International Journal of Infectious Diseases 91 (2020) 32–37

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

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
JMI Laboratories, North Liberty, IA, USA

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: To evaluate the antimicrobial activities of cefoperazone-sulbactam and comparator agents
Received 30 August 2019 tested against a large collection of clinical isolates of Gram-negative organisms.
Received in revised form 4 November 2019 Methods: A total of 19 545 Gram-negative organisms were collected from medical centers located in
Accepted 5 November 2019
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
Keywords: susceptibility tested by reference broth microdilution methods.
Cefoperazone-sulbactam
Results: Overall, 91.5% of Enterobacterales were susceptible (16 mg/L) to cefoperazone-sulbactam, with
Antimicrobial resistance
Enterobacterales
susceptibility rates ranging from 82.0% (E-EUR) to 94.4% (W-EUR); overall susceptibility to cefoperazone-
Acinetobacter spp. sulbactam, piperacillin-tazobactam, imipenem, and ceftriaxone was 91.5%, 85.4%, 90.5%, and 72.1%,
ESBL respectively. Among Pseudomonas aeruginosa isolates, cefoperazone-sulbactam susceptibility rates were
higher in W-EUR, APAC, and LATAM (83.0–84.6%) compared to E-EUR (59.5%). Susceptibility to
piperacillin-tazobactam, imipenem, and ceftazidime was 78.3%, 76.2%, and 82.0% in W-EUR; 52.3%, 43.5%,
and 57.4% in E-EUR; 83.5%, 80.1%, and 84.5% in APAC; and 81.5%, 72.8%, and 83.0% in LATAM, respectively.
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-
EUR. Based on the potency and activity spectrum, cefoperazone-sulbactam remains among the most
active compounds in vitro at published breakpoints.
© 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction geographic regions to treat various infection types, including

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 h, 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 many
nosocomial pneumonia, intra-abdominal infections, gynecological
infections, sepsis, and infections in febrile neutropenic patients
(Aynioglu et al., 2016; 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 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
Surveillance Program.

* Corresponding author at: JMI Laboratories, 345 Beaver Kreek Centre, Suite A,
North Liberty, IA 52317, USA.
E-mail address: helio-sader@jmilabs.com (H.S. Sader).

https://doi.org/10.1016/j.ijid.2019.11.006
1201-9712/© 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 H.S. Sader et al. / International Journal of Infectious Diseases 91 (2020) 32–37 33

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. 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, Slovakia, Slovenia, and Turkey in
E-EUR; Australia, Japan, Malaysia, New Zealand, Philippines,
Singapore, South Korea, Taiwan, and Thailand in APAC; and

