Antimicrobial activity of cefoperazone-sulbactam tested against Gram-Negative organisms from Europe, Asia-Pacific, and Latin America

Journal Pre-proof Antimicrobial Activity of Cefoperazone-Sulbactam Tested against Gram-Negative Organisms from Europe, Asia-Pacific, and Latin America Helio S. Sader, Cecilia G. Carvalhaes, Jennifer M. Streit, Mariana Castanheira, Robert K. Flamm

PII:

S1201-9712(19)30445-X

DOI:

https://doi.org/10.1016/j.ijid.2019.11.006

Reference:

IJID 3827

To appear in:

International Journal of Infectious Diseases

Received Date:

30 August 2019

Revised Date:

4 November 2019

Accepted Date:

5 November 2019

Please cite this article as: Sader HS, Carvalhaes CG, Streit JM, Castanheira M, Flamm RK, Antimicrobial Activity of Cefoperazone-Sulbactam Tested against Gram-Negative Organisms from Europe, Asia-Pacific, and Latin America, International Journal of Infectious Diseases (2019), doi: https://doi.org/10.1016/j.ijid.2019.11.006

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IJID-D-19-01100-R1

Antimicrobial Activity of Cefoperazone-Sulbactam Tested against Gram-Negative Organisms from Europe, Asia-Pacific, and Latin America

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Running Title: Cefoperazone-Sulbactam Activity

Cecilia G. Carvalhaes, Jennifer M. Streit,

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Mariana Castanheira,

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Helio S. Sader,

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Robert K. Flamm

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JMI Laboratories, North Liberty, IA, USA

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Corresponding Author: Helio S. Sader, MD, PhD JMI Laboratories 345 Beaver Kreek Centre, Suite A North Liberty, IA 52317 Email: [email protected]

Highlights -

19545 Gram-negative isolates were collected from medical centers located worldwide

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82.0-94.4% of Enterobacterales (91.5% overall) were susceptible to cefoperazone-sulbactam at ≤16 mg/L

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59.5-84.6% of P. aeruginosa (77.8% overall) were susceptible to cefoperazone-sulbactam at ≤16 mg/L

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Resistance rates varied widely and were generally higher in eastern Europe

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Cefoperazone-sulbactam was among the most active compounds in vitro

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Key words: Cefoperazone, sulbactam, Enterobacterales, Enterobacteriaceae, Pseudomonas aeruginosa

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ABSTRACT Objectives: To evaluate the antimicrobial activities of cefoperazone-sulbactam and comparator agents tested against a large collection of clinical isolates of Gram-negative organisms. Methods: A total of 19 545 Gram-negative organisms were collected from medical centers located in western Europe (W-EUR; n = 10 626), eastern Europe and the Mediterranean region (E-EUR; n = 4029), the Asia-Pacific region (APAC; n = 2491), and Latin America (LATAM; n = 2399) in 2015–2016 and susceptibility tested by reference broth microdilution methods.

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Results: Overall, 91.5% of Enterobacterales were susceptible (≤16 mg/L) to cefoperazone-sulbactam, with susceptibility rates ranging from 82.0% (E-EUR) to 94.4% (W-EUR); overall susceptibility to cefoperazone-

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sulbactam, piperacillin-tazobactam, imipenem, and ceftriaxone was 91.5%, 85.4%, 90.5%, and 72.1%,

respectively. Among Pseudomonas aeruginosa isolates, cefoperazone-sulbactam susceptibility rates were

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higher in W-EUR, APAC, and LATAM (83.0-84.6%) compared to E-EUR (59.5%). Susceptibility to piperacillintazobactam, imipenem, and ceftazidime was 78.3%, 76.2%, and 82.0% in W-EUR; 52.3%, 43.5%, and 57.4% in

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E-EUR; 83.5%, 80.1%, and 84.5% in APAC; and 81.5%, 72.8%, and 83.0% in LATAM, respectively.

