. Ceftazidime and cefotaxime bind preferentially to PBP3 while carbapenems bind to PBP2 [47]. Against essential PBPs (PBP1b, PBP1c, PBP 2 and 3), ceftolozane exhibits greater affinity than ceftazidime and imipenem [47]. PBP4 is a nonessential PBP that has been 1313

Drug Profile

Maseda, Aguilar, Gimenez & Gilsanz

shown to be a trap for b-lactams that is connected to the AmpC induction pathway [48]. The affinity of ceftolozane for PBP4 is not significant enough to induce AmpC b-lactamase expression [46] and is 15-fold lower than that of imipenem [47].

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In vitro activity of ceftolozane/tazobactam

A published study investigating the antimicrobial activity of ceftolozane/tazobactam (at different ratios or using different fixed concentrations of tazobactam) against Enterobacteriaceae, P. aeruginosa and B. fragilis concluded that the greatest enhanced effect of tazobactam was obtained with tazobactam at the fixed concentration of 4 mg/ml [45]. This fixed concentration of tazobactam in combination with doubling concentrations of ceftolozane is used for testing the activity of ceftolozane/tazobactam in in vitro studies. At present, no breakpoints have been set for the combination of ceftolozane and tazobactam, but a susceptibility breakpoint value of £8 mg/ml has been proposed [42,49,50]. Activity against target Gram-positive bacteria

Ceftolozane/tazobactam does not exhibit in vitro activity against S. aureus, Enterococcus faecalis or Enterococcus faecium, with MIC50/MIC90 values ‡64/‡64 mg/ml [46]. Activity against anaerobes

Against anaerobes of the B. fragilis group, no in vitro activity is obtained with ceftolozane alone (MIC50/MIC90 values ‡64/ ‡64 mg/ml), but the combination ceftolozane/tazobactam exhibits good activity against the main intra-abdominal anaerobic pathogen (B. fragilis), with MIC50/MIC90 values of 1/4 mg/ml, but lower activity against other members of the B. fragilis group (Bacteroides ovatus, Bacteroides vulgatus, Bacteroides thetaiotamicron), with MIC50/MIC90 values of 4/32 mg/ml [46,51]. Although the addition of tazobactam to ceftolozane enhances its activity against species of the B. fragilis group, it may be only significant for the species B. fragilis, the most common isolated species in IAIs. For these reasons, from the microbiological perspective, it seems reasonable its combination with more potent antianaerobic agents in the management of cIAIs [51]. Activity against Enterobacteriaceae isolates

In a recent multicenter study in 31 centers from 14 European countries, including 4518 Enterobacteriaceae isolates, ceftolozane/tazobactam demonstrated the same potency as ceftazidime against ceftazidime-susceptible isolates but remain active against ceftazidime nonsusceptible strains. Overall MIC50/MIC90 values were 0.25/1 mg/ml for ceftolozane/tazobactam, 0.25/32 mg/ml for ceftazidime and £0.06/£0.06 mg/ml for imipenem, with susceptibility rates of 95.3% (considering £8 mg/ml as susceptibility breakpoint), 77.5 and 97.8%, respectively [52]. Same values of MIC50/MIC90 (0.25/1 mg/ml) were reported for ceftolozane/ tazobactam in a multicenter study in USA including 7071 Enterobacteriaceae isolates [53] and in a study testing Enterobacteriaceae isolates from hospitalized patients with pneumonia (1530 isolates; MIC50/MIC90 values of 0.25/4 mg/ml; 94.6% 1314

inhibited at £8 mg/ml) [54]. The largest published in vitro study tested 8341 Enterobacteriaceae isolates (31 centers in 13 European countries plus Turkey and Israel) and showed MIC50/ MIC90 of 0.2/2 mg/ml, with 95.2% inhibited at £8 mg/ml [55]. MIC50/MIC90 of ceftolozane/tazobactam for the 1387 MDR and the 187 extensively drug-resistant (following the definition by Magiorakos et al. [56]) Enterobacteriaceae isolates found in the study were 2/>32 mg/ml (75.5% susceptibility) and 32/>32 mg/ml (36.9% susceptibility), respectively [55]. TABLE 1 shows in vitro activity (MIC50/MIC90, % susceptibility) from recent published studies of ceftolozane/tazobactam compared with another b-lactam/b-lactamase inhibitor combination and other cephalosporin against enterobacteria [46,53,55,57–60]. When specifically tested against E. coli with ESBL phenotype, reported MIC50/MIC90 values for ceftolozane/tazobactam were 0.5/4 mg/ml [46,53,55], tazobactam highly enhancing the activity of ceftolozane alone (‡64/‡64 mg/ml) [46]. Similar results were obtained in other studies testing E. coli with ESBL phenotype, with MIC50/MIC90 values of 0.5/1 mg/ml (100% susceptibility) [59] and of 0.5/4 mg/ml (97.4% susceptibility) [60]. In both studies, the percentage of susceptible isolates for ceftolozane/tazobactam was greater than for piperacillin/tazobactam (32 mg/ml (72.7% susceptibility) [57] and 4/>32 mg/ml (54.8% susceptibility) [58]. Susceptibility rates for piperacillin/tazobactam (22.6%) and ceftazidime (0.0%) Expert Rev. Anti Infect. Ther. 12(11), (2014)