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

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

W-EUR E-EUR APAC LATAM All

Enterobacterales (8440) (2543) (1645) (1789) (14 417)
Cefoperazone-sulbactam 94.4b/-c 82.0b/- 94.2b/- 89.5b /- 91.6b /-
Piperacillin-tazobactam 88.8/85.1 72.5/66.8 89.8/86.5 83.7/78.0 85.4/81.1
Ampicillin-sulbactam 43.5/43.5 27.3/27.3 45.0/45.0 33.4/33.4 39.5/39.5
Amikacin 98.2/96.9 94.1/90.5 99.0/97.3 96.4/93.0 97.4/95.3
Aztreonam 82.8/80.4 56.8/53.6 81.6/78.2 66.1/63.7 76.0/73.3
Cefepime 85.7/83.9 57.7/55.4 83.2/81.8 67.5/65.8 78.2/76.4
Ceftazidime 84.3/80.3 58.3/53.9 82.0/78.5 68.4/64.1 77.5/73.4
Ceftriaxone 79.4/79.4 51.5/51.5 76.8/76.8 62.3/62.3 72.1/72.1
Ciprofloxacin 77.3/73.8 55.1/49.4 78.3/73.4 60.3/54.2 71.4/67.0
Colistin -/82.6 -/84.0 -/85.8 -/81.3 -/83.0
Gentamicin 89.8/89.4 70.1/69.6 86.0/85.6 73.6/72.5 83.9/83.4
Imipenem 90.7/96.3 86.7/93.1 94.3/97.4 91.0/94.5 90.5/95.6
Levofloxacin 79.6/75.4 59.8/54.0 80.5/76.4 65.9/58.8 74.5/69.7
Meropenem 97.6/97.8 91.5/92.8 97.6/97.7 94.5/95.0 96.1/96.5
Tigecyclined 98.0/92.7 97.8/91.6 99.0/95.2 98.3/93.0 98.1/92.8
Tobramycin 87.3/84.9 63.7/60.5 85.4/81.7 69.4/65.5 80.7/77.8
TMP-SMX 72.0/72.0 52.6/52.6 72.4/72.4 54.7/54.7 66.5/66.5
E. coli (4,378) (1030) (703) (742) (6,853)
Cefoperazone-sulbactam 94.2b/- 87.5b/- 93.3b/- 91.6b/- 92.8b/-
Piperacillin-tazobactam 92.7/89.6 87.2/81.9 95.0/92.5 92.6/87.2 92.1/88.5
Ampicillin-sulbactam 45.4/45.4 33.8/33.8 41.8/41.8 36.3/36.3 42.3/42.3
Amikacin 99.4/97.6 98.3/95.5 99.6/98.0 98.9/96.0 99.2/97.1
Aztreonam 84.3/81.8 66.0/62.8 81.4/76.1 68.3/65.6 79.5/76.6
Cefepime 84.1/82.7 65.9/63.3 80.7/79.8 69.6/67.6 79.4/77.8
Ceftazidime 87.8/82.6 71.7/64.6 83.4/77.5 72.4/67.8 83.3/77.8
Ceftriaxone 82.2/82.2 62.5/62.5 76.5/76.5 65.4/65.4 76.8/76.8
Ciprofloxacin 68.9/68.9 54.6/54.6 67.8/67.8 50.8/50.8 64.7/64.7
Colistine 99.5/99.5 99.2/99.2 99.6/99.6 98.5/98.5 99.3/99.3
Gentamicin 89.0/88.9 80.5/80.4 79.9/79.5 72.8/71.7 85.1/84.8
Imipenem 99.8/99.9 98.5/99.4 99.4/99.4 99.7/99.9 99.6/99.8
Levofloxacin 70.0/70.0 56.8/56.8 68.8/68.8 51.6/51.6 65.9/65.9
Meropenem 99.9/99.9 99.2/99.4 99.3/99.3 99.9/99.9 99.7/99.7
Tigecyclined >99.9/99.4 100.0/99.5 99.7/99.0 100.0/99.1 >99.9/99.3
Tobramycin 86.7/84.8 75.7/72.4 80.9/76.5 70.9/67.0 82.8/80.1
TMP-SMX 64.6/64.6 52.8/52.8 61.2/61.2 43.5/43.5 60.2/60.2
K. pneumoniae (1466) (842) (559) (530) (3,397)
Cefoperazone-sulbactam 77.7b/- 47.0b/- 81.8b /- 68.1b/- 69.3c/-
Piperacillin-tazobactam 76.0/70.2 48.1/40.5 82.1/78.0 67.7/59.5 68.8/62.5
Ampicillin-sulbactam 51.2/51.2 20.7/20.7 65.8/65.8 39.4/39.4 44.2/44.2
Amikacin 91.9/90.2 88.6/81.8 97.7/95.2 93.0/88.9 92.2/88.7
Aztreonam 68.3/67.6 30.9/29.2 76.9/75.1 50.9/49.8 57.8/56.5
Cefepime 69.1/68.3 30.0/29.5 77.6/76.7 51.0/49.9 58.0/57.2
Ceftazidime 68.1/66.4 30.5/29.1 75.8/74.2 51.7/48.7 57.5/55.7
Ceftriaxone 67.4/67.4 28.1/28.1 75.0/75.0 49.2/49.2 56.1/56.1
Ciprofloxacin 63.0/63.0 29.8/29.8 69.5/69.5 44.4/44.4 53.0/53.0
Colistine 93.8/93.8 90.1/90.1 97.0/97.0 91.8/91.8 93.1/93.1
Gentamicin 83.4/83.8 51.4/51.1 86.8/86.6 64.8/64.5 73.1/72.9
Imipenem 86.7/87.7 80.0/84.7 93.4/94.1 85.1/85.1 85.9/87.6
Levofloxacin 69.0/69.0 37.6/37.6 75.3/75.3 53.3/53.3 59.8/59.8
Meropenem 87.2/87.8 77.4/81.1 93.0/93.6 83.4/85.1 85.1/86.7
Tigecyclined 98.8/84.7 98.8/83.5 99.1/88.2 99.1/84.7 98.9/85.0
Tobramycin 73.3/71.0 37.1/34.0 84.6/81.6 55.7/53.4 63.4/60.8
TMP-SMX 66.9/66.9 38.0/38.0 74.1/74.1 49.6/49.6 58.2/58.2
a
Criteria as published by CLSI (2018b) and EUCAST (2018).
b
Sulperazone Package Insert (Sulperazone1 , 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). Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region,
APAC, Asia-Pacific region; LATAM, Latin America; TMP-SMX, trimethoprim-sulfamethoxazole.
34 H.S. Sader et al. / International Journal of Infectious Diseases 91 (2020) 32–37
Figure 1. Antimicrobial activity of cefoperazone-sulbactam against Enterobacterales isolates stratified by geographic region.
Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Guatemala,
Mexico, Panama, Peru, and Venezuela in LATAM.
Isolates were collected from patients with bloodstream infec-
tions (6170; 31.6%), pneumonia (5537 isolates; 28.3%), skin and skin
structure infections (4136; 21.2%); urinary tract infections (2372;
12.1%), intra-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 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 suscepti-
bility of cefoperazone-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 Sulperazone1
package insert (Sulperazone1 , 2009); i.e., 16 mg/L for susceptible
and 64 mg/L for resistance. CLSI and European Committee on
Antimicrobial Susceptibility Testing (EUCAST) susceptibility inter-
pretive criteria were used to determine susceptibility/resistance
rates for comparator agents (CLSI, 2018b; EUCAST, 2018).
Results
Overall, 91.6% of Enterobacterales were susceptible to cefoper-
azone-sulbactam at 16 mg/L (Sulperazone1 , 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 CLSI/EUCAST; ranging
from 97.6%/97.8% in W-EUR to 91.5%/92.8% in E-EUR; Table 1).
Table 2
Frequency of E. coli and K. pneumoniae isolates with an ESBL phenotype stratified by
geographic region.
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.
Comparator agents generally had lower susceptibility rates in E-
EUR and LATAM compared to W-EUR 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%, and 77.4% in E-EU,
respectively; and 63.0%, 83.4%, and 87.2% in W-EU, respectively.
Similarly, extended-spectrum β-lactamase (ESBL)-phenotype rates
among E. coli and K. pneumoniae isolates were higher in E-EUR
(38.2% and 72.4%, respectively) and LATAM (34.7% and 51.8%,
respectively) compared to W-EUR (18.4% and 34.2%, respectively)
and APAC (26.2% and 25.1%, respectively; Table 2).
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% 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 (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
E-EUR; 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
Antimicrobial resistance varies substantially worldwide
depending on the bacterial species, antimicrobial class, and
 H.S. Sader et al. / International Journal of Infectious Diseases 91 (2020) 32–37 35