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Acinetobacter spp. susceptibility rates varied from 43.0% in E-EUR to 75.8% in LATAM (53.2% overall) for cefoperazone-sulbactam and from 19.8% in E-EUR to 40.2% in W-EUR (26.4% overall) for imipenem. Conclusions: Susceptibility rates varied widely among geographic regions and were generally lowest in E-

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EUR. Based on the potency and activity spectrum, cefoperazone-sulbactam remains among the most active compounds in vitro at published breakpoints.

Keywords: Cefoperazone-sulbactam; Antimicrobial resistance; Enterobacterales; Acinetobacter spp.;

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Stenotrophomonas maltophilia

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Introduction Cefoperazone is a third-generation cephalosporin with broad-spectrum antimicrobial activity against Gram-positive and Gram-negative organisms, including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. (Fass et al., 1990). Cefoperazone has a long elimination half-life of approximately 2 hours, which allows for twice-daily administration, and it was widely used in the 1980s to treat infections in immunocompetent and neutropenic patients (Klastersky, 1988). Because of its lability to β-lactamases, cefoperazone was combined with the β-lactamase inhibitor sulbactam, and this combination has been used in

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many geographic regions to treat various infection types, including nosocomial pneumonia, intra-abdominal infections, gynecological infections, sepsis, and infections in febrile neutropenic patients (Aynioglu et al., 2016,

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Bin et al., 2006, Demir et al., 2011, Karaman et al., 2012, Sipahi et al., 2014).

In this study, we evaluated the antimicrobial activities of cefoperazone-sulbactam and comparator

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agents tested against 19 545 Gram-negative organisms collected in 2015 and 2016 from individual medical centers in Europe, Latin America, and the Asia-Pacific region (APAC) as part of the SENTRY Antimicrobial

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Surveillance Program.

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Materials and Methods Organism collection A total of 19 545 organisms, including 14 417 Enterobacterales, 3818 P. aeruginosa, and 1310 Acinetobacter spp. isolates, were collected from medical centers located in western Europe (W-EUR; n = 10 626; 26 centers in 10 nations), eastern Europe and the Mediterranean region (E-EUR; n = 4,029; 15 centers in 11 nations), the Asia-Pacific region (APAC; n = 2,491; 18 centers in 9 nations), and Latin America (LATAM; n = 2,399; 17 centers in 11 nations) in 2015–2016 as part of the SENTRY Antimicrobial Surveillance Program.

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The countries surveyed were Belgium, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and United Kingdom in W-EUR; Belarus, Croatia, Czech Republic, Hungary, Israel, Poland, Romania, Russia,

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Slovakia, Slovenia, and Turkey in E-EUR; Australia, Japan, Malaysia, New Zealand, Philippines, Singapore, South Korea, Taiwan, and Thailand in APAC; and Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador,

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Guatemala, Mexico, Panama, Peru, and Venezuela in LATAM.

Isolates were collected from patients with bloodstream infections (6170; 31.6%), pneumonia (5537

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isolates; 28.3%), skin and skin structure infections (4136; 21.2%); urinary tract infections (2372; 12.1%), intra-

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abdominal infections (1153; 5.9% and other infection types (177; 0.9%). Participating centers identified the organisms, and JMI Laboratories (North Liberty, Iowa, USA) confirmed the species, when necessary, by Vitek 2 or by matrix-assisted laser desorption ionization-time of flight mass spectrometry using the Bruker Daltonics

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MALDI Biotyper (Billerica, Massachusetts, USA) and by following manufacturer instructions. Susceptibility testing

Broth microdilution test methods were conducted at a reference laboratory according to the Clinical and Laboratory Standards Institute (CLSI) guidelines to determine the antimicrobial susceptibility of cefoperazone-

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sulbactam and comparator agents (CLSI, 2018a). Frozen-form MIC panels were prepared at JMI Laboratories and cefoperazone-sulbactam was tested at a 1:1 ratio. Concurrent quality control (QC) testing was performed to ensure proper test conditions and procedures, and QC strains included Escherichia coli ATCC 25922 and 35218, Klebsiella pneumoniae ATCC 700603, P. aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 29213. All QC results were within published ranges. Cefoperazone-sulbactam MIC breakpoints used were found in the Sulperazone® package insert (Sulperazone®, 2009); i.e., ≤16 mg/l for susceptible and ≥64 mg/l for resistance. CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility

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interpretive criteria were used to determine susceptibility/resistance rates for comparator agents (CLSI, 2018b,

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EUCAST, 2018).