Ceftolozane/tazobactam (CXA 201) for the treatment of IAIs

Drug Profile

Table 1. In vitro activity of ceftolozane/tazobactam and selected comparators against enterobacteria in published studies. Isolates

Escherichia coli

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ESBL-phenotype

Klebsiella pneumoniae ESBL-phenotype

Origin/susceptibility criteria

Ceftolozane/ tazobactam MIC50/MIC90 (%S)†

Piperacillin/ tazobactam MIC50/MIC90 (%S)

Ceftazidime MIC50/MIC90 (%S)

Ref.

IAIs (n = 341)/CLSI

0.25/0.5 (98.5)

2/16 (92.7)

0.12/1 (92.1)

[57]

IAIs (n = 291)/EUCAST

0.25/0.5 (98.3)

2/16 (86.3)

0.12/4 (87.3)

[58]

Previous studies – review

0.5/4

–

16/>32

[46]

European multicenter study (n = 715)/EUCAST

0.5/4 (95.7)

8/>64 (56.2)

16/>32 (10.2)

[55]

US isolates (n = 327)/CLSI

0.5/4 (94.5)

8/>64 (77.4)

16/>32 (31.8)

[53]

Urinary tract infections (n = 145)/EUCAST

0.5/1 (100)

8/64 (63.4)

8/>32 (9.0)

[59]

Pneumonia (n = 114)/CLSI

0.5/4 (97.4)

8/>64 (50.9)

16/>32 (5.3)

[60]

IAIs (n = 38)/CLSI

0.5/32 (89.5)

–

–

[57]

IAIs (n = 41)/EUCAST

0.5/32 (87.8)

16/>64 (46.3)

16/>32 (9.8)

[58]

IAIs (n = 126)/CLSI

0.25/16 (88.9)

4/>64 (80.2)

0.25/>32 (78.6)

[57]

IAIs (n = 88)/EUCAST

0.25/32 (84.1)

4/>64 (69.3)

0.25/>32 (64.8)

[58]

Previous studies – review

0.5/64

–

>32/>32

[46]

European multicenter study (n = 633)/EUCAST

4/>32

64/>64 (24.2)

>32/>32 (1.9)

[55]

US isolates (n = 244)/CLSI

32/>32 (41.8)

>64/>64 (25.4)

>32/>32 (5.3)

[53]

Urinary tract infections (n = 81)/EUCAST

2/>32 (69.1)

32/>64 (35.8)

32/>32 (4.9)

[59]

Pneumonia (n = 224)/CLSI

4/>32 (67.9)

>64/>64 (19.2)

>32/>32 (9.8)

[60]

IAIs (n = 21)/CLSI

1/>32 (72.7)

–

–

[57]

IAIs (n = 31)/EUCAST

4/>32 (54.8)

64/>64 (22.6)

32/>32 (0.0)

[58]

Previous studies – review

0.25/8

–

0.25/>32

[46]

European multicenter study (n = 899)‡/EUCAST

0.5/8 (92.9)

4/64 (74.1)

0.5/32 (66.2)

[55]

Pneumonia (n = 239)/CLSI

0.5/8 (94.1)

4/64 (68.6)

0.5/>32 (60.3)

[60]

§

IAIs (n = 82) /CLSI

0.5/8 (90.2)

4/>64 (70.2)

0.5/>32 (59.8)

[57]

Previous studies – review

0.5/1

–

0.25/0.25

[46]

European multicenter study (n = 485)/EUCAST

0.5/1 (98.8)

2/16 (89.5)

0.12/1 (92.8)

[55]

IAIs (Serratia spp., n = 11)/CLSI

0.5/1 (100)

–

–

[57]

Urinary tract infections (Serratia spp., n = 44)/CLSI

0.5/2 (100)

–

–

[57]

Pneumonia (n = 71)/CLSI

0.25/4 (95.8)

2/32 (78.9)

0.25/>32 (83.1)

[60]

ESCPM group Enterobacter spp.

Serratia marcescens

Citrobacter spp.

