Infection and Drug Resistance Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Ceftolozane/tazobactam for the treatment of complicated intra-abdominal and urinary tract Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 infections: current perspectives and place in therapy This article was published in the following Dove Press journal: Infection and Drug Resistance Laura Escolà-Vergé 1,2 Abstract: The current prevalence of infections caused by multidrug-resistant (MDR) organisms Carlos Pigrau 1,2 is a global threat, and thus, the development of new antimicrobial agents with activity against For personal use only. Benito Almirante 1,2 these pathogens is a healthcare priority. Ceftolozane–tazobactam (C/T) is a new combination of 1 a cephalosporin with a β-lactamase inhibitor that shows excellent in vitro activity against a broad Infectious Diseases Department, Hospital Universitari Vall d’Hebron, spectrum of Enterobacteriaceae and Pseudomonas aeruginosa, including extended spectrum β- Medicine Department, Universitat lactamase-producing (ESBL) strains and MDR or extensively drug-resistant (XDR) Autònoma de Barcelona, Barcelona, P. aeruginosa. In phase III randomized clinical trials, C/T demonstrated similar efficacy to Spain; 2Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain meropenem for the treatment of complicated intra-abdominal infections (cIAIs) and superior efficacy to levofloxacin for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis. The drug is generally safe and well tolerated and its PK/PD profile is very favorable. Observational studies with C/T have revealed good efficacy for the treatment of different types of infection caused by MDR or XDR P. aeruginosa, including some that originated from the digestive or urinary tracts. The place of C/T in therapy is not well defined, but its use could be recommended in a carbapenem-sparing approach for the treatment of infections caused by ESBL-producing strains or for the treatment of infections caused by P. aeruginosa if there are no other more favorable therapeutic options. Further clinical experience is needed to position this new antimicrobial drug for the empirical treatment of cIAIs or cUTIs. Keywords: ceftolozane-tazobactam, complicated intra-abdominal infections, complicated urinary tract infections, multidrug-resistant Pseudomonas aeruginosa Extent of complicated intra-abdominal and urinary tract infections in the era of bacterial multiresistance Complicated intra-abdominal infections (cIAIs) are defined as infections resulting from perforation of the gastrointestinal tract that extend into the peritoneal space and are associated with either abscess formation or peritonitis.1 This type of infection is usually polymicrobial and dominated by Gram-negative bacilli, parti- cularly Enterobacteriaceae and Pseudomonas aeruginosa (found less frequently), and Gram-positive cocci and anaerobes have also been identified.2 Correspondence: Benito Almirante These infections require immediate surgery combined with adequate antimicro- Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Paseo de la bial treatment. The most widely used antimicrobial treatments are the combination Vall d’Hebron, 119-129, Barcelona 08035, of cefotaxime or ceftriaxone with metronidazole and monotherapy with amoxicillin/ Spain Email balmirante@vhebron.net clavulanic acid. However, the use of piperacillin/tazobactam and even carbapenems submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1853–1867 1853 DovePress © 2019 Escolà-Vergé et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing http://doi.org/10.2147/IDR.S180905 the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress is becoming more common, even for community-acquired hospitalization; d) patients who reside in a nursing infections. The reason for this change is the unstoppable home or long-term care facility (LTCF); and e) patients dissemination of extended spectrum β-lactamase- who underwent an invasive urinary procedure in the 30 producing (ESBL) enterobacteria. The global prevalence days before the episode or who have a long-term of class A ESBL-producing enterobacteria fecal coloniza- indwelling urethral catheter. This increased resistance tion is 14%, as inferred from a meta-analysis that included has impacted the choice of empiric antibiotic therapy a population of 28,909 healthy people from five conti- because higher failure rates with a poor outcome could nents, and this prevalence shows an annual increase of be obtained if an adequate antibiotic therapy is not Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 5.4%. Africa and Asia are the continents with the highest administered.3,4 prevalence, with rates of 45% and 15%, respectively, and Two recent studies5,6 found that the P. aeruginosa these are followed by Southern Europe (6%), Central etiology and resistance rates in HCA-UTIs were higher Europe (3%), Northern Europe (4%) and Northern than those in community-acquired urinary tract infections America (2%).2 In this context, the available antimicrobial (CA-UTIs). In our experience the resistance rates of CA- treatment for cIAIs can be suboptimal, particularly in the UTIs and HCA-UTIs among 607 patients with acute pye- countries and hospitals with the most unfavorable lonephritis (APN) were as follows: amoxicillin/clavulanic epidemiology. acid, 22.4% versus 53.2%; cefuroxime, 7.7% versus The definition of complicated urinary tract infections 43.5%; cefotaxime, 4.3% versus 32.6%; ciprofloxacin, (cUTIs) varies among studies, but the guidelines3,4 define 22.8% versus 74.5%; and cotrimoxazole, 34.5% versus For personal use only. cUTIs as urinary tract infections in patients with one or 58.7%. In both studies, previous antibiotic use (in the more of the following conditions: a) men, children, preg- last 3 months) was also identified as an independent risk nant women or individuals aged ≥65 years; b) women with factor for antibiotic resistance. functional or anatomical urinary tract abnormalities that cause obstruction or voiding disorders, any sort of ureteral Current management of complicated derivation or foreign body (including indwelling bladder catheters), polycystic kidney disease, single kidney, recent intra-abdominal and urinary tract (within 1 month) instrumentation or urinary tract surgery, infections diabetes mellitus, renal insufficiency or transplantation, Complicated intra-abdominal infections other immunosuppressed states or underlying diseases The management of cIAIs includes a combination of (liver cirrhosis, active malignancy, congestive heart fail- source control and adjunctive antibiotic therapy. Source ure); and c) severe sepsis. The above conditions are fre- control is defined as any procedure that eliminates infec- quently used to determine whether the patient needs to be tious foci, control factors that promote ongoing infection, admitted to the hospital, and some of these cUTIs are more and correct or control anatomic derangements that restore likely to be related to multidrug-resistant (MDR) patho- normal physiologic function7 and can be achieved surgi- gens. However, the resistance rates in some of these popu- cally and/or by percutaneous drainage of the associated lations, such as men, the elderly, patients with diabetes or abscess. acute urinary tract infection (UTI) following ureteral stone As mentioned above, due to the increasing resistance to obstruction, might be similar to those of uncompli- aminopenicillins, third-generation cephalosporins, fluoro- cated UTI. quinolones and aminoglycosides among Escherichia coli The increased risk of UTIs due to MDR microor- and the spread of ESBL-producing Enterobacteriaceae, ganisms is substantial in the group of healthcare- antibiotic recommendations, in particularly those for high- associated urinary tract infections (HCA-UTIs), which risk and healthcare-associated infections,8,9 have changed includes the following: a) patients who received intra- because studies have shown that ineffective antimicrobial venous therapy, wound care or specialized nursing care therapy is strongly associated with unfavorable outcomes at home in the 30 days prior to the episode; b) patients in septic patients.10 who attended a hemodialysis center or received intra- For patients with mild-to-moderate community-acquired venous chemotherapy in the 30 days before the episode; cIAIs, the current recommendation is to use narrower-spec- c) patients who were hospitalized in an acute-care hos- trum antibiotics with activity against Enterobacteriaceae, pital for ≥2 days in the 90 days before the current aerobic streptococci, and anaerobes, and avoid submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1854 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al antipseudomonal coverage. Cefotaxime or ceftriaxone plus a carbapenem, because the overuse of carbapenems might metronidazole or ertapenem are some recommended agents increase the risk of infections due to CPE.3–6,15,16 for the initial therapy. As mentioned above, amoxicillin/ Risk factors for ESBL-producing bacterial infections are clavulanic acid and fluoroquinolones are no longer advisable previous colonization, recurrent UTIs, previous use of third- as an empiric treatment due to frequent resistance, and clin- generation cephalosporins or quinolones, healthcare- damycin