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Results Overall, 91.6% of Enterobacterales were susceptible to cefoperazone-sulbactam at ≤16 mg/l (Sulperazone®, 2009) (MIC50/90, 0.5/16 mg/l) with susceptibility rates ranging from 94.4% in W-EUR, 94.2% in APAC, 89.5% in LATAM, and 82.0% in E-EUR (Table 1 and Figure 1). The most active comparator agents were tigecycline (98.1%/92.8% susceptible per US Food and Drug Administration (FDA)/EUCAST; ranging from 99.0%/95.2% in APAC to 97.8%/91.6% in E-EUR), amikacin (97.4%/95.3% susceptible per CLSI/EUCAST; ranging from 99.0%/97.3% in APAC to 94.1%/90.5% in E-EUR), and meropenem (96.1%/96.5% susceptible per

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CLSI/EUCAST; ranging from 97.6%/97.8% in W-EUR to 91.5%/92.8% in E-EUR; Table 1).

Comparator agents generally had lower susceptibility rates in E-EUR and LATAM compared to W-EUR

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and APAC (Table 1). Importantly, a marked difference was observed between E-EU and W-EU. Among K. pneumoniae for example, susceptibility (CLSI) to ciprofloxacin, gentamicin and meropenem were 29.8%, 51.4%,

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and 77.4% in E-EU, respectively; and 63.0%, 83.4%, and 87.2% in W-EU, respectively. Similarly, extendedspectrum β-lactamase (ESBL)-phenotype rates among E. coli and K. pneumoniae isolates were higher in E-

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EUR (38.2% and 72.4%, respectively) and LATAM (34.7% and 51.8%, respectively) compared to W-EUR

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(18.4% and 34.2%, respectively) and APAC (26.2% and 25.1%, respectively; Table 3). Cefoperazone-sulbactam activity against P. aeruginosa was substantially higher in W-EUR (83.0% susceptible), APAC (84.6% susceptible), and LATAM (83.0% susceptible) compared to E-EUR (59.5%

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susceptible; Table 3 and Figure 2). The most active comparator agents tested against P. aeruginosa were colistin (99.7% susceptible per CLSI and EUCAST), amikacin (86.8%/82.6% susceptible per CLSI/EUCAST), and tobramycin (82.7% susceptible per CLSI and EUCAST; Table 3). Moreover, susceptibility rates to all comparator agents, except colistin, were substantially lower in E-EUR compared to the other regions evaluated

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(Table 3).

Cefoperazone-sulbactam (53.2% susceptible) was the most active agent tested against Acinetobacter

spp. after colistin (89.3% susceptible per CLSI and EUCAST; Table 4 and Figure 3). Cefoperazone-sulbactam susceptibility rates varied from 75.8% in LATAM, 63.5% in W-EUR, 48.1% in the APAC region, and 43.0% in EEUR; Table 4 and Figure 3). In general, Acinetobacter spp. susceptibility rates to comparator agents were highest in W-EUR, followed by LATAM, APAC, and E-EUR (Table 4). Discussion

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Antimicrobial resistance varies substantially worldwide depending on the bacterial species, antimicrobial class, and geographic region (Sader et al., 2019). Results from the European Antimicrobial Resistance Surveillance Network (EARS-NET) program have shown a north-to-south and west-to-east gradient of resistance rates for many organism–antimicrobial combinations with lower resistance rates being reported by countries in the north and higher resistance rates being reported in the south and east of Europe (ECDC, 2017). Data from the Central Asian and Eastern European Surveillance of Antimicrobial Resistance (CAESAR) program coordinated by the World Health Organization (WHO) has shown higher resistance rates in eastern

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Europe and central Asia compared to western Europe (WHO, 2017). Moreover, antimicrobial resistance

country and/or organism (Bazzo et al., 2018, Mohd Rani et al., 2017).