Proposed susceptibility breakpoint: £8 mg/ml. Includes 198 Enterobacter aerogenes isolates. Includes 20 E. aerogenes isolates. { Includes 303 Morganella morganii and 20 Providencia rettgeri isolates. # Includes 72 M. morganii and 15 P. rettgeri isolates. IAIs: Intra-abdominal infections. † ‡ §

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Drug Profile

Maseda, Aguilar, Gimenez & Gilsanz

Table 1. In vitro activity of ceftolozane/tazobactam and selected comparators against enterobacteria in published studies (cont.).

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Isolates

Indole-positive Proteae

Ref.

Origin/susceptibility criteria

Ceftolozane/ tazobactam MIC50/MIC90 (%S)†

Piperacillin/ tazobactam MIC50/MIC90 (%S)

Ceftazidime MIC50/MIC90 (%S)

European multicenter study (n = 389)/EUCAST

0.25/8 (92.0)

2/64 (78.8)

0.25/>32 (76.6)

[55]

IAIs (n = 38)/CLSI

0.25/32 (84.2)

–

–

[57]

Previous studies – review

0.25/1

–

0.12/16

[46]

European multicenter study (n = 449){/EUCAST

0.25/1 (98.2)

£0.5/2 (97.6)

0.12/8 (82.2)

[55]

Pneumonia (n = 62)/CLSI

0.25/1 (100)

£0.5/1 (100)

0.06/2 (87.1)

[60]

IAIs (n = 24)/CLSI

0.25/0.5 (95.8)

–

–

[57]

Urinary tract infections (n = 118)#

0.25/1 (96.6)

£0.5/4 (94.1)

0.12/16 (88.9)

[57]

Proposed susceptibility breakpoint: £8 mg/ml. Includes 198 Enterobacter aerogenes isolates. Includes 20 E. aerogenes isolates. { Includes 303 Morganella morganii and 20 Providencia rettgeri isolates. # Includes 72 M. morganii and 15 P. rettgeri isolates. IAIs: Intra-abdominal infections. † ‡ §

were poor [58]. Overall MIC values (those for all K. pneumoniae intra-abdominal isolates tested) were lower in both studies: MIC50/MIC90 values of 0.25/16 mg/ml (88.9% susceptibility) [57] and of 0.25/32 mg/ml (84.1% susceptibility) [58]. Against K. pneumoniae producing specific common ESBLs as CTX-M-14 (6 isolates) and CTX-M-15 (11 isolates), MIC50/ MIC90 values were equal than those mentioned for E. coli for ceftolozane/tazobactam (£0.25/1 mg/ml) [61]. Against isolates belonging to the ESCPM group (all producing AmpC inducible b-lactamases), similar MIC values were found for ceftolozane/tazobactam and ceftolozane alone [46] since this cephalosporin is mostly not affected by AmpC b-lactamases. Reported MIC50/MIC90 values of ceftolozane/ tazobactam were 0.5/8 mg/ml (>90% susceptibility) against Enterobacter spp. in contrast to ceftazidime (60–80% susceptibility) and piperacillin/tazobactam (~70% susceptibility) [55,57,60]. Against Enterobacter isolates nonsusceptible to ceftazidime (AmpC + ESBL) MIC50/MIC90 values of ceftolozane/ tazobactam were slightly higher (4/‡16 mg/ml; ~80% susceptibility) [55,60] but markedly lower than those of piperacillin/tazobactam, with only 15.9% susceptibility [60]. Values of MIC50/ MIC90 against Serratia marcescens were 0.5/1–2 mg/ml (>98.8% susceptibility) [46,55,57], against Citrobacter spp. were 0.25/4– 32 mg/ml (>84% susceptibility) [55,57,60] and against indolepositive Proteae 0.25/1 mg/ml (>95% susceptibility) [46,55,57,60] regardless ceftazidime susceptibility or not. In a recent study including 500 Enterobacteriaceae isolates, ceftolozane/tazobactam showed high in vitro activity against wild-type isolates (MIC50/MIC90 0.25/0.5 mg/ml; 100% susceptibility) and ESBL-producing E. coli isolates (MIC50/MIC90 0.5/1 mg/ml; 100% susceptibility), with lower activity against 1316

ESBL-producing K. pneumoniae isolates (MIC50/MIC90 4/16 mg/ml; 87.5% susceptibility) and AmpC hyperproducers (MIC50/MIC90 1/16 mg/ml; 88.9% susceptibility) [62]. Ceftolozane/tazobactam was at least fourfold more active than ceftazidime and piperacillin/tazobactam [62]. Ceftolozane/tazobactam is not active against KPC- and carbapenemase-producing bacteria [46,62]. Activity against P. aeruginosa