Table 3
Antimicrobial activity of cefoperazone-sulbactam and comparator agents tested against Pseudomonas aeruginosa isolates stratified by geographic region.

Antimicrobial agent % susceptible (CLSI/EUCAST)a

W-EUR (1838) E-EUR (891) APAC (636) LATAM (453) All (3818)
Cefoperazone-sulbactam 83.0b /-c 59.5b/- 84.6b /- 83.0b/- 77.8b /-
Piperacillin-tazobactam 78.3/78.3 52.3/52.3 83.5/83.5 81.5/81.5 73.5/73.5
Amikacin 93.7/89.4 66.5/61.0 94.7/92.3 87.9/84.1 86.8/82.6
Cefepime 85.4/85.4 60.5/60.5 88.2/88.2 83.0/83.0 79.8/79.8
Ceftazidime 82.0/82.0 57.4/57.4 84.5/84.5 83.0/83.0 76.8/76.8
Ciprofloxacin 78.5/75.5 52.7/47.6 85.7/82.7 78.1/75.7 73.7/70.2
Colistin 99.9/99.9 99.3/99.3 99.7/99.7 99.8/99.8 99.7/99.7
Gentamicin 84.8/84.8 56.2/56.2 91.4/91.4 81.2/81.2 78.8/78.8
Imipenem 76.2/80.1 43.5/48.5 80.1/82.4 72.8/75.5 68.8/72.6
Levofloxacin 76.8/69.3 49.3/41.3 84.0/76.8 76.1/67.9 71.5/63.9
Meropenem 78.9/78.9 46.1/46.1 82.6/82.6 74.8/74.8 71.4/71.4
Tobramycin 88.5/88.5 61.7/61.7 94.0/94.0 84.1/84.1 82.7/82.7

Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM, Latin America.
a
Criteria as published by CLSI (2018b) and EUCAST (2018).
b
Sulperazone Package Insert (2009) (Sulperazone1 , 2009).
c
-, no breakpoint has been established.