should also be avoided due to the increasing resis- associated infections and recent travel to high-risk areas. tance rates among Bacteroides fragilis.1,11,12 In our setting, Germany and other countries with high Empirical treatment with broad-spectrum agents is resistance rates to amoxicillin, cotrimoxazole, amoxicillin/ Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 needed for patients with high-risk community-acquired clavulanic acid, and quinolones, a second- or third- cIAIs. At present, piperacillin–tazobactam, doripenem, generation cephalosporin or an aminoglycoside are ade- imipenem–cilastatin, meropenem, ceftazidime or cefe- quate initial options for non-severe patients without risk pime plus metronidazole are some of the recommended factors for ESBL-producers.3,5,6 Aztreonam, an aminogly- regimens.1,11,12 For the empirical treatment of health- coside, a carbapenem, or intravenous fosfomycin could be care-associated cIAIs, the choice of antibiotic should used for allergic patients. be guided by regional epidemiological and resistance For more severe infections or patients with risk factors data.1,11,12 ESBL-producer coverage is usually needed, for ESBL-producing bacteria, a carbapenem or piperacillin– and the use of piperacillin/tazobactam in this scenario tazobactam may be used.17 Other options could be amino- remains controversial.13 Thus, carbapenems have been glycosides or intravenous fosfomycin, although the experi- For personal use only. considered the preferred agents, but the spread of car- ence with these antimicrobial agents is limited. bapenemase-producing Enterobacteriaceae (CPE) and An antipseudomonal agent should be used for the treat- MDR P. aeruginosa has become a global threat world- ment of nosocomial or health-care cUTIs because wide. Therefore, new antibiotics, such as ceftolozane/ P. aeruginosa is the most commonly found pathogen tazobactam (C/T) and ceftazidime/avibactam in combi- (15% of our HCA-UTIs). The choice of empirical agent nation with metronidazole appear promising. should be based on local susceptibility data. In our setting, Finally, the tailoring of antimicrobial treatment once 25–35% of the isolated agents are resistant to piperacillin– the results of susceptibility reports become available is tazobactam, ceftazidime, aztreonam, cefepime, fosfomy- essential, and limiting the length of antimicrobial therapy cin, gentamicin, tobramycin or antipseudomonal carbape- to four days in patients with adequate source control is nem. Amikacin (which has the lowest resistance rates) also important.14 Patients showing ongoing signs of infec- should be included in the treatment of septic cases. C/T tion after five days of adequate antibiotic treatment should or ceftazidime–avibactam might be other alternatives, par- undergo a diagnostic investigation and be reassessed for ticularly for cases with previous MDR or extremely drug- a possible new source control intervention.1 resistant (XDR) P. aeruginosa colonization. In countries with a high incidence and risk factors for carbapenem- Complicated urinary tract infections resistant microorganisms, ceftazidime–avibactam, aztreo- According to the IDSA guidelines,4 the empiric antimicro- nam, aminoglycosides, fosfomycin, colistin or bial therapy for APN should be based on local suscept- a combination with a carbapenem should be considered. ibility antibiotic data. It has been recommended that For patients with indwelling urinary devices and septic antibiotics with a resistance rate higher than 10% should shock, antimicrobial coverage against multiresistant Gram- be avoided in empirical therapy. However, this recommen- positive microorganisms, such as methicillin-resistant dation is not based on clinical studies. Staphylococcus aureusand Enterococcus faecium, should The mortality rates of CA-UTIs are low (1%), and in be considered; however, a recent study that included con- our clinical practice, an inadequate empirical antibiotic is secutive adult (mainly elderly) patients with a chronic not associated with a worse outcome, particularly in indwelling catheter-associated UTI and sepsis revealed patients without septic shock.5 Thus, when discussing that appropriate antibiotic treatment had no significant a new local guideline for the treatment of cUTIs, the effect on short- and long-term survival or on the length severity of the underlying infection and the risk of an of stay and length of febrile illness. The overall mortality MDR microorganism should be balanced with the initia- was approximately 30%, but the mortality rate of patients tion of an antibiotic with broad-spectrum coverage, such with an MDR Gram-negative infection and that of submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1855 DovePress Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress patients with enterococcal infection were 55% and only against Enterobacteriaceae.26,30 C/T is very active against 8.6%, respectively.18 These data suggest that enterococci E. coli (MIC50/90, 0.25/0.5 mg/L; 98.5–99.9% inhibited at likely have little impact on mortality. an MIC of ≤8 mg/L), and many of the MDR (MIC50/90, 0.5/ 2–>32 mg/L) and ESBL-phenotype strains (MIC50/90, 0.5/ Spectrum and in vitro activity of 2–>32 mg/L). It also showed activity against most K. pneumoniae strains (MIC50/90, 0.25/16 mg/L, ceftolozane/tazobactam 88.9–89.6% inhibited at an MIC of ≤8 mg/L), but elevated Chemistry and mode of action MIC values were found for some ESBL-phenotype strains Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 C/T is a new combination of a novel semisynthetic anti- (MIC50/90, 4–8/>32 mg/L) and MDR (MIC50/90, 16/>32 mg/ pseudomonal cephalosporin with a well-established β- L).29 C/T was very active as well against other lactamase inhibitor (2:1 ratio).19 The approved indications Enterobacteriaceae, such as Enterobacter spp. (MIC50/90, of C/T are the treatment of cUTIs and the treatment of 0.5/8 mg/L), Citrobacter spp. (MIC50/90, 0.25/32 mg/L), cIAIs when administered in combination with metronida- Serratia spp. (MIC50/90, 0.5/2 mg/L), K. oxytoca zole, and it is currently investigated in phase III trials for (MIC50/90, 0.25/2 mg/L), Proteus mirabilis (MIC50/90, 0.5/ the treatment of hospital-acquired pneumonia. 0.5 mg/L), and indole-positive Proteae (MIC50/90, 0.25/ Ceftolozane is an oxyimino-aminothiazolyl cephalos- 0.5 mg/L).29,30 However, C/T lacks activity against CPE porin that is structurally similar to ceftazidime but has (MIC50/90, 32/>32 mg/L)30,31 because it has no activity a modified side chain that contributes to the stability of against metallo-β-lactamases, K. pneumoniae carbapene- For personal use only. the drug in the presence of AmpC β-lactamases, prevents mases, and class D enzymes.23 the hydrolysis of the β-lactam ring, and thus confers potent However, the standout quality of C/T is its singular activity against P. aeruginosa.20,21 This cephalosporin potency against P. aeruginosa. C/T generally showed four- exerts its bactericidal activity by binding to penicillin- fold higher activity against P. aeruginosa compared with binding proteins (PBPs) and causing cell death.21 ceftazidime,28 and it was the most potent β-lactam agent Compared with ceftazidime, ceftolozane shows at least two- and inhibited >90% of isolates at an MIC of <8 mg/L.28,30 fold higher potency in terms of minimum inhibitory con- In addition, C/T had activity against many MDR centration (MIC) and binding affinities for PBP1b, PBP1c, P. aeruginosa strains (MIC50/90, 2–4/>32 mg/L), ceftazi- PBP2, and PBP3.21 Ceftolozane is not a substrate of the dime-nonsusceptible strains (MIC50/90, 2–4/>32 mg/L), carbapenem-specific porin OprD or the efflux pumps found and meropenem-nonsusceptible strains (MIC50/90, 2/ in P. aeruginosa.22 However, the ceftolozane activity can be >32 mg/L).29 Only colistin was more active; specifically, affected by some other β-lactamases, such as ESBLs. Thus, colistin inhibited 99.5% of isolates.31 However, C/T has it has been formulated in combination with tazobactam to no in vitro activity against other nonfermenting bacteria broaden its antimicrobial activity.23 Tazobactam is a sulfone such as Acinetobacter spp. or Stenotrophomonas spp. β-lactamase inhibitor that binds irreversibly to the active In contrast, C/T lacks activity against many Gram- site of serine β-lactamases and thereby protects the β-lactam positive pathogens. Although it shows some in vitro activity against hydrolysis. It inhibits most class A narrow-spectrum against Streptococcus species, it has very limited activity β-lactamases, ESBLs, and some class C enzymes and against S. aureus and no anti-enterococcal activity. The enhances the activity of ceftolozane against some ESBL- activity of C/T against anaerobic bacteria is very variable: producing Enterobacteriaceae and anaerobes.24,25 it shows in vitro activity against Fusobacterium spp., ade- quate activity against B. fragilis and Prevotella, and low or Spectrum and in vitro activity no activity against other Bacteroides spp. and Clostridium C/T primarily shows in vitro activity against many aerobic spp.32 Based on this finding, metronidazole should be added Gram-negative bacilli, including most ESBL-producing to C/T to ensure for anaerobic coverage in cIAIs.33–35 E. coli (particularly TEM- and CTX-M-type ESBLs), but