P. aeruginosa has an extraordinary capacity to develop resistance to almost any available antibiotic [63]. The acquisition of potent exogenous b-lactamases as metallobetalactamases (MBLs) or ESBLs through horizontal gene transfer is a growing threat, but b-lactam resistance is still more frequently caused by a selection of a complex repertoire of chromosomal mutations [64]: repression or inactivation of the carbapenem porin OprD, upregulation of efflux pumps, hyperproduction of chromosomal cephalosporinase AmpC and modification of target PBPs [63,64]. Ceftolozane appears to be stable against the most common resistance mechanisms driven by mutations in this species [63]. The spontaneous mutation rate at 4 MIC for the development of ceftolozane-resistant mutants is extremely low (64 (62.6)

16/128 (43.9)

>8/>8 (20.7) (imipenem)

[45]

1971

0.5/2 (98.5)

8/>64 (76.8)

2/32 (82.9)

0.5/8 (80.3) (meropenem)

[53]

2435

0.5/1 (99.0)

4/32 (85.1)

4/32 (83.7)

0.5/8 (83.5) (meropenem)

[67]

971

1/>32 (86.1)

8/>64 (61.1)

4/>32 (65.0)

1/>8 (64.4) (meropenem)

[60]

141

0.5/32 (88.7)

8/>64 (59.6)

4/32 (69.5)

0.5/>8 (73.8) (meropenem)

[59]

500

0.5/4

16/>32 (63.6)

4/32 (76.0)

2/16 (60.0) (imipenem)

[68]

2191

1/>32 (86.3)

8/>64 (63.0)

4/>32 (67.2)

1/>8 (67.1) (meropenem)

[55,69]

From IAIs

53

0.5/32 (88.7)

8/>64 (56.6)

2/>32 (66.0)

0.5/8 (73.6) (meropenem)

[58]

From IAIs

115

0.5/4

8/>64 (72.2)

2/32 (77.4)

0.5/8 (79.1) (meropenem)

[57]

Ceftazidime nonsusceptible

13

2/4

–

64/128

16/32 (imipenem)

[66]

371

4/>32 (66.6)

–

–

–

[55]

398

1/4 (96.5)

–

–

–

[67]

179

4/>32 (68.2)

>64/>64 (3.4)

32/>32 (0.0)

8/>8 (33.0) (meropenem)

[60]

135

2/16

256/256

64/256

4/32 (meropenem)

[70]

From IAIs

26

2/>32

>64/>64 (0.0)

32/>32 (0.0)

4/>8 (42.3) (meropenem)

[57]

Carbapenem nonsusceptible

35

0.5/1

–

4/16

16/32 (imipenem)

[66]

720

4/>32 (61.4)

–

–

–

[55]

401

1/4 (96.5)

–

–

–

[67]

346

2/>32 (64.5)

64/>64 (24.9)

>32/>32 (32.4)

8/>8 (0.0) (meropenem)

[60]

24

2/>32

64/>64 (29.2)

32/>32 (37.5)

8/>8 (0.0) (meropenem)

[57]

133

1/8

32/256

16/128

16/32 (meropenem)

[70]

60

2/>32 (73.3)

64/>64 (11.7)

16/>32 (28.3)

4/>8 (43.3) (meropenem)

[59]

698

4/>32 (57.4)

>64/>64 (5.4)

32/>32 (13.8)

8/>8 (17.6) (Meropenem)

[55]

310

2/8 (90.3)

>64/>64 (11.0)

32/>32 (22.6)

8/>8 (19.4) (meropenem)

[53]

401

1/4 (96.5)

–

–

–

[67]

95

2/>64

256/256

64/256

16/128 (meropenem)

[70]

From IAIs

21

2/>32 (71.4)

32/>64 (4.8)

32/>32 (14.3)

2/8 (47.6) (meropenem)

[58]

From IAIs

19

4/>32

>64/>64 (0.0)

32/>32 (10.5)

8/>8 (10.5) (meropenem)

[57]

175

4/16 (85.7)

>64/>64 (2.3)

32/>32 (9.1)

8/>8 (7.4) (meropenem)

[53]

538

32/>32 (46.3)

–

–

–

[55]

13

4/>32

>64/>64 (0.0)

32/>32 (15.4)

8/>8 (0.0) (meropenem)

[57]

MDR

XDR

From IAIs

Proposed susceptibility breakpoint: £8 mg/ml. IAIs: Intra-abdominal infections; MDR: Multidrug-resistant; XDR: Extensively drug-resistant; following definition in [56].

†

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Table 3. Mean (standard deviation) pharmacokinetic values for ceftolozane (1500/500 mg every 8 h) after single (day 1) and multiple (day 10) doses. Day 1

Day 10

Cmax (mg/ml)

69.1 (11.3)

74.4 (13.6)

Tmax (h; median [range])

1.02 (1.01–1.10)

1.07 (1.0–1.1)

AUC0–last (mg h/ml)

172.0 (13.8)

197 (16.6)

t1/2 (h)

2.77 (30.0)

3.12 (21.9)

Cl (l/h)

5.86 (13.7)

5.58 (12.6)

CLr (l/h)

5.58 (24.0)

6.80 (49.4)

Vss (l)

14.6 (16.0)

14.2 (16.6)

Accumulation index

–

1.14 (5.7)

AUC0–last: Area under concentration–time curve from zero to last time point; CL: Clearance; CLR: Renal clearance; Cmax: Maximum plasma concentration; Tmax: Time of maximum plasma concentration; t1/2: Half-life; Vss: Volume of distribution at steady state. Data taken from [87].