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

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

Antimicrobial agent % susceptible (CLSI/EUCAST)a

W-EUR (348) E-EUR (595) APAC (210) LATAM (157) All (1310)
Cefoperazone-sulbactamb 63.5b/-c 43.0b/- 48.1b/- 75.8b /- 53.2b/-
Piperacillin-tazobactam 35.9/- 7.2/- 19.0/- 17.2/- 17.9/-
Ampicillin-sulbactam 37.6/- 16.5/- 22.9/- 23.1/- 23.9/-
Amikacin 46.6/45.1 16.8/14.5 33.8/31.9 36.3/27.4 29.8/26.9
Cefepime 37.1/- 9.9/- 17.1/- 20.6/- 19.6/-
Ceftazidime 36.2/- 8.7/- 22.4/- 22.3/- 19.8/-
Ciprofloxacin 37.5/37.5 7.6/7.6 21.9/21.9 19.1/19.1 19.2/19.2
Colistin 82.1/82.1 90.7/90.7 91.9/91.9 96.2/96.2 89.3/89.3
Gentamicin 43.1/43.1 19.0/19.0 31.0/31.0 32.5/32.5 28.9/28.9
Imipenem 40.2/40.2 19.8/19.8 25.2/25.2 22.3/22.3 26.4/26.4
Levofloxacin 38.5/37.4 9.1/7.6 24.8/22.4 20.4/19.7 20.8/19.3
Meropenem 40.2/40.2 17.3/17.3 24.3/24.3 21.7/21.7 25.0/25.0
Tigecyclined -/- -/- -/- -/- -/-
Tobramycin 44.8/44.8 40.3/40.3 35.2/35.2 50.6/50.6 41.9/41.9

Abbreviations: W-EUR, Western Europe; E-EUR, Eastern Europe and Mediterranean region, APAC, Asia-Pacific region; LATAM, Latin America.
a
Criteria as published by CLSI (2018b) and EUCAST (2018).
b
Sulperazone Package Insert (Sulperazone1 , 2009).
c
-, no breakpoint has been established.
d
US FDA breakpoints (Tygacil, 2018).

geographic region (Sader et al., 2019). Results from the European with lower resistance rates being reported by countries in the
Antimicrobial Resistance Surveillance Network (EARS-NET) pro- north and higher resistance rates being reported in the south and
gram have shown a north-to-south and west-to-east gradient of east of Europe (ECDC, 2017). Data from the Central Asian and
resistance rates for many organism–antimicrobial combinations Eastern European Surveillance of Antimicrobial Resistance
36 H.S. Sader et al. / International Journal of Infectious Diseases 91 (2020) 32–37
Figure 3. Antimicrobial activity of cefoperazone-sulbactam against Acinetobacter spp. isolates stratified by geographic region.
(CAESAR) program coordinated by the World Health Organization
(WHO) has shown higher resistance rates in eastern Europe and
central Asia compared to western Europe (WHO, 2017). Moreover,
antimicrobial resistance surveillance data from the Asia-Pacific
region and Latin America are scarce and usually restricted to
a specific country and/or organism (Bazzo et al., 2018; Rani et al.,
2017).
Our investigation results align with the data reported by EARS-
NET and CAESAR programs and provide 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 substantially
lower in E-EUR compared to the other geographic regions
surveyed, and other surveillance 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; Wojkowska-Mach et al.,
2018). A total of 2543 Enterobacterales isolates from E-EUR were
evaluated and the isolate 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 aminoglyco-
sides 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 Sulperazone1 and Cefobid1 package inserts (susceptible at
16 mg/L and resistant at 64 mg/L; CEFOBID1 , 2006;
Sulperazone1 , 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 ceftriax-
one (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 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 cover-
age 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).
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 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
(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 51.8%, respectively). Susceptibility rates were also low among
P. aeruginosa isolates, 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 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 ceftolozane-tazobactam, are not available in
many Latin American countries, leaving very few options for
treatment of 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 Taiwan and Thailand (data not shown).
Based on the package insert breakpoints (CEFOBID1 , 2006;
Sulperazone1 , 2009), cefoperazone-sulbactam coverage against
 H.S. Sader et al. / International Journal of Infectious Diseases 91 (2020) 32–37
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, cefoperazone-
sulbactam 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 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 cefoper-
azone-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, cefoperazone-sulbactam continues to have a
role for treating infections caused by Gram-negative organisms
and remains among the most active compounds in vitro against
Enterobacterales, P. aeruginosa, and Acinetobacter spp. at published
breakpoints.
Author disclosure statement
MI 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
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 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., Gateway Pharmaceutical
LLC, GenePOC Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc,
Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-
La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum
Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics,
Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx
Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc,
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., 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 Colo-
rado, University of Southern California-San Diego, University of
North Texas Health Science Center, VenatoRx Pharmaceuticals,
Inc., Vyome Therapeutics Inc., 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.
Acknowledgements
This study at JMI Laboratories was supported by Pfizer Inc. (New
York, NY), and JMI Laboratories received compensation for services
37
related to preparing the manuscript. The authors would like to
thank Lori Flanigan, Michael Janechek, Judy Oberholser, and Gauri
Deshpande for valuable editorial assistance.
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