its potency against ESBL-producing K. pneumoniae is lower.23,26,27 Several studies have tested the in vitro activity Pharmacokinetics and pharmacodynamics of C/T against clinical isolates from intra-abdominal and of ceftolozane/tazobactam urinary tract infections (Table 1).28–30 C/T, amikacin, and When ceftolozane is administered as a 1-h intravenous infusion meropenem are the antibiotics with the highest activity at a dose of 1.5 g (1 g of ceftolozane and 0.5 g of Tazobactam), submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1856 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al Table 1 In vitro activity of ceftolozane–tazobactam against clinical isolates from intra-abdominal and urinary tract infections Source Pathogen Number of TOL/TAZ TOL/TAZ TOL/TAZ S%a isolates MIC50 (µg/mL; MIC90 (µg/mL; range) range) Aerobic Gram-negative Escherichia coli 1,674 0.25 0.5 98.5–99.9 organisms isolated from MDR E. coli 85 0.5 2 to >32 75–98.6 intra-abdominal and K. pneumoniae 442 0.25 16 88.9–89.6 urinary tract infections MDR K. pneumoniae 78 16 >32 NR Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 in hospitals in Europe Enterobacter spp. 228 0.25–0.5 4–8 NR and the USA (2012)29 Citrobacter spp. 113 0.25 2 NR Proteus mirabilis 117 0.5 0.5 NR P. aeruginosa 327 0.5 4 93.4–95.7 MDR P. aeruginosa 59 2–4 >32 65–73.7 XDR P. aeruginosa 43 4–8 >32 56.7–61.5 CAZ-NS P. aeruginosa 61 2–4 >32 60–80.8 MEM-NS P. aeruginosa 77 2 >32 75.5–79.2 Pathogen Number of TOL/TAZ TOL/TAZ TOL/TAZ S% isolates MIC50 (µg/mL) MIC90 (µg/mL) (CLSI/EUCAST) Enterobacteriaceae and Enterobacteriaceae 5,950 0.25 1 93.5/91.3 For personal use only. Pseudomonas aeruginosa ESBL non-CRE phenotype 906 0.5 8 82.8/74.9 causing urinary tract and Escherichia coli 3,460 0.25 0.5 98.8/98 intra-abdominal infec- ESBL non-CRE phenotype 559 0.5 2 92.7/87.8 tions in Europe (2012– K. pneumoniae 917 0.25 >32 79.3/75.8 2015)30 ESBL phenotype 373 4 >32 49.1/41.6 ESBL non-CRE phenotype 280 1 >32 65.4/55.4 Enterobacter spp. 432 0.5 8 78/69.7 Enterobacter cloacae 278 0.5 16 76.6/70.1 Citrobacter koseri 101 0.25 0.5 100/100 Citrobacter freundii 111 0.25 8 79.3/78.4 P. mirabilis 368 0.5 0.5 97.3/95.7 ESBL phenotype 32 1 8 71.9/56.2 Indole-positive Proteeae 237 0.25 1 97.5/94.9 Serratia spp. 77 0.5 2 98.7/88.3 P. aeruginosa 603 0.5 4 91.7/91.7 CAZ-NS P. aeruginosa 139 4 >32 65.5/65.5 MEM-NS P. aeruginosa 126 2 >32 65.9/65.9 PIP/TAZ-NS P. aeruginosa 162 2 >32 70.4/70.4 Notes: aPercentage of isolates inhibited at an MIC of ceftolozane-tazobactam of ≤8 mg/L. Adapted with permission from Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect. 2014;69(3):266–277. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.29 And from: Pfaller MA, Bassetti M, Duncan LR, Castanheira M. Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosacausing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012–15). J Antimicrob Chemother. 2017;72(5):1386–1395. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.30 Abbreviations: TOL/TAZ, ceftolozane–tazobactam; MIC, minimum inhibitory concentration; S, susceptible; MDR, multidrug-resistant; XDR, extensively drug-resistant; CAZ-NS, ceftazidime-non-susceptible; MEM-NS, meropenem-non-susceptible; ESBL, extended-spectrum β-lactamase; CRE, carbapenem-resistant Enterobacteriaceae; PIP/ TAZ-NS, piperacillin–tazobactam-non-susceptible. including when it is administered at multiple doses, it exhibits protein binding is approximately 20%. The steady-state dis- dose-linear pharmacokinetics (PK), with a mean Cmax of tribution volume (VD) of ceftolozane is approximately 14 L, 74 mg/dL (Table 2).19,36–39 Unlike piperacillin, which which is close to the average extracellular volume, which increases the tazobactam levels, the combination of ceftolo- suggests that ceftolozane can reach its therapeutic levels at zane with tazobactam does not affect the PK of tazobactam. extracellular sites of infection. The VD might be increased in The mean plasma half-life is approximately 2.3 h and the patients with obesity and infection.19 The plasma to epithelial submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1857 DovePress Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress Table 2 Pharmacokinetics of ceftolozane–tazobactam in doses, particularly for patients with abscesses, due to the healthy adults38,39 lower penetration of antibiotics at the site of the infection.41 Antibiotic (1 g ceftolo- Ceftolozane Tazobactam Although the VD and ClCr might be different from that zane – 0.5 g tazobactam) of healthy adults, a recent study of severely obese patients Cmax mg/dl 58–92 18.0–18.4 (BMI >35 kg/m2) achieved a PTA of bactericidal activity Plasma half-life (h) 1.86−2.64 1.0–1.1 of >90% at an MIC up to 8 mg/L. Moreover, pivotal phase Protein binding (%) 16–21 30% 3 studies on cUTIs and cIAIs revealed similar clinical AUC (mg h/L) 143–230 24–25 outcomes in severely obese and nonobese patients, and Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 Volume of distribution (L) 13–17 18.2 thus, no drug adjustments are needed in these cases.42 Epithelial lining fluid (ELF) (%) 0.46–0.60 44–46 The FDA-approved dose adjustments for C/T for patients ELF (mean mg/dL) 21 8 Urinary elimination (%) 97−100 >80% with renal failure (RF) are as follows: for a ClCr of Hemodialysis removal >90% - 30–50 mL/min, 500/250 mg/8 h; for a ClCr of Notes: Adapted from: Miller B, Hershberger E, Benziger D, Trinh M, Friedland I. 15–29 mL/min, 250/125 mg/8 h, and for end-stage renal Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult disease (EERD), loading dose of 500/250 followed by 100/ subjects following single and multiple ascending doses. Antimicrob Agents Chemother. 2012;56(6):3086–3091. Copyright © 2012, American Society for 50 mg/8 h.19 However, two randomized controlled trials Microbiology. All Rights Reserved.38 And from: Ge Y, Whitehouse MJ, Friedland I, (RCT) on cIAIs and cUTIs showed that the clinical outcome Talbot GH. Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single and multi- in patients with moderate RF, which was observed in ple-dose intravenous infusions. Antimicrob Agents Chemother. 2010;54(8):3427–3431. approximately 6% of cases, was lower compared with that Copyright © 2010, American Society for Microbiology.39 For personal use only. of patients with mild or no RF.43 Moreover, a recent study revealed that patients with EERD and renal-replacement lining fluid penetration (ELF) of ceftolozane is approximately therapy showed lower cure rates.44 50%, with a 42% interindividual variability.40 To our knowl- In a recent review, that included >10,000 patients with edge, there are no data on biliary excretion. different types of infections, approximately 20% of the Ceftolozane is mainly eliminated by renal excretion, patients with cUTIs or cIAIs had acute kidney failure and tazobactam is mainly eliminated by renal excretion (AKF), which resolved by 48 h in >50% of the cases.45 and by an M1 metabolite (Table 2). Ceftolozane has These data suggest that in septic patients with AKF, renal a linear PK over the range of renal function, and dose clearance improvement might lead to lower antibiotic adjustments are required for subjects who show creatinine plasma levels which could partially explain the higher clearance (CLCr) <50 mL/min.36,37 Because approximately failure rates observed in cases with RF. Thus, close renal 90% of the drug is removed during hemodialysis, it should clearance monitoring is necessary in cases with AKF. be administered after dialysis. For patients on hemodialysis and difficult-to-treat infec- Similar to other cephalosporins, C/T is bactericidal, tions, such as P. aeruginosa pneumonia, higher doses (a and the pharmacodynamic (PD) parameter that best pre- loading dose of C/T of 1.5 g followed by 300 mg/8 h) have dicts the bacteriologic efficacy is the time above the MIC been administered.46 There are scarce data for critically ill (T>MIC) for 40–50% of the dosing interval.36,37 Based on patients on continuous hemofiltration. It has been suggested Monte Carlo simulation models the probabilities of target that a C/T dose of 1.5 g/8 h administered during an extended- attainment (PTAs) with a C/T dose of 1.5 g every 8 h for infusion time of 4 h might work.47 50% T>MIC are 100% with an MIC ≤4 mg/L and 90% C/T has a low potential for clinically relevant drug–drug with an MIC =8 mg/L. For patients with pneumonia, and interactions because it is not a substrate for CYP and is not MIC values up to 8 mg/L, the PTAs in ELF for 40% and transported by OAT1 and OAT3 enzymes.48 50% T>MIC are 75% and 59%, respectively, and for a dose of 3 g every 8 h these values increase to 96% and Importance of inappropriate 88%, respectively. Thus, it has been suggested that higher doses should be administered to patients with treatment in complicated pneumonia.40 intra-abdominal and urinary tract For patients with cUTIs or cIAIs, the conventional dose infections of 1.5 g every 8 h is used, but real-life studies for the Severe sepsis and septic shock remain a significant public treatment of XDR P. aeruginosa infections have used higher health concern. Although the associated mortality has submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1858 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al decreased due to increased awareness and improved