TABLE 2 includes data on in vitro activity of ceftolozane/ tazobactam and comparators against P. aeruginosa reported in recently published studies [45,53,55,57–60,66–70]. In terms of intrinsic activity (MIC50/MIC90) against nonselected P. aeruginosa isolates, ceftolozane/tazobactam exhibited lower values than piperacillin/tazobactam or ceftazidime, with higher susceptibility rates than these compounds and carbapenems. The same figure was obtained regardless the resistance phenotype of isolates (ceftazidime nonsusceptible, carbapenem nonsusceptible, MDR or extensively drug-resistant) as well as against isolates from IAIs. Among isolates from patients with cystic fibrosis, development of pan-resistance is common. Against this type of isolates, ceftolozane showed good activity (96% susceptibility) and was the only antibiotic tested with similar susceptibility rates in early and late isolates [71]. Other studies testing ceftolozane or ceftolozane/tazobactam against isolates with carbapenem resistance mainly driven by the mutational inactivation of OprD (clinical isolates or laboratory mutants) or against isolates with upregulated efflux or total AmpC derepression also showed MIC50/ MIC90 values of 1/4 mg/ml [72–74]. These results are in accordance with in vitro studies showing that development of resistance to ceftolozane/tazobactam occurs much slower than resistance to other antipseudomonal agents [63], even in experiments with hypermutable strains in biofilm growth [75]. All these published studies show that ceftolozane/tazobactam is a valuable antipseudomonal agent conserving activity against MDR strains by minimizing the development of self- and cross-resistance [63], and with resistance restricted to still uncommon strains producing MBLs [73].

Pharmacodynamics

Tazobactam exhibits a concentration-dependent potentiation of ceftolozane against ESBL-producers and AmpC hyperproducers [43]. As all b-lactams, ceftolozane/tazobactam (at 1318

concentration 2 to 16 MIC) exhibits a concentrationindependent bactericidal activity as demonstrated against multiple isolates of P. aeruginosa and E. coli among others, with 99.9% reduction (3 log10) in bacterial counts within 6– 8 h [76,77]. In a recently published study, once the ceftolozane/ tazobactam exposure (4 MIC) ceased against ESBLproducing E. coli (CTX-M-15), the inhibition of bacterial growth (postantibiotic effect) persisted for 0.8–0.9 h while with the removal of tazobactam alone (post-b-lactamase inhibitory effect) the inhibitory effect persisted for 1.3–2.1 h [78]. Similar to other cephalosporins, the pharmacodynamic parameter predicting in vivo bacteriological efficacy is the time that serum concentrations exceed the MIC (t > MIC), with values of around 30–40% in a neutropenic murine thigh infection model by ESBL- producing enterobacteria or P. aeruginosa [79,80]. The reported values lower than those for other cephalosporins may be due to the more rapid killing of ceftolozane/ tazobactam [79,80]. The in vivo efficacy of ceftolozane in pulmonary, urinary and burn wound Pseudomonas infection models was significantly higher than that of ceftazidime (in all models) or imipenem (in the urinary and burn models, with comparable results in the pulmonary model) [66]. In another murine P. aeruginosa acute pneumonia model, ceftolozane not only significantly reduced bacterial counts in lung but also prevented development of lung damage and increased the recruitment of neutrophils within the infected lung without increasing lung endothelial permeability [81]. Two murine models of experimental peritonitis comparing efficacy in terms of ED50 (pharmacodynamically effective dose for 50% of the population exposed) showed that ESBLs do not have an impact on in vivo activity of ceftolozane/tazobactam [82,83]. In both models, the efficacy of ceftolozane/tazobactam was superior or similar to ceftazidime (on strain basis) and markedly higher than that of piperacillin/tazobactam [82,83]. With respect to models simulating human pharmacokinetics (PK)/pharmacodynamics, a murine thigh infection model by ESBL-producing E. coli and K. pneumoniae simulating % t>MIC for ceftolozane/tazobactam in humans showed 1 to 3 log10 reductions with ‡37.5% t > MIC, improving efficacy versus piperacillin/tazobactam [84]. In this sense, a dose-ranging infection hollow-fiber in vitro model using an ESBL-producing E. coli (CTX-M-15) isolate showed that the dosing regimen used in humans (1000/500 mg every 8 h for 10 days) not only virtually sterilized the model but also prevented resistance amplification [85]. Pharmacokinetics