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surveillance data from the Asia-Pacific region and Latin America are scarce and usually restricted to a specific

Our investigation results align with the data reported by EARS-NET and CAESAR programs and provide

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additional data for regions not covered by these two programs, i.e., eastern Asian countries, the Australia-New Zealand region, and Latin America (ECDC, 2017, WHO, 2017). Our results showed susceptibility rates

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substantially lower in E-EUR compared to the other geographic regions surveyed, and other surveillance

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programs have shown that this region includes countries with important antimicrobial resistance problems, such as Belarus, Poland, Russia, and Turkey (Durdu et al., 2018, Fursova et al., 2015, WHO, 2017, WojkowskaMach et al., 2018). A total of 2543 Enterobacterales isolates from E-EUR were evaluated and the isolate

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frequencies showed an ESBL phenotype (38.2% among E. coli and 72.4% among K. pneumoniae) or carbapenem resistance (CRE; 8.5%/7.2% not susceptible to meropenem per CLSI/EUCAST; data not shown) were extremely elevated in the region. Moreover, resistance rates to aminoglycosides and fluoroquinolones among Enterobacterales isolates were also elevated and higher than rates from other geographic regions. Based on the cefoperazone-sulbactam breakpoints published in the Sulperazone® and Cefobid® package

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inserts (susceptible at ≤16 mg/l and resistant at ≥64 mg/l; (CEFOBID®, 2006, Sulperazone®, 2009), cefoperazone-sulbactam activity against Enterobacterales isolates in the E-EUR region (82.0% susceptible) was superior to the activity of piperacillin-tazobactam (72.5%/66.8% susceptible per CLSI/EUCAST) and the cephalosporins cefepime (57.7%/55.4%), ceftazidime (58.3%/53.9%), and ceftriaxone (51.5%/51.5%). Similarly, P. aeruginosa and Acinetobacter spp. susceptibility rates were markedly lower in E-EUR compared to other regions. The most active antimicrobial agent against P. aeruginosa in E-EUR after colistin

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was amikacin with only 61.0% susceptibility per EUCAST criteria (compared to 84.1-92.3% in other regions), and only 46.1% of isolates were susceptible to meropenem (compared to 74.8-82.6%% in other regions). Cefoperazone-sulbactam coverage against P. aeruginosa in the E-EUR region was comparable to cefepime and ceftazidime coverage and superior to the carbapenems imipenem and meropenem. Against Acinetobacter spp. from E-EUR, only colistin was active against >50% of isolates. Elevated resistance rates in the E-EUR region have been related to multiple factors, including elevated antimicrobial usage and resistance gene/clone dissemination (Fursova et al., 2015, van Duin and Doi, 2017, Wojkowska-Mach et al., 2018).

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LATAM is a very diverse region with significant antimicrobial resistance problems in most countries and scarce surveillance data (De Belder et al., 2018, Escandon-Vargas et al., 2017, Jones et al., 2013). Our results

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showed low susceptibility rates among Enterobacterales from LATAM for cephalosporins (62.3% for ceftriaxone per CLSI and EUCAST), fluoroquinolones (65.9%/58.8% for levofloxacin per CLSI/EUCAST), aminoglycosides

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(73.6%/72.5% for gentamicin per CLSI/EUCAST), and carbapenems (94.5%/95.0% for meropenem per CLSI/EUCAST), and elevated rates of E. coli and K. pneumoniae displaying an ESBL phenotype (34.7% and