man- been suggested that antimicrobial therapy plays an impor- agement, it remains high, and a value of approximately tant role in the management of cIAIs. In severe septic 20% was obtained in the most recent multicenter trials.49 patients, an insufficient or otherwise inadequate antimicro- In 2010, a Cochrane Review on patients with sepsis con- bial regimen is one of the variables most strongly asso- cluded that although there is some evidence supporting the ciated with an unfavorable outcome. To our knowledge, early administration of antimicrobials for these patients, the impact of an adequate empirical antimicrobial therapy a strong recommendation cannot be provided given the lack on conditions with low mortality, such as noncomplicated of prospective trials.50 The Survival Sepsis Campaign (SSC) appendicitis and non-severe cholecystitis, has not been Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 released their latest guidelines in 2012, which included state- adequately studied when the patients are treated with ments emphasizing that in patients with septic shock (1B) or early surgery, but in our opinion the place of antibiotic severe sepsis (1C) antibiotics should be administered within therapy is probably irrelevant, because mortality is very an hour of recognition.51 A recent systematic review of the low, and the recommended postoperative duration of ther- available literature (2005–2015) concluded that patients with apy is very short. Excessive antimicrobial use might con- septic shock who received appropriate antimicrobial therapy tribute to the emergence and spread of drug-resistant within 1 h of recognition had the greatest benefit in mortality.49 microorganisms and increase the overall treatment costs.12 In patients with severe sepsis or septic shock, the control In the IDSA guidelines1 for IAI, the selection of the of the infectious foci (for example, abscess drainage in appropriate antimicrobial regimen is selected primarily intrabdominal infection or insertion of a pig-tail urinary based on the presence or absence of risk factors for For personal use only. tract catheter for ureter obstruction) also has an important potential failure. The populations of patients at high impact on mortality. In this sense, in a large study that risk include those with severe anatomically unfavorable included 3,663 patients with severe sepsis admitted to the infections or healthcare-related infections. In the WSES ICU, lower mortality (21.2% versus 25.1%) was detected in guidelines, high-risk patients are those with cIAIs with those who underwent source control for the infectious foci.52 a specific risk for antimicrobial-resistant bacteria and/ In UTIs, discordant antimicrobial therapy selected based or a severe clinical IAI.57 In the worldwide CIAOW on in vitro antimicrobial susceptibility test results does not study on cIAIs,58 which included 1,898 patients with always yield a poor clinical outcome of the nonbacteremic an overall mortality of 10%, the factors associated with UTI, because urinary concentrations of most antimicrobial a higher mortality were the presence of sepsis or septic agents are much higher than those in blood.53 However, in shock, a health-care infection, colonic nondiverticular community-acquired bacteremic APNs, discordant empirical perforation, a postoperative infection, complicated therapy leads to a notably worse early clinical response and diverticulitis, malignancy or immunosuppression, longer hospital stay than concordant therapy, even though it delayed surgery and, logically, ICU admission, but the does not affect the overall mortality or clinical cure rates.54 study did not analyze the impact of adequate antibiotic. Other studies have found that appropriate antibiotic therapy All these factors should be considered in the future has no impact on mortality but reduces the hospital stay and when analyzing an appropriate antibiotic therapy. costs.55,56 Most likely, appropriate antibiotic therapy has no Moreover, the appropriateness of an antibiotic therapy impact on mortality because the death rates related to APN might also depend on the causative agents and the type of are low (1%),5 even in elderly febrile UTI patients with intrabdominal foci. A retrospective study revealed that the severe underlying conditions.18 However, in our experience mortality of patients with P. aeruginosa of an intraabdominal with APN, significantly higher (8.5% versus 14.7%, p>0.01) non-hepatobiliary source who received inappropriate antibio- relapse rates are obtained if antibiotic therapy is not tailored tic therapy as higher than that of adequately treated patients.59 based on available susceptibility data.5 However, discordant antimicrobial therapy has no impact on An antimicrobial-based approach for the treatment of the mortality of patients with hepatobiliary disease. cIAIs always involves a delicate balance between the As in UTIs, the identifications of risk factors for optimization of empirical therapy, which has been shown ESBL-IAIs might be useful for selection of the initial to improve clinical outcomes, in some situations, and the antibiotic therapy. In recent studies in patients with bacter- reduction of excessive antimicrobial use, which has been emia from an intrabdominal source, carbapenem therapy proven to increase the rate of emergence of antimicrobial- was associated with a lower mortality rate than that of resistant strains. In several reviews or guidelines,1,12 it has piperacillin-tazobactam treatment.13 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1859 DovePress Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress The influence of adequate antibiotic therapy on the infections) combined two identical prospective, double- incidence of postoperative surgical site infections has blind, randomized, multicenter phase III clinical trials not been adequately studied. In a recent worldwide that compared C/T plus metronidazole with meropenem study of 567 patients with acute cholecystitis treated for the treatment of cIAIs. Hospitalized adult patients mainly with surgery, factors associated with the pre- with cIAIs that required surgical intervention were ran- sence of MDR microorganisms (mainly ESBL- domized 1:1 to receive C/T (1.5 g IV q8h) plus metro- producing enterobacteria) were the presence of a health- nidazole (500 mg IV q8h) or meropenem (1 g IV q8h) care infection and recent antibiotic therapy. However, for 4–14 days. The C/T dose for patients with ClCr of Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 factors associated with a poor outcome were the pre- 30–50 mL/minute was reduced to 750 mg every 8 h, and sence of diffuse peritonitis and an inadequate source the meropenem dose was reduced to 1 g every 12 h. The control, but the inadequacy of the empiric antibiotic study endpoints were to demonstrate statistical noninfer- therapy had no influence on mortality.60 iority in clinical cure rates in the mMITT and ME In conclusion, in cUTIs, due to its low rates of mortal- populations using a noninferiority margin of 10% at ity, an appropriate antibiotic therapy seems to have little the test-of-cure (TOC) visit (24–32 days from the start impact on the outcome mortality but has an impact on the of therapy). Of 993 patients that were randomized only clinical outcome, hospital stay and risk of relapse. In 806 (81.2%) met the criteria for the mMITT population. severe cIAIs, inadequate antibiotic therapy has an impact Statistical noninferiority was demonstrated in both on the outcome, with the control of the infection source populations. The clinical cure rates were 83% (323/ For personal use only. being essential. The impact of adequate empiric antibiotic 389) for C/T plus metronidazole and 87.3% (364/417) therapy on less severe IAIs when treated early with sur- for meropenem in the mMITT population (weighted gery (cholecystectomy, appendicectomy) is less relevant. difference, −4.2%; 95% CI, −8.91–0.54), and 94.2% (259/275) for C/T plus metronidazole and 94.7% (304/ 321) for meropenem (weighted difference, −1.0; 95% Ceftolozane/tazobactam in the CI, −4.52–2.59) in the ME population. treatment of complicated Most diagnoses were appendicular perforation or intra-abdominal infections peri-appendicular abscess (43.3%) and peritonitis was Clinical trials present in >80% of both patient populations. The dis- A phase II prospective, double-blind, randomized and tribution of pathogens and the per-pathogen clinical cure multicenter trial compared C/T plus metronidazole to rates were similar in both arms, and most infections in meropenem for the treatment of cIAIs.33 Hospitalized both populations were polymicrobial. Resistant bacteria adult patients with cIAIs that required surgical interven- were slightly represented but equally distributed: 29 tion were randomized 2:1 to receive C/T (1.5 g IV q8h) ESBL-producing Enterobacteriaceae in each group plus metronidazole (500 mg IV q8h) or meropenem (1 (overall rate of 7.2%), and three of the 52 isolated g IV q8h). Clinical response at the test-of-cure visit in P. aeruginosa were resistant to three or more classes the microbiologically modified intent-to-treat (mMITT) of antipseudomonal antibiotics. In patients with ESBL- and microbiologically evaluable (ME) per-protocol producing Enterobacteriaceae, the clinical cure