After parenterally administered (as 1 h infusion), ceftolozane exhibits linear PK up to 2000 mg as a single dose [86,87]. TABLE 3 shows mean PK parameters determined in healthy volunteers after 1000/500 mg single (day 1) and multiple doses (every 8 h for 10 days). PK parameters of ceftolozane were not affected by coadministration of tazobactam. Ceftolozane exhibits rapid tissue distribution, low protein binding (20%) [46] and concentrates well at extracellular sites of infection [87]. An excellent Expert Rev. Anti Infect. Ther. 12(11), (2014)

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Ceftolozane/tazobactam (CXA 201) for the treatment of IAIs

lung penetration with mean Cmax in the epithelial lining fluid of 21.8 mg/ml has been reported, exceeding for >60% of the 8 h dosing interval MIC values for P. aeruginosa [88]. Clearance of ceftolozane occurs exclusively via renal elimination with ca. 100% of the dose recovered unchanged in urine in the subsequent 24 h [87], with negligible drug accumulation as evidenced by minimal changes in the area under the concentration–time curve after 10 days of repeated dosing [86,87]. Slight increases in patients with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on hemodialysis require a decrease in dose, a change in frequency of dosing or both to achieve exposures within safety and efficacy margins [89]. The absence of any known interaction with hepatic metabolic pathways suggests a low likelihood of cytochrome P450-dependent drug–drug interactions [86]. In this sense, a recent study has shown that there is minimal potential for clinically relevant drug interactions with CYP1A2 and CYP3A4 substrate drugs and compounds that are transported by organic anion transporters OAT1 and OAT3 [90]. Lack of interaction with coadministration of ceftolozane and tazobactam has been described in contrast to piperacillin that decreases the clearance of tazobactam and increases its area under the concentration–time curve [91], probably because ceftolozane is eliminated via glomerular filtration and does not undergo active tubular secretion (as tazobactam) [87]. The longer half-life of ceftolozane compared with other cephalosporins is a potential advantage for achieving longer t > MIC [87]. A recently published Monte Carlo simulation concluded that >90% of simulated patients achieved free-drug t > MIC ‡32.2% for P. aeruginosa with MIC = 8 mg/ml considering the standard 1000/500 mg every 8 h dosing regimen, thus supporting the proposed in vitro susceptibility breakpoint of 8 mg/ml [49]. Clinical trials: clinical efficacy

A recent analysis combining data from two identical Phase III trials in complicated UTI (cUTI) including pyelonephritis (1083 patients in total) showed that ceftolozane/tazobactam (1000/500 mg every 8 h for 7 days) achieved higher clinical and microbiological cure rates than levofloxacin (750 mg once daily for 7 days) [92]. Per-pathogen microbiological eradication rates were (ceftolozane/tazobactam vs levofloxacin): 90.5 versus 79.6% for E. coli, 84.0 versus 60.9% for K. pneumoniae and 85.7 versus 58.3% for P. aeruginosa [92]. A Phase II, prospective, multicenter, double-blind, randomized (2:1) study in cIAI requiring surgical intervention as inclusion criteria compared ceftolozane/tazobactam (1000/500 mg every 8 h) plus metronidazole (500 mg every 8 h) versus meropenem (1 g every 8 h) for 7–14 days in 122 patients. Clinical cure rates were 83.6% (51/61) for ceftolozane/tazobactam plus metronidazole and 96.0% (24/25) for meropenem in the modified microbiological intention-to-treat population analysis, and 88.7% (47/53) and 95.8% (23/24), respectively, in the microbiologically evaluable population [46,93]. When considering informahealthcare.com

Drug Profile

only E. coli, the most frequent pathogen, microbiological success rates were 89.5% (34/38) for ceftolozane/tazobactam and 94.7% (18/19) for meropenem [46,93]. A recent analysis combining data from two multicenter, double-blind, randomized Phase III trials in cIAI (993 patients in total) compared ceftolozane/tazobactam (1000/500 mg every 8 h) plus metronidazole (500 mg every 8 h) versus meropenem (1 g every 8 h) plus placebo for 4–10 days [94]. In the microbiological evaluable population, overall clinical cure was obtained in 94.2% patients in the ceftolozane group and 94.7% in the meropenem group. Per-pathogen microbiological eradication rates were (ceftolozane/tazobactam + metronidazole vs meropenem + placebo): 96.0% (193/201) versus 95.1% (214/225) for E. coli, 100% (28/28) versus 88.0% (22/25) for K. pneumoniae, 100% (25/25) versus 100% (28/28) for P. aeruginosa and 98.2% (107/109) versus 97.8% (134/137) for Gram-negative anaerobes. Clinical cure for ESBLproducing Enterobacteriaceae was achieved in 86.2% (25/29) and 82.8% (24/29) patients treated with ceftolozane/ tazobactam + metronidazole and meropenem + placebo, respectively [94]. Safety & tolerability