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51.8%, respectively). Susceptibility rates were also low among Acinetobacter spp. and P. aeruginosa isolates,

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especially for tobramycin (84.1%), amikacin (87.9%/84.1% per CLSI/EUCAST), and meropenem (74.8%). Moreover, cefoperazone-sulbactam activity was comparable to imipenem activity against Enterobacterales, was comparable to cefepime and ceftazidime activities against P. aeruginosa, and was superior to all β-lactam

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comparator activities against Acinetobacter spp. It is important to note that antimicrobial agents active against CRE and multidrug-resistant (MDR) P. aeruginosa isolates that have been recently approved by the US FDA and European Medicines Agency, such as ceftazidime-avibactam, meropenem-vaborbactam, and ceftolozanetazobactam, are not available in many Latin American countries, leaving very few options for treatment of

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infections caused by MDR Gram-negative organisms. Higher susceptibility rates were observed in W-EUR and APAC when compared to E-EUR and LATAM;

however, antimicrobial resistance varied markedly among the W-EUR and among the APAC countries included in this investigation. As shown by other investigators (ECDC, 2017), antimicrobial resistance was generally higher in the southern countries of W-EUR, such as Italy and Greece, compared to northern countries, such as Sweden and Germany. Variability was even greater in APAC where susceptibility of Enterobacterales to meropenem varied from >99.0% in Australia, Japan, New Zealand, Singapore, and South Korea, to <90.0% in

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Taiwan and Thailand (data not shown). Based on the package insert breakpoints (CEFOBID®, 2006, Sulperazone®, 2009), cefoperazone-sulbactam coverage against Enterobacterales in the W-EUR and APAC regions was similar to imipenem coverage and was superior to piperacillin-tazobactam and the cephalosporins cefepime, ceftazidime and ceftriaxone. Against P. aeruginosa isolates from these regions, cefoperazonesulbactam exhibited susceptibility rates similar to those of the cephalosporins cefepime and ceftazidime, and slightly higher than those displayed by the carbapenems imipenem and meropenem. In summary, antimicrobial susceptibility rates for agents commonly used to treat serious systemic

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infections varied widely among geographic regions and were generally lowest in E-EUR. Susceptibility results of almost 20 000 Gram-negative organisms from 76 medical centers in 41 countries indicate that cefoperazone-

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sulbactam continues to demonstrate good in vitro activity against Enterobacterales and P. aeruginosa isolates from Europe, the Asia-Pacific region, and Latin America. Based on its potency and activity spectrum,

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cefoperazone-sulbactam continues to have a role for treating infections caused by Gram-negative organisms

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Acinetobacter spp. at published breakpoints.

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and remains among the most active compounds in vitro against Enterobacterales, P. aeruginosa, and

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Author Disclosure Statement This study at JMI Laboratories was supported by Pfizer Inc. (New York, NY), and JMI Laboratories received compensation for services related to preparing the manuscript. JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea

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Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMerieux SA, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., CorMedix Inc., DePuy

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Synthes, Destiny Pharma, Discuva Ltd., Dr. Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics,

Eurofarma Laboratorios SA, US Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc.,

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Gateway Pharmaceutical LLC, GenePOC Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals

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Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc,

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NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Ra Pharmaceuticals, Inc.,

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Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc.,SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, The Medicines Company, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Vyome Therapeutics Inc.,

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Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.

Conflicts of Interest/ Ethical Approval None of the authors has a conflict of interest. Ethical Approval not required.

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Acknowledgements

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The authors would like to thank Lori Flanigan, Michael Janechek, Judy Oberholser, and Gauri Deshpande for valuable editorial assistance.