rate was populations was the primary endpoint. Eighty-two 95.8% (23/24) for C/T plus metronidazole and 88.5% patients received C/T, and 39 patients received merope- (23/26) for meropenem, and clinical cure rates of 100% nem. Clinical cure was observed in 83.6% (51/61) of (13/13) and 72.7% (8/11) were obtained in patients with patients who received C/T versus 96% (24/25) of CTX-M-14/15 ESBLs, respectively. The type and fre- patients in the meropenem arm (difference −12.4%; quency of adverse events (AEs) was similar in both 95% CI,−34.9–11.1%) in the mMITT population, and groups (44.0% versus 42.7%). in 88.7% (47/53) and 95.8% (23/24) of the patients who received C/T and meropenem, respectively (differ- Real-life clinical experience ence −7.1%; 95% CI, −30.7% to 16.9%), in the ME As mentioned above, C/T has proven effective for the treat- population.33 ment of cIAIs, with a clinical success rate of more than 80% The ASPECT-cIAIs (assessment of the safety profile in RCTs,33,34 but MDR microorganisms were not very well and efficacy of C/T in complicated intra-abdominal represented, particularly MDR P. aeruginosa,for which submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1860 DovePress Powered by TCPDF (www.tcpdf.org) Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 For personal use only. Powered by TCPDF (www.tcpdf.org) Table 3 Clinical characteristics and outcome of patients treated with ceftolozane–tazobactam for multidrug-resistant Pseudomonas aeruginosa intra-abdominal infections Dovepress Age/sex Comorbidities Type of Procedure Presence Initial pre- Duration, Creatinine Other anti- Clinical Microbiological CT MIC (reference) infection of bactere- sentation of dose of C/ clearance mL/ pseudomonal outcome outcome (μg/mL, mia infection T treat- min) agents given (days) initial → ment in combina- subsequent) tion with CT 65/F61 Diabetes Abdominal Drainage of Yes Septic shock 14 days, 1.5 No data No data Cure Eradication 0.25 abscess g q8h Infection and Drug Resistance 2019:12 70/M61 None Intrabdominal Drainage of No Septic shock 21 days, 1.5 No data No data Cure Eradication 0.5 infection abscess g q8h 53/M61 Hepatitis Intrabdominal Laparotomy No Septic shock 11 days, 1.5 No data No data Death Persistence <4 C infection infection g q8h 76/F61 Diabetes mellitus, Biliary infection Biliary No Septic shock 9 days, 1.5 No data No data Cure Eradication, late 1 → 48 COPD drainage gq8h colonization with resistant isolate 58/F62 Pancreatitis, venti- Intrabdominal No data No data SAPS II 26, 40 days, 15–29 Inhaled colistin Cure Colonization with 4 → 128 lator-dependent infection SOFA Score 8 750 mg q8h resistant isolate respiratory failure during treatment 54/M63 Acute myeloid Perirectal No data No data No data 21 days, 3 >70 No Cure Eradication 1.5 leukemia abscess g q8h 70/M63 Liver Liver abscess No data No data No data 28 days, 1.5 >50 No Cure Eradication 0.75 transplantation g q8h 71/F63 Uterine Pelvic abscess No data No data No data 7 days, 30–50 IV Death Eradication 2 malignancy 750 mg q8h ciprofloxacin 48/F64 Pancreatic cancer Intrabdominal No data No data No data 16 days, 3 69 No Cure No data No data infection g q8h 53/F64 Autoimmune Intraabdominal No data No data No data 15 days, 1.5 19 No Death No data No data hepatitis infection g q8h 74/M65 Liver cirrhosis, Hepatic Percutaneous No No data 6 weeks, 46 IV colistin Cure No data 3 recent subtotal abscess sec- drainage 1.5 g q8h colectomy, che- ondary to bili- motherapy and ary leakage resection of hepa- tic metastases 44/M65 Liver transplanta- Cholangitis No Yes Septic shock 4 weeks, >90 No Cure Eradication 1 tion due to scler- 1.5 g q8h DovePress submit your manuscript | www.dovepress.com osing cholangitis (Continued) 1861 Escolà-Vergé et al Escolà-Vergé et al Dovepress ceftolozane–tazobactam might be important. Therefore, sev- subsequent) eral case reports and series have focused on analyzing the initial → CT MIC (μg/mL, outcome of patients with cIAIs due to MDR P. aeruginosa 1.5 who were treated with C/T in daily practice. Table 3 shows the clinical characteristics and outcomes of Microbiological different cases of cIAIs due to MDR P. aeruginosa (the last five cases are due to XRD P. aeruginosa) that were treated outcome No data with C/T.61–65 Overall, 10 of 13 (76.9%) exhibited a good Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 clinical outcome, and the other three died; in addition, in two (15.4%) of the cases with favorable clinical outcome showed outcome Clinical (days) colonization with a C/T-resistant P. aeruginosa isolate. Each Cure of two other unicenter observational studies of MDR P. aeruginosa infections treated with C/T (one with 38 pseudomonal tion with CT agents given in combina- Other anti- patients and the other with 58 patients) also included four cases of cIAIs, and in both studies three (75%) of the cIAI No patients exhibited a good clinical outcome.41,44 Two published multicenter retrospective studies also clearance mL/ included some cases of cIAIs treated with C/T. In one study, Creatinine For personal use only. which was performed in Italy,66 C/T was administered to 101 min) >90 patients with diverse infections, including 13 (12.8%) with cIAIs. Almost half of the P. aeruginosa strains included in dose of C/ Duration, 9 days, 1.5 this series were XDR (51%), concomitant antibiotics were T treat- ment g q8h administered to 35% of patients, and high doses of C/T (3 g every 8 h) were given to 30.7% of patients, including two patients with cIAIs. The overall clinical success rate for cIAIs sentation of Initial pre- was 76.9% (10 of 13). The other multicenter study, which was infection No data performed in the USA,67 included 205 patients, and 20 (9.8%) of these patients had a cIAI. Thirty-day or inpatient mortality was observed in two (10%) of the patients with cIAI, clinical of bactere- Presence success was seen in 15 (75%) of the cIAI patients, and mia a microbiological cure was achieved in 18 (90%). No The reasons for clinical failure in patients treated with C/ Percutaneous T for P. aeruginosa infections have been analyzed. The risk Procedure drainage factors associated with clinical failure that have been identi- fied are a higher Simplified Acute Physiology Score-II (SAPS-II) score,62 sepsis,66 the administration of continuous renal replacement therapy during C/T treatment,66 and an Abdominal infection inadequate source control.41 In a unicenter study, Type of abscess a comparative univariate analysis evaluating risk factors for clinical failure found significant differences in disease sever- gastric carcinoma, with suture leak- age, needing sur- Gastrectomy for Comorbidities ity, ventilator-dependent respiratory failure, XDR profile, reintervention high-risk clone ST175, negative control culture, and resis- Table 3 (Continued). tance development, but the multivariate analysis only identi- gical fied ventilator-dependent respiratory failure as an independent risk factor.44 One study also found that the (reference) initiation of C/T treatment within 4 days of culture collection Age/sex 54/F65 is a significant predictor of survival, clinical success, and microbiological success.67 Concomitant anti-pseudomonal submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1862 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al therapy or high doses of C/T have not been identified as with C/T and levofloxacin were 86% (6/7) and 58% significant risk factors. (7/12), respectively. Based on these data, the clinical and Another issue of concern is the selection of microbiological efficacy of C/T in MDR pathogens, which C/T-resistant strains due to mutations or overexpression is one of the main indications for this drug, is insufficient in the resident AmpC β-lactamase during therapy,44 which because the efficacy of C/T for ESBL infections has not has been observed in some cases of intraabdominal been compared with the gold-standard antibiotic therapy, infections,41,61,62 particularly in those with inadequate carbapenems, and patients with XDR P. aeruginosa infec- source control.41 tions were not included. In addition, only a few patients had Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 severe infections, because bacteremia was uncommon.69 Ceftolozane/tazobactam in the Real-life clinical experience treatment of complicated urinary Most of the real-life published clinical experience on C/T tract infections involves the treatment of MDR P. aeruginosa cUTIs. The Clinical trials published studies are case reports and small series of dif- The evidence for the efficacy of C/T in cUTIs is based on ferent types of MDR or XDR P. aeruginosa that include the ASPECT-cUTI phase III trial, which was a prospective cases of cUTIs.41,62 Among these studies, the overall clin- randomized, double-blind, double-dummy-controlled non- ical efficacy was approximately 70%, and 30–50% of the inferiority trial undertaken in 135 centers worldwide.68 cases were treated with high doses of C/T. In our limited For personal use only. This trial included 1,083 hospitalized patients with clinical experience with patients with P. aeruginosa, patients with evidence of APN (82%) or complicated lower UTI (18%), cUTI are usually treated with low C/T doses (only one case defined by symptoms of acute cystitis plus one of the with a prostatic