Based on safety data from Phase I to Phase III clinical trials, the adverse effect profile of ceftolozane/tazobactam does not appear to be different to that of other b-lactams. In Phase I studies, adverse events were infrequent and considered mild, and included abdominal pain, nausea, headache, paresthesia, somnolence, vulvovaginitis and constipation [46,86,87]. The nature and incidence of adverse events reported in Phase I studies not appeared to be dose-dependent and no doselimiting toxicities were identified [46,87]. In the ascending dose Phase I study, doses up to 3000/1500 mg per day were generally safe and well tolerated, with infrequent and mild adverse events generally infusion-related that occurred after having the iv. line for >24 h [87]. Treatment-emergent adverse events occurring in ‡3% patients in the Phase II cUTI were constipation, diarrhea, infusion site irritation, insomnia, nausea and pyrexia [46]. In the Phase II study in cIAI, the rate of drugrelated adverse events was 8.5% with ceftolozane/tazobactam and 33.3% with meropenem. In ceftolozane/tazobactam, 17.1% patients with adverse events presented serious events but none of them were related to the study drug [93]. In the Phase III study in cUTI, drug-related adverse events occurred in 10.3% patients treated with ceftolozane/tazobactam and 12% of those treated with levofloxacin. Two serious drugrelated events were reported with ceftolozane/tazobactam, both Clostridium difficile infections that resolved [92]. In the Phase III study in cIAI (487 patients receiving ceftolozane/tazobactam plus metronidazole vs 506 patients receiving meropenem plus placebo), the most frequent adverse events were nausea (7.9 vs 5.8%), diarrhea (6.2 vs 5.0%) and pyrexia (5.2 vs 4.0%) [94]. Drug-related serious adverse events only occurred in one patient per treatment group, both C. difficile infection that resolved [94]. 1319

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Regulatory affairs

In April 2014, Cubist submitted a New Drug Application (NDA) to the US FDA for approval of ceftolozane/tazobactam for the treatment of cUTI and cIAI based on positive data from pivotal Phase III clinical trials that met primary endpoints agreed upon with the FDA and EMA [95]. In the second half of 2014, the company plans to submit a Marketing Authorization Application to the EMA. Additionally, a pivotal Phase 3 clinical trial of ceftolozane/tazobactam in the treatment of hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia is in the process of being initiated [95]. Conclusion

Ceftolozane/tazobactam is a new b-lactam/b-lactamase inhibitor with an in vitro activity covering Gram-negative facultative bacteria involved in IAIs, as shown in in vitro studies, animal models and pharmacodynamic studies. In the majority of IAIs, Gram-negative anaerobes should also be covered; therefore, as used in Phase II–III trials for cIAIs, ceftolozane/tazobactam should be co-administered with an antianaerobe agent. In animal models of experimental peritonitis, ceftolozane/tazobactam showed superior efficacy to piperacillin/tazobactam, with noninferior efficacy to meropenem in the treatment of cIAIs in the Phase III trials carried out. Ceftolozane is not affected by efflux pumps and porin changes and presents stability against AmpC b-lactamases, while tazobactam protects it against ESBLs. These characteristics represent important advantages for ceftolozane/ tazobactam, more even when no cross-resistance with other antibiotics affected by ESBLs, AmpC, loss of porin channels or overexpression in efflux pumps has been reported. Based on this, ceftolozane/tazobactam is of interest, among other indications, for the treatment of cIAIs of nosocomial origin where ESBL-producing E. coli and K. pneumoniae and/or enterobacteria of the ESCPM group may be involved. In addition, it covers most P. aeruginosa isolates, which is of interest for the treatment of cIAIs in severely ill patients in the ICU where infectious respiratory foci may complicate the patient’s prognosis. Expert commentary

Therapeutic management within the wide field of IAIs is diverse according to the patient’s characteristics, sites involved and setting and origin of the infection. cIAIs, mainly those of nosocomial origin, represent the battlefield for antibiotic therapy. This is especially important for physicians at surgical ICUs where growing antibiotic resistance poses a threat to available drugs, dramatically reducing therapeutic alternatives. From this perspective, ceftolozane/tazobactam represent a valuable coming option, with ceftolozane exhibiting potent bactericidal activity against Gram-negative isolates as Enterobacteriaceae and multidrug-resistant P. aeruginosa, and tazobactam enhancing its spectrum to ESBL-producing isolates, a growing problem compromising antibiotics as third-generation cephalosporins against Enterobacteriaceae. In the treatment of cIAIs, combined therapy is needed to extend the coverage of ceftolozane/tazobactam to anaerobes. In 1320