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Figure 1. Antimicrobial activity of cefoperazone-sulbactam against Enterobacterales isolates stratified by geographic region

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Figure 2. Antimicrobial activity of cefoperazone-sulbactam against P. aeruginosa isolates stratified by geographic region

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Figure 3. Antimicrobial activity of cefoperazone-sulbactam against Acinetobacter spp. isolates stratified by geographic region

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Table 1 Antimicrobial activity of cefoperazone-sulbactam and comparator agents tested against Enterobacterales isolates stratified by geographic region

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All (14 417) 91.6b/85.4/81.1 39.5/39.5 97.4/95.3 76.0/73.3 78.2/76.4 77.5/73.4 72.1/72.1 71.4/67.0 -/83.0 83.9/83.4 90.5/95.6 74.5/69.7 96.1/96.5 98.1/92.8 80.7/77.8 66.5/66.5 (6,853) 92.8b/92.1/88.5 42.3/42.3 99.2/97.1 79.5/76.6 79.4/77.8 83.3/77.8 76.8/76.8 64.7/64.7 99.3/99.3 85.1/84.8 99.6/99.8 65.9/65.9 99.7/99.7 >99.9/99.3 82.8/80.1 60.2/60.2 (3,397) 69.3c/-

ro

LATAM (1789) 89.5b/83.7/78.0 33.4/33.4 96.4/93.0 66.1/63.7 67.5/65.8 68.4/64.1 62.3/62.3 60.3/54.2 -/81.3 73.6/72.5 91.0/94.5 65.9/58.8 94.5/95.0 98.3/93.0 69.4/65.5 54.7/54.7 (742) 91.6b/92.6/87.2 36.3/36.3 98.9/96.0 68.3/65.6 69.6/67.6 72.4/67.8 65.4/65.4 50.8/50.8 98.5/98.5 72.8/71.7 99.7/99.9 51.6/51.6 99.9/99.9 100.0/99.1 70.9/67.0 43.5/43.5 (530) 68.1b/-

-p

APAC (1645) 94.2b/89.8/86.5 45.0/45.0 99.0/97.3 81.6/78.2 83.2/81.8 82.0/78.5 76.8/76.8 78.3/73.4 -/85.8 86.0/85.6 94.3/97.4 80.5/76.4 97.6/97.7 99.0/95.2 85.4/81.7 72.4/72.4 (703) 93.3b/95.0/92.5 41.8/41.8 99.6/98.0 81.4/76.1 80.7/79.8 83.4/77.5 76.5/76.5 67.8/67.8 99.6/99.6 79.9/79.5 99.4/99.4 68.8/68.8 99.3/99.3 99.7/99.0 80.9/76.5 61.2/61.2 (559) 81.8b/-

re

E-EUR (2543) 82.0b/72.5/66.8 27.3/27.3 94.1/90.5 56.8/53.6 57.7/55.4 58.3/53.9 51.5/51.5 55.1/49.4 -/84.0 70.1/69.6 86.7/93.1 59.8/54.0 91.5/92.8 97.8/91.6 63.7/60.5 52.6/52.6 (1030) 87.5b/87.2/81.9 33.8/33.8 98.3/95.5 66.0/62.8 65.9/63.3 71.7/64.6 62.5/62.5 54.6/54.6 99.2/99.2 80.5/80.4 98.5/99.4 56.8/56.8 99.2/99.4 100.0/99.5 75.7/72.4 52.8/52.8 (842) 47.0b/-