abscess received high C/T doses).41 following: obstructive uropathy, indwelling urinary cathe- In a study that included 58 patients (cUTI was ter or anatomical urogenital tract abnormality. Patients the second type of treated infection), 8 of 10 patients with severe progressive disease or septic shock, immuno- with cUTI were cured.44 In another study that included suppressed patients, patients with severe renal failure (ClCr 23 patients, among which seven had a cUTI (all were <30 ml/min), patients with an infection that the investiga- treated with conventional C/T doses), only one showed tor determined would require more than 7 days of therapy clinical failure.65 Furthermore, in four studies that and patients who were not expected to survive 5 weeks included a limited number of cases of cUTIs, none of the were excluded. Only 7.8% of the patients had bacteremia. five included cases treated with low doses of C/T showed The infection was monomicrobial in 97% of the infections, clinical failure.61–64 A recent nationwide multicenter E. coli was isolated in 79% of the cases, 14.8% of the Italian study66 with 101 patients treated with C/T for patients had ESBL-producing Enterobacteriaceae, and serious P. aeruginosa infections showed clinical failure only 2.9% of the infections were due to P. aeruginosa. in only one of 14 (7.1%) patients with a cUTI. Overall, The participants were randomized 1:1 to receive C/T at 1.5 30% of the cases were treated with high doses, but the g/8 h (n=543) or levofloxacin at 750 mg (n=540) daily for dose to patients with a UTI was not specified. In the 7 days. Of note, approximately 25% of the isolated patho- largest series, which included 205 patients with MDR gens were resistant to quinolones, and 2.7% to C/T. Pseudomonas infection treated with C/T, the overall clin- Based on the composite cure outcome, which included ical and microbiological cure rates were 73.7% and 70.7%, clinical cure and microbiological eradication at 5–9 days respectively, and those for patients with cUTIs were 89% after the last dose, C/T was superior to levofloxacin in both (22/25) (89%) and 89% (22/25), respectively.67 the mMITT analysis (77% versus 68%) and the per-protocol In summary, 49/57 (86%) of the cases with MDR analysis (83% versus 75%). However, if only the patients P. aeruginosa cUTIs treated with C/T, usually with conven- with susceptible pathogens were analyzed, the outcomes tional doses (when specified), were cured, and this percen- were similar. As expected for ESBL-producing E. coli tage is higher than the overall cure rate. In these studies infections, higher microbiological cure rates were obtained patients with severe infections were included, because with C/T [27/36 (75%) versus 18/36 (50%)] due to the high a significant percentage had bacteremia, and some patients resistance rates to fluoroquinolones. For P. aeruginosa had undergone solid organ or hematopoietic stem cell trans- infections, the microbiological eradication rates obtained plantation, had EERD and/or were admitted to the ICU. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1863 DovePress Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress Safety and tolerability of In the first clinical situation, the use of C/T for the treatment of ESBL-producing Gram-negative rod infections ceftolozane/tazobactam has been proposed for the recovery of carbapenem activity C/T has a safety and tolerability profile similar to that of in a given health institution. It has been well demonstrated any other cephalosporin, as demonstrated by RCTs, which that the overuse of carbapenems can condition the appear- showed a percentage of AEs ranging from 35% to 50% ance and dissemination of carbapenem-producing [overall 438 AEs over 1,097 (39.9%) patients treated with Enterobacteriaceae (CPE), which would significantly limit C/T] and no significant differences with respect to their the potential use of these drugs. The reduction in the use of Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 comparators. Between 3% and 17% of the patients pre- carbapenems is associated with a decrease in the frequency sented severe adverse events (SAEs), although only three of CPE infections. In centers where ESBL-producing cases of Clostridium difficile infection were considered to Gram-negative rod infections are endemic, a carbapenem- be related to C/T. In the RCTs, no drug-related death was sparing strategy (in either first-line therapy or de-escalation reported, and the most frequently reported AEs (with an therapy) could be effective in preventing the appearance incidence greater than 5% in either indication) experienced and dissemination of CPE. The recently published results by the patients treated with C/T were nausea, headache, of the MERINO study13 demonstrate the superiority of diarrhea, and pyrexia.33,34,68 a carbapenem regimen over piperacillin–tazobactam for In a postmarketing safety evaluation, seven cases of med- the treatment of infections caused by ceftriaxone-resistant ication errors were reported to the FDA: these patients were E. coli or K. pneumoniae, and thus this therapeutic alter- administered a dose of C/T that was 50% higher than the For personal use only. native should not be used in a carbapenem-sparing strategy. prescribed dose and experienced no AEs related to the med- However, the results of the MERINO study could have been ication error.70 Similarly, a multicenter, retrospective study of subject to numerous biases, both in the selection of patients, patients with carbapenem-resistant P. aeruginosa infections in the choice of the primary outcome, in the inclusion of who were treated with C/T ranging from 375 mg to 3,000 mg patients from countries with different profiles and rates of every 8 h for 5–27 days observed only two AEs (self-limited antimicrobial resistance, and in the manner of administra- diarrhea and peripheral eosinophilia with eosinophiluria pos- tion of piperacillin–tazobactam. Therefore, its conclusions sibly due to interstitial nephritis), which resolved after the should be considered with caution. drug was stopped.63 In a retrospective series of 38 patients Although there is no relevant clinical information, the with XDR P. aeruginosa infections treated with C/T for 15.5 stability of C/T against AmpC beta-lactamases would days (range of 3–62 days), 60.5% of the patients were admi- allow its alternative use to carbapenems for the treatment nistered doses of 3 g every 8 h, and no AEs that forced the of infections caused by SPACE organisms (Serratia, withdrawal of the antibiotic were observed.41 Providencia, Acinetobacter, Citrobacter, Enterobacter). In summary, C/T is a cephalosporin with a safety profile C/T maintains its activity against P. aeruginosa spe- and tolerability similar to those of the remaining cephalospor- cies with multiple resistance mechanisms (efflux pumps, ins and can be administered to patients with cIAIs or cUTIs, reduction uptake through porin channels, or modifica- and in particular, C/T can be used, if necessary, at doses of up tion of penicillin-binding proteins). Several observa- to 3 g every 8 h for a prolonged time (at least for 4 weeks). tional studies have found that C/T can be an effective therapy for the treatment of serious infections caused by Conclusions and place in therapy MDR or XDR P. aeruginosa. In particular, when admi- C/T is a cephalosporin with activity against most ESBL- nistered at an adequate dose (usually up to 3 g every 8 producing Gram-negative rods and against MDR or XDR h), C/T can act on the source of the infection and the P. aeruginosa. Different published RCTs have reported the MIC value for C/T does not exceed 4 mg/L. C/T ther- efficacy and safety profile for the treatment of cIAIs and apy for these serious infections provides a clinical suc- cUTIs, and the results show that the drug has a favorable PK/ cess rate (in-hospital survival plus resolution of signs PD profile. The use of C/T for the treatment of these infections and symptoms) of approximately 75%. Although the should be considered in two clinical situations: as a potential published experience in the treatment of cIAIs or alternative therapy to carbapenems in a carbapenem-sparing cUTIs produced by MDR or XDR P. aeruginosa is strategy, or for the treatment of infections caused by MDR or very limited, the absence of effective therapeutic alter- XDR P. aeruginosa. natives with an acceptable safety profile would make C/ submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1864 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al T a first-line therapeutic option for these infections. 9. Hackel MA, Badal RE, Bouchillon SK, Biedenbach DJ, Hoban DJ. Resistance rates of intra-abdominal isolates from intensive care units Therefore, C/T should be routinely tested against every and non-intensive care units in the United States: the study for Gram-negative rod, and particularly against MDR or monitoring antimicrobial resistance trends 2010–2012. Surg Infect XDR P. aeruginosa. (Larchmt). 2015;16(3):298–304. doi:10.1089/sur.2014.060 10. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. Acknowledgments 2010;54(11):4851–4863. doi:10.1128/AAC.00627-10 The authors are funded by the Plan Nacional de I+D+I 11. Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 2013-2016 and the Instituto de Salud Carlos III, Spain revised guidelines on the management of intra-abdominal infection. Surg Infect (Larchmt). 2017;18(1):1–76. doi:10.1089/sur.2016.261 [REIPI RD16/0016/0003]. We would like to acknowledge 12. Sartelli M, Chichom-Mefire A, Labricciosa FM, et al. The manage- the professional manuscript services of Nature Publishing ment of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. Group Language Editing. World J Emerg Surg. 2017;12(1). doi:10.1186/s13017-017-0141-6 13. Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for Disclosure patients with E. coli or Klebsiella pneumoniae bloodstream infection The authors have no other relevant affiliations or financial and ceftriaxone resistance: a randomized clinical trial. JAMA. involvement with any organization or entity with a financial 2018;320(10):984–994. doi:10.1001/jama.2018.12163 14. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course interest in or financial conflict with the subject matter or antimicrobial therapy for intraabdominal infection. N Engl J Med. materials discussed in the manuscript apart from those 2015;372(21):1996–2005. doi:10.1056/NEJMoa1411162 15. Bader MS, Loeb M, Brooks AA. An update on the management of urinary disclosed. For personal use only. tract infections in the era of antimicrobial resistance. Postgrad Med. 2017;129(2):242–258. doi:10.1080/00325481.2017.1246055 16. Hawkey PM, Warren RE, Livermore DM, et al. Treatment of infections References caused by multidrug-resistant Gram-negative bacteria: report of the 1. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and manage- British Society for Antimicrobial Chemotherapy/Healthcare Infection ment of complicated intra-abdominal infection in adults and children: Society/British Infection Association Joint Working Party. J Antimicrob guidelines by the Surgical Infection Society and the Infectious Chemother. 2018;73(suppl_3):iii2–iii78. doi:10.1093/jac/dky027 Diseases Society of America. Clin Infect Dis. 2010;50(2):133–164. 17. Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á; doi:10.1086/649554 Extended-Spectrum Beta-Lactamases–red Española de Investigación 2. Babinchak T, Badal R, Hoban D, et al. Trends in susceptibility of en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria selected gram-negative bacilli isolated from intra-abdominal infections Group. β-Lactam/β-lactam inhibitor combinations for the treatment in North America: SMART 2005–2010. Diagn Microbiol Infect Dis. of bacteremia due to extended-spectrum β-lactamase-producing 2013;76(3):379–381. doi:10.1016/j.diagmicrobio.2013.02.031 Escherichia coli: a post hoc analysis of prospective cohorts. Clin 3. de Cueto M, Aliaga L, Alós J-I, et al. Executive summary of the Infect Dis. 2012;54(2):167–174. doi:10.1093/cid/cir790 diagnosis and treatment of urinary tract infection: guidelines of the 18. Babich T, Zusman O, Elbaz M, et al. Empirical antibiotic treatment Spanish Society of Clinical Microbiology and Infectious Diseases does not improve outcomes in catheter-associated urinary tract infec- (SEIMC). Enferm Infecc Microbiol Clin. 2017;35(5):314–320. tion: prospective cohort study. Clin Infect Dis. 2017;65 doi:10.1016/j.eimc.2016.11.005 (11):1799–1805. doi:10.1093/cid/cix680 4. Gupta K, Hooton TM, Naber KG, et al. International clinical practice 19. van Duin D, Bonomo RA. Ceftazidime/avibactam and ceftolozane/ guidelines for the treatment of acute uncomplicated cystitis and pye- tazobactam: second-generation β-lactam/β-lactamase inhibitor combi- lonephritis in women: a 2010 update by the Infectious Diseases nations. Clin Infect Dis. 2016;63(2):234–241. doi:10.1093/cid/ciw243 Society of America and the European Society for Microbiology and 20. Murano K, Yamanaka T, Toda A, et al. Structural requirements for the Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–e120. stability of novel cephalosporins to AmpC β-lactamase based on 3D- doi:10.1093/cid/ciq257 structure. Bioorg Med Chem. 2008;16(5):2261–2275. doi:10.1016/j. 5. Bosch-Nicolau P, Falcó V, Viñado B, et al. A cohort study of risk bmc.2007.11.074 factors that influence empirical treatment of patients with acute 21. Moya B, Zamorano L, Juan C, Ge Y, Oliver A. Affinity of the new pyelonephritis. Antimicrob Agents Chemother. 2017;61(12). cephalosporin cxa-101 to penicillin-binding proteins of Pseudomonas doi:10.1128/AAC.01317-17 aeruginosa. Antimicrob Agents Chemother. 2010;54(9):3933–3937. 6. Bischoff S, Walter T, Gerigk M, Ebert M, Vogelmann R. Empiric doi:10.1128/AAC.00296-10 antibiotic therapy in urinary tract infection in patients with risk factors 22. Moya B, Dötsch A, Juan C, et al. β-Lactam resistance response triggered for antibiotic resistance in a German emergency department. BMC by inactivation of a nonessential penicillin-binding protein. Ausubel FM, Infect Dis. 2018;18. doi:10.1186/s12879-018-2960-9 ed. PLoS Pathog. 2009;5(3):e1000353. doi:10.1371/journal.ppat.1000353 7. Marshall JC, Maier RV, Jimenez M, Dellinger EP. Source control in 23. Livermore DM, Mushtaq S, Ge Y. Chequerboard titration of cepha- the management of severe sepsis and septic shock: an evidence-based losporin CXA-101 (FR264205) and tazobactam versus review. Crit Care Med. 2004;32(11 Suppl):S513–S526. beta-lactamase-producing Enterobacteriaceae. J Antimicrob 8. Morrissey I, Hackel M, Badal R, Bouchillon S, Hawser S, Chemother. 2010;65(9):1972–1974. doi:10.1093/jac/dkq248 Biedenbach D. A review of ten years of the study for monitoring 24. Cluck D, Lewis P, Stayer B, Spivey J, Moorman J. Ceftolozane- antimicrobial resistance trends (SMART) from 2002 to 2011. tazobactam: a new-generation cephalosporin. Am J Health Syst Pharmaceuticals. 2013;6(11):1335–1346. doi:10.3390/ph6111335 Pharm. 2015;72(24):2135–2146. doi:10.2146/ajhp150049 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1865 DovePress Powered by TCPDF (www.tcpdf.org) Escolà-Vergé et al Dovepress 25. Bush K, Macalintal C, Rasmussen BA, Lee VJ, Yang Y. Kinetic 39. Ge Y, Whitehouse MJ, Friedland I, Talbot GH. Pharmacokinetics and interactions of tazobactam with b-lactamases from all major struc- safety of CXA-101, a new antipseudomonal cephalosporin, in healthy tural classes. Antimicrob Agents Chemother. 1993;37:8. doi:10.1128/ adult male and female subjects receiving single- AAC.37.4.851 and multiple-dose intravenous infusions. Antimicrob Agents Chemother. 26. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of 2010;54(8):3427–3431. doi:10.1128/AAC.01753-09 ceftolozane-tazobactam tested against Enterobacteriaceae and 40. Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazo- Pseudomonas aeruginosa with various resistance patterns isolated in bactam pharmacokinetic/pharmacodynamic-derived dose justification U.S. hospitals (2011-2012). Antimicrob Agents Chemother. 2013;57 for phase 3 studies in patients with nosocomial pneumonia. J Clin (12):6305–6310. doi:10.1128/AAC.01802-13 Pharmacol. 2016;56(1):56–66. doi:10.1002/jcph.566 27. Titelman E, Karlsson IM, Ge Y, Giske CG. In vitro activity of 41. Escolà-Vergé L, Pigrau C, Los-Arcos I, et al. Ceftolozane/tazobactam Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and for the treatment of XDR Pseudomonas aeruginosa infections. CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Infection. 2018;46(4):461–468. doi:10.1007/s15010-018-1133-5 Diagn Microbiol Infect Dis. 2011;70(1):137–141. doi:10.1016/j. 42. Xiao AJ, Huntington JA, Long J, Caro L. Ceftolozane/tazobactam dose diagmicrobio.2011.02.004 regimens in severely/morbidly obese patients with complicated 28. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. intra-abdominal infection or complicated urinary tract infection. Antimicrobial activity of ceftolozane/tazobactam tested against Int J Antimicrob Agents. 2018;52(3):324–330. doi:10.1016/j. Pseudomonas aeruginosa and Enterobacteriaceae with various resis- ijantimicag.2018.03.004 tance patterns isolated in European hospitals (2011–12). J Antimicrob 43. Kullar R, Wagenlehner FM, Popejoy MW, Long J, Yu B, Chemother. 2014;69(10):2713–2722. doi:10.1093/jac/dku184 Goldstein EJC. Does moderate renal impairment affect clinical out- 29. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam comes in complicated intra-abdominal and complicated urinary tract activity tested against aerobic Gram-negative organisms isolated from infections? Analysis of two randomized controlled trials with intra-abdominal and urinary tract infections in European and United ceftolozane/tazobactam. J Antimicrob Chemother. 2016;dkw486. States hospitals (2012). J Infect. 2014;69(3):266–277. doi:10.1016/j. doi:10.1093/jac/dkw486 jinf.2014.04.004 44. Díaz-Cañestro M, Periañez L, Mulet X, et al. Ceftolozane/tazo- 30. Pfaller MA, Bassetti M, Duncan LR, Castanheira M. Ceftolozane/ bactam for the treatment of multidrug resistant Pseudomonas For personal use only. tazobactam activity against drug-resistant Enterobacteriaceae and aeruginosa: experience from the Balearic Islands. Eur J Clin Pseudomonas aeruginosa causing urinary tract and intraabdominal Microbiol Infect Dis. 2018;37(11):2191–2200. doi:10.1007/ infections in Europe: report from an antimicrobial surveillance pro- s10096-018-3361-0 gramme (2012–15). J Antimicrob Chemother. 2017;72(5):1386–1395. 45. Crass RL, Rodvold KA, Mueller BA, Pai MP. Renal dosing of doi:10.1093/jac/dkx009 antibiotics: are we jumping the gun? Clin Infect Dis. 2018. 