this sense, in clinical trials, ceftolozane/tazobactam was combined with an anaerobicidal agent as metronidazole and compared with meropenem, with similar microbiological and clinical efficacy. In surgical ICUs, some types of patients that are usually excluded from clinical trials on cIAIs are attended as patients with septic shock, with previous prolonged treatment with cephalosporins, immunosuppressed patients at risk for bacteremia, patients with valvular heart disease or prosthetic intravascular materials and patients with recurrent IAIs accompanied by severe sepsis. In these cases, it is necessary to extend the coverage to potential pathogens as methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci, which may be involved. Therefore, in the critically ill patient with cIAI, the potential combination of ceftolozane/tazobactam with other antibiotics as tigecycline warrants attention considering the resistance profile of Gram-negatives, Gram-positives and anaerobes. The key point for inclusion of ceftolozane/ tazobactam in the therapeutic armamentarium in our setting lies in its good anti-Pseudomonal activity, not only because P. aeruginosa is the third most frequent pathogen in cIAIs of nosocomial origin but, more importantly, because in ICU patients it is not infrequent the association of IAI with pulmonary foci infection. In these cases and in those patients with IAI and shock septic criteria, it is of paramount importance to anticipate the spectrum of bacteria when initiating antimicrobial therapy (performing de-escalation when microbiological data is available) since the consequences of treatment failure are the greatest. Results of the pivotal Phase III clinical trial of ceftolozane/tazobactam in the treatment of hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia would be of high interest. Five-year view

The heavy use of carbapenems after dissemination of MDR Enterobacteriaceae (due to ESBL and AmpC b-lactamases) raises the fear of the relationship between the use of these antibiotics and the selection and diffusion of carbapenemaseproducing strains. In this context, restriction of carbapenem use seems prudent since unfortunately therapeutic alternatives are few. A future increase in carbapenemase-producing Enterobacteriaceae and P. aeruginosa should be expected. The new cephalosporin/b-lactamase inhibitor, ceftolozane/tazobactam, improves the therapeutic armamentarium against ESBL- and AmpC-producing Enterobacteriaceae when compared with previous penicillin/b-lactamase inhibitors. In this sense, its use as alternative treatment may help in reducing carbapenem use, thus possibly delaying carbapenemase selection and diffusion. In nosocomial cIAIs, the broad spectrum of potential pathogens, with its broad mechanisms of resistance, will continue to necessarily require combined therapy. Ceftolozane/tazobactam will have an important role among therapeutic candidates since its resistance is restricted to strains producing MBLs. If the more pessimistic predictions about carbapenemases diffusion are confirmed and MBL-producing strains become not rare Expert Rev. Anti Infect. Ther. 12(11), (2014)

Ceftolozane/tazobactam (CXA 201) for the treatment of IAIs

(nowadays are still uncommon), ceftolozane/tazobactam, as current carbapenems, would require co-administration with non-b-lactam antibiotics (as currently tigecycline) covering carbapenemase-producing strains that also exhibit other multiple resistance determinants to other compounds as current aminoglycosides and quinolones. The development of carbapenemase inhibitors is encouraging.

Drug Profile

Financial & competing interests disclosure

E Maseda has received payments for lectures from Astellas Pharma, Pfizer and Merck Sharp and Dohme. 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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Key issues • In Gram-negative bacilli, b-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of intra-abdominal infections (IAIs), especially for complicated IAIs and for those of nosocomial origin in severely ill patients. • Ceftolozane/tazobactam is a new cephalosporin/b-lactamase inhibitor with good activity against extended spectrum b-lactamaseproducing Enterobacteriaceae, with stability to AmpC b-lactamases and good antipseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa. • The longer half-life of ceftolozane compared with other cephalosporins is a potential advantage for achieving longer t > MIC. The standard 1000/500 mg every 8 h dosing regimen achieved free-drug t > MIC ‡32.2% for P. aeruginosa with MIC = 8 mg/ml in >90% of simulated patients, supporting the proposed in vitro susceptibility breakpoint of 8 mg/ml. • Phase III trials in cIAI comparing ceftolozane/tazobactam plus metronidazole versus meropenem showed noninferiority with respect to clinical cure rates and bacterial eradication. • Based on safety data from Phase I to Phase III clinical trials, the adverse effect profile of ceftolozane/tazobactam does not appear to be different to that of other b-lactams. • In the treatment of complicated IAIs, combined therapy is needed to extend the coverage of ceftolozane/tazobactam to anaerobes (as in the clinical trials performed) and to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in specific patients at risk. • The use of ceftolozane/tazobactam as alternative treatment may help in reducing carbapenem use, thus possibly delaying carbapenemase selection and diffusion.

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