ur na

W-EUR Enterobacterales (8440) Cefoperazone-sulbactam 94.4b/-c Piperacillin-tazobactam 88.8/85.1 Ampicillin-sulbactam 43.5/43.5 Amikacin 98.2/96.9 Aztreonam 82.8/80.4 Cefepime 85.7/83.9 Ceftazidime 84.3/80.3 Ceftriaxone 79.4/79.4 Ciprofloxacin 77.3/73.8 Colistin -/82.6 Gentamicin 89.8/89.4 Imipenem 90.7/96.3 Levofloxacin 79.6/75.4 Meropenem 97.6/97.8 Tigecyclined 98.0/92.7 Tobramycin 87.3/84.9 TMP-SMX 72.0/72.0 E. coli (4,378) Cefoperazone-sulbactam 94.2b/Piperacillin-tazobactam 92.7/89.6 Ampicillin-sulbactam 45.4/45.4 Amikacin 99.4/97.6 Aztreonam 84.3/81.8 Cefepime 84.1/82.7 Ceftazidime 87.8/82.6 Ceftriaxone 82.2/82.2 Ciprofloxacin 68.9/68.9 Colistine 99.5/99.5 Gentamicin 89.0/88.9 Imipenem 99.8/99.9 Levofloxacin 70.0/70.0 Meropenem 99.9/99.9 d Tigecycline >99.9/99.4 Tobramycin 86.7/84.8 TMP-SMX 64.6/64.6 K. pneumoniae (1466) Cefoperazone-sulbactam 77.7b/-

% susceptible per CLSI/EUCAST (no. of isolates)a

lP

Antimicrobial agent

48.1/40.5 20.7/20.7 88.6/81.8 30.9/29.2 30.0/29.5 30.5/29.1 28.1/28.1 29.8/29.8 90.1/90.1 51.4/51.1 80.0/84.7 37.6/37.6 77.4/81.1 98.8/83.5 37.1/34.0 38.0/38.0

82.1/78.0 65.8/65.8 97.7/95.2 76.9/75.1 77.6/76.7 75.8/74.2 75.0/75.0 69.5/69.5 97.0/97.0 86.8/86.6 93.4/94.1 75.3/75.3 93.0/93.6 99.1/88.2 84.6/81.6 74.1/74.1

67.7/59.5 39.4/39.4 93.0/88.9 50.9/49.8 51.0/49.9 51.7/48.7 49.2/49.2 44.4/44.4 91.8/91.8 64.8/64.5 85.1/85.1 53.3/53.3 83.4/85.1 99.1/84.7 55.7/53.4 49.6/49.6

68.8/62.5 44.2/44.2 92.2/88.7 57.8/56.5 58.0/57.2 57.5/55.7 56.1/56.1 53.0/53.0 93.1/93.1 73.1/72.9 85.9/87.6 59.8/59.8 85.1/86.7 98.9/85.0 63.4/60.8 58.2/58.2

of

76.0/70.2 51.2/51.2 91.9/90.2 68.3/67.6 69.1/68.3 68.1/66.4 67.4/67.4 63.0/63.0 93.8/93.8 83.4/83.8 86.7/87.7 69.0/69.0 87.2/87.8 98.8/84.7 73.3/71.0 66.9/66.9

ro

Piperacillin-tazobactam Ampicillin-sulbactam Amikacin Aztreonam Cefepime Ceftazidime Ceftriaxone Ciprofloxacin Colistine Gentamicin Imipenem Levofloxacin Meropenem Tigecyclined Tobramycin TMP-SMX

Criteria as published by CLSI 2018 (CLSI, 2018b) and EUCAST 2018 (EUCAST, 2018).

b

Sulperazone Package Insert (Sulperazone®, 2009).

c

-, no breakpoint has been established.

d

US FDA breakpoints (Tygacil, 2018).

e

Values for CLSI indicates percentage of wild type based on ECV (CLSI M100).

lP

re

-p

a

Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM,

ur na

Latin America; TMP-SMX, trimethoprim-sulfamethoxazole.

Table 2. Frequency of E. coli and K. pneumoniae isolates with an ESBL phenotype stratified by geographic region

Jo

Organism

% of isolates with ESBL phenotype (CLSI)

W-EUR

E-EUR

APAC

LATAM

E. coli

18.4

38.2

26.2

34.7

K. pneumoniae

34.2

72.4

25.1

51.8

Abbreviations: ESBL, extended-spectrum β-lactamase; W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM, Latin America.