31. Shortridge D, Pfaller MA, Castanheira M, Flamm RK. Antimicrobial doi:10.1093/cid/ciy790 activity of ceftolozane-tazobactam tested against Enterobacteriaceae and 46. Alessa MA, Almangour TA, Alhossan A, Alkholief MA, Alhokail M, Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Tabb DE. Ceftolozane-tazobactam for the treatment of Hospitals (2013–2016) as part of the surveillance program: program to multidrug-resistant Pseudomonas aeruginosa pneumonia in assess ceftolozane-tazobactam susceptibility. Microb Drug Resist. a patient receiving intermittent hemodialysis. Am J Health Syst 2018;24(5):563–577. doi:10.1089/mdr.2017.0266 Pharm. 2018;75(9):e184–e188. doi:10.2146/ajhp170056 32. Snydman DR, McDermott LA, Jacobus NV. Activity of 47. Oliver WD, Heil EL, Gonzales JP, et al. Ceftolozane-tazobactam phar- ceftolozane-tazobactam against a broad spectrum of recent clinical macokinetics in a critically ill patient on continuous venovenous anaerobic isolates. Antimicrob Agents Chemother. 2014;58 hemofiltration. Antimicrob Agents Chemother. 2015;60(3):1899–1901. (2):1218–1223. doi:10.1128/AAC.02253-13 doi:10.1128/AAC.02608-15 33. Lucasti C, Hershberger E, Miller B, et al. Multicenter, double-blind, 48. Scott LJ. Ceftolozane/tazobactam: a review in complicated randomized, phase ii trial to assess the safety and efficacy of intra-abdominal and urinary tract infections. Drugs. 2016;76 ceftolozane-tazobactam plus metronidazole compared with meropenem (2):231–242. doi:10.1007/s40265-015-0524-5 in adult patients with complicated intra-abdominal infections. Antimicrob 49. Sherwin R, Winters ME, Vilke GM, Wardi G. Does early and appro- Agents Chemother. 2014;58(9):5350–5357. doi:10.1128/AAC.00049-14 priate antibiotic administration improve mortality in emergency 34. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam department patients with severe sepsis or septic shock? J Emerg plus metronidazole for complicated intra-abdominal infections in an Med. 2017;53(4):588–595. doi:10.1016/j.jemermed.2016.12.009 era of multidrug resistance: results from a randomized, double-blind, 50. Siddiqui S, Razzak J. Early versus late pre-intensive care unit admis- phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60 sion broad spectrum antibiotics for severe sepsis in adults. Cochrane (10):1462–1471. doi:10.1093/cid/civ097 Database Syst Rev. 2010;(10):CD007081. doi:10.1002/14651858. 35. Armstrong ES, Farrell DJ, Palchak M, Steenbergen JN. In Vitro CD007081.pub2 activity of ceftolozane-tazobactam against anaerobic organisms iden- 51. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: tified during the ASPECT-cIAI Study. Antimicrob Agents Chemother. international guidelines for management of severe sepsis and septic 2016;60(1):666–668. doi:10.1128/AAC.01964-15 shock: 2012. Crit Care Med. 2013;41(2):580–637. doi:10.1097/ 36. Cho JC, Fiorenza MA, Estrada SJ. Ceftolozane/Tazobactam: a novel CCM.0b013e31827e83af cephalosporin/β-lactamase inhibitor combination. Pharmacotherapy. 52. Martínez ML, Ferrer R, Torrents E, et al. Impact of source control in 2015;35(7):701–715. doi:10.1002/phar.1609 patients with severe sepsis and septic shock. Crit Care Med. 2017;45 37. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: (1):11–19. doi:10.1097/CCM.0000000000002011 a novel cephalosporin/β-lactamase inhibitor combination with activ- 53. Stamey TA, Fair WR, Timothy MM, Millar MA, Mihara G, ity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74 Lowery YC. Serum versus urinary antimicrobial concentrations in (1):31–51. doi:10.1007/s40265-013-0168-2 cure of urinary-tract infections. N Engl J Med. 1974;291(22): 38. Miller B, Hershberger E, Benziger D, Trinh M, Friedland I. 1159–1163. doi:10.1056/NEJM197411282912204 Pharmacokinetics and safety of intravenous ceftolozane-tazobactam 54. Lee SS, Kim Y, Chung DR. Impact of discordant empirical therapy in healthy adult subjects following single and multiple ascending on outcome of community-acquired bacteremic acute doses. Antimicrob Agents Chemother. 2012;56(6):3086–3091. pyelonephritis. J Infect. 2011;62(2):159–164. doi:10.1016/j. doi:10.1128/AAC.06349-11 jinf.2010.10.009 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1866 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Escolà-Vergé et al 55. Yang Y-S, Ku C-H, Lin J-C, et al. Impact of Extended-spectrum β- 64. Dinh A, Wyplosz B, Kernéis S, et al. Use of ceftolozane/tazobactam lactamase-producing Escherichia coli and Klebsiella pneumoniae on as salvage therapy for infections due to extensively drug-resistant the outcome of community-onset bacteremic urinary tract infections. Pseudomonas aeruginosa. Int J Antimicrob Agents. 2017;49 J Microbiol Immunol Infect. 2010;43(3):194–199. doi:10.1016/S1684- (6):782–783. doi:10.1016/j.ijantimicag.2017.04.001 1182(10)60031-X 65. Xipell M, Paredes S, Fresco L, et al. Clinical experience with cefto- 56. Spoorenberg V, Hulscher MEJL, Akkermans RP, Prins JM, lozane/tazobactam in patients with serious infections due to resistant Geerlings SE. Appropriate antibiotic use for patients with urinary Pseudomonas aeruginosa. J Glob Antimicrob Resist. tract infections reduces length of hospital stay. Clin Infect Dis. 2018;13:165–170. doi:10.1016/j.jgar.2018.01.010 2014;58(2):164–169. doi:10.1093/cid/cit688 66. Bassetti M, Castaldo N, Cattelan A, et al. Ceftolozane/tazobactam for 57. Sartelli M, Malangoni MA, May AK, et al. World Society of the treatment of serious P. aeruginosa infections: a multicenter nation- Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 37.15.48.178 on 02-Jun-2021 Emergency Surgery (WSES) guidelines for management of skin and wide clinical experience. Int J Antimicrob Agents. 2018. doi:10.1016/ soft tissue infections. World J Emerg Surg. 2014;9(1):57. j.ijantimicag.2018.11.001 doi:10.1186/1749-7922-9-57 67. Gallagher JC, Satlin MJ, Elabor A, et al. Ceftolozane-tazobactam for the 58. Sartelli M, Catena F, Ansaloni L, et al. Complicated intra-abdominal treatment of multidrug-resistant Pseudomonas aeruginosa infections: infections worldwide: the definitive data of the CIAOW Study. World a multicenter study. Open Forum Infect Dis. 2018. doi:10.1093/ofid/ J Emerg Surg. 2014;9(1):37. doi:10.1186/1749-7922-9-37 ofy280 59. Joo E-J, Kang C-I, Ha YE, et al. Impact of inappropriate empiric 68. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. antimicrobial therapy on outcome in Pseudomonas aeruginosa bacter- Ceftolozane-tazobactam compared with levofloxacin in the treatment aemia: a stratified analysis according to sites of infection. Infection. of complicated urinary-tract infections, including pyelonephritis: 2011;39(4):309–318. doi:10.1007/s15010-011-0124-6 a randomised, double-blind, phase 3 trial (ASPECT-cUTI). The 60. Coccolini F, Sartelli M, Catena F, et al. Antibiotic resistance pattern Lancet. 2015;385(9981):1949–1956. doi:10.1016/S0140-6736(14) and clinical outcomes in acute cholecystitis: 567 consecutive world- 62220-0 wide patients in a prospective cohort study. Int J Surg. 69. Popejoy MW, Paterson DL, Cloutier D, et al. Efficacy of ceftolozane/ 2015;21:32–37. doi:10.1016/j.ijsu.2015.07.013 tazobactam against urinary tract and intra-abdominal infections 61. Castón JJ, De la Torre Á, Ruiz-Camps I, Sorlí ML, Torres V, Torre- caused by ESBL-producing Escherichia coli and Klebsiella pneumo- For personal use only. Cisneros J. Salvage therapy with ceftolozane-tazobactam for niae: a pooled analysis of Phase 3 clinical trials. J Antimicrob multidrug-resistant Pseudomonas aeruginosa infections. Antimicrob Chemother. 2017;72(1):268–272. doi:10.1093/jac/dkw374 Agents Chemother. 2017;61(3):e02136–16. doi:10.1128/AAC.02136-16 70. Drug Safety and Availability - FDA Drug Safety Communication: 62. Haidar G, Philips NJ, Shields RK, et al. Ceftolozane-tazobactam for FDA cautions about dose confusion and medication errors for anti- the treatment of multidrug-resistant Pseudomonas aeruginosa bacterial drug Zerbaxa (ceftolozane and tazobactam). Available from: Infections: clinical effectiveness and evolution of resistance. https://www.fda.gov/Drugs/DrugSafety/ucm445919.htm. Accessed Clin Infect Dis. 2017;65(1):110–120. doi:10.1093/cid/cix182 February 24, 2019. 63. Munita JM, Aitken SL, Miller WR, et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017;65(1):158–161. doi:10.1093/cid/cix014 Infection and Drug Resistance Dovepress Publish your work in this journal Infection and Drug Resistance is an international, peer-reviewed open- antibiotic resistance and the mechanisms of resistance development and access journal that focuses on the optimal treatment of infection diffusion in both hospitals and the community. The manuscript manage- (bacterial, fungal and viral) and the development and institution of ment system is completely online and includes a very quick and fair peer- preventive strategies to minimize the development and spread of resis- review system, which is all easy to use. Visit http://www.dovepress.com/ tance. The journal is specifically concerned with the epidemiology of testimonials.php to read real quotes from published authors. Submit your manuscript here: https://www.dovepress.com/infection-and-drug-resistance-journal submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 1867 DovePress Powered by TCPDF (www.tcpdf.org)