20

Table 3 Antimicrobial activity of cefoperazone-sulbactam and comparator agents tested against Pseudomonas aeruginosa isolates stratified by geographic region Antimicrobial agent E-EUR (891)

APAC (636)

LATAM (453)

All (3818)

83.0b/-c 78.3/78.3 93.7/89.4 85.4/85.4 82.0/82.0 78.5/75.5 99.9/99.9 84.8/84.8 76.2/80.1 76.8/69.3 78.9/78.9 88.5/88.5

59.5b/52.3/52.3 66.5/61.0 60.5/60.5 57.4/57.4 52.7/47.6 99.3/99.3 56.2/56.2 43.5/48.5 49.3/41.3 46.1/46.1 61.7/61.7

84.6b/83.5/83.5 94.7/92.3 88.2/88.2 84.5/84.5 85.7/82.7 99.7/99.7 91.4/91.4 80.1/82.4 84.0/76.8 82.6/82.6 94.0/94.0

83.0b/81.5/81.5 87.9/84.1 83.0/83.0 83.0/83.0 78.1/75.7 99.8/99.8 81.2/81.2 72.8/75.5 76.1/67.9 74.8/74.8 84.1/84.1

77.8b/73.5/73.5 86.8/82.6 79.8/79.8 76.8/76.8 73.7/70.2 99.7/99.7 78.8/78.8 68.8/72.6 71.5/63.9 71.4/71.4 82.7/82.7

-p

ro

of

W-EUR (1838)

re

Cefoperazone-sulbactam Piperacillin-tazobactam Amikacin Cefepime Ceftazidime Ciprofloxacin Colistin Gentamicin Imipenem Levofloxacin Meropenem Tobramycin

% susceptible (CLSI/EUCAST)a

Criteria as published by CLSI 2018 (CLSI, 2018b) and EUCAST 2018 (EUCAST, 2018).

b

Sulperazone Package Insert (2009) (Sulperazone®, 2009).

c

-, no breakpoint has been established.

lP

a

Jo

Latin America.

ur na

Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM,

21

Table 4 Antimicrobial activity of cefoperazone-tazobactam and comparator agents tested against Acinetobacter spp. stratified by geographic region

E-EUR (595)

APAC (210)

LATAM (157)

All (1310)

63.5b/-c 35.9/37.6/46.6/45.1 37.1/36.2/37.5/37.5 82.1/82.1 43.1/43.1 40.2/40.2 38.5/37.4 40.2/40.2 -/44.8/44.8

43.0b/7.2/16.5/16.8/14.5 9.9/8.7/7.6/7.6 90.7/90.7 19.0/19.0 19.8/19.8 9.1/7.6 17.3/17.3 -/40.3/40.3

48.1b/19.0/22.9/33.8/31.9 17.1/22.4/21.9/21.9 91.9/91.9 31.0/31.0 25.2/25.2 24.8/22.4 24.3/24.3 -/35.2/35.2

75.8b/17.2/23.1/36.3/27.4 20.6/22.3/19.1/19.1 96.2/96.2 32.5/32.5 22.3/22.3 20.4/19.7 21.7/21.7 -/50.6/50.6

53.2b/17.9/23.9/29.8/26.9 19.6/19.8/19.2/19.2 89.3/89.3 28.9/28.9 26.4/26.4 20.8/19.3 25.0/25.0 -/41.9/41.9

ro

of

W-EUR (348)

-p

Cefoperazone-sulbactamb Piperacillin-tazobactam Ampicillin-sulbactam Amikacin Cefepime Ceftazidime Ciprofloxacin Colistin Gentamicin Imipenem Levofloxacin Meropenem Tigecyclined Tobramycin

% susceptible (CLSI/EUCAST)a

re

Antimicrobial agent

Criteria as published by CLSI 2018 (CLSI, 2018b) and EUCAST 2018 (EUCAST, 2018).

b

Sulperazone Package Insert (Sulperazone®, 2009).

c

-, no breakpoint has been established.

d

US FDA breakpoints (Tygacil, 2018).

ur na

lP

a

Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM,

Jo

Latin America.

22