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ORIGINAL RESEARCH

Clinical Efficacy of Cefoperazone-Sulbactam

versus Piperacillin-Tazobactam in the Treatment of
Hospital-Acquired Pneumonia and
Ventilator-Associated Pneumonia

Chia-Hung Chen 1 Objective: The aim of this study was to compare the usefulness of cefoperazone-sulbactam
Chih-Yen Tu 1 and that of piperacillin-tazobactam in the treatment of hospital-acquired pneumonia (HAP)
Wei-Chih Chen 2 and ventilator-associated pneumonia (VAP).
Li-Kuo Kuo 3 Methods: This retrospective study included the adult patients receiving cefoperazone-
sulbactam or piperacillin-tazobactam against HAP/VAP in nine hospitals in Taiwan from
Yao-Tung Wang 4
March 1, 2018 to May 30, 2019. Primary outcome was clinical cure rate.
Pin-Kuei Fu 5
Results: A total of 410 patients were enrolled. Among them, 209 patients received cefoperazone-
Shih-Chi Ku 6
sulbactam and 201 patients received piperacillin-tazobactam. Overall, cefoperazone-sulbactam
Wen-Feng Fang 7 group had similar distribution of age, sex, or SOFA scores as piperacillin-tazobactam group.
Chin-Ming Chen 8 However, cefoperazone-sulbactam had higher comorbidity score and disease severity than piper­
Chih-Cheng Lai 9 acillin-tazobactam group (Charlson score: 6.5 ± 2.9 vs 5.7 ± 2.7, p < 0.001; APACHE II score: 21.4
1
Division of Pulmonary and Critical Care ± 6.2 vs 19.3 ± 6.0, p = 0.002). Regarding clinical outcomes, no significant difference in clinical
Medicine, Department of Internal cure and failure rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam
Medicine, China Medical University
Hospital, Taichung, Taiwan; 2Department group (clinical cure rate: 80.9% vs 80.1% and clinical failure rate: 17.2% vs 18.4%, p = 0.943).
of Medicine, Taipei Veterans General Moreover, no significant difference in clinical effectiveness and ineffectiveness rates was observed
Hospital, Taipei, Taiwan; 3Division of between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical effective rate: 80.9%
Pulmonary and Critical Care Medicine,
Department of Internal Medicine, Mackay vs 80.6% and clinical ineffective rate: 17.7% vs 18.9%, p = 0.711). The all-cause mortality rates of
Memorial Hospital, Taipei, Taiwan; the cefoperazone-sulbactam and piperacillin-tazobactam groups were similar (23.9% vs 20.9%, p =
4
Division of Pulmonary Medicine,
0.48). After adjustment of Charlson score and APACHE II score, the similarities in these clinical
Department of Internal Medicine, Chung
Shan Medical University Hospital, outcomes did not change in overall patients and patients with HAP or VAP.
Taichung, Taiwan; 5Department of Critical Conclusion: For treating adult patients with nosocomial pneumonia, cefoperazone-
Care Medicine, Taichung Veterans
General Hospital, Taichung, Taiwan;
sulbactam was as effective as piperacillin-tazobactam.
6
Division of Chest Medicine, Department Keywords: cefoperazone-sulbactam, hospital-acquired pneumonia, piperacillin-tazobactam,
of Internal Medicine, National Taiwan ventilator-associated pneumonia
University Hospital, Taipei, Taiwan;
7
Division of Pulmonary and Critical Care
Medicine, Department of Internal
Medicine, Kaohsiung Chang Gung
Memorial Hospital, Kaohsiung, Taiwan;
8
Department of Intensive Care Medicine,
Introduction
Chi Mei Medical Center, Tainan, Taiwan; Hospital-acquired pneumonia (HAP) is the most common type of hospital-acquired
9
Department of Internal Medicine,
Kaohsiung Veterans General Hospital,
infections,1,2 and ventilator-associated pneumonia (VAP) is also a common type of
Tainan Branch, Tainan, Taiwan infection in intensive care units (ICUs).3 Importantly, both HAP and VAP are asso­
ciated with high morbidity, mortality, and health-care expenditure.2–4 Although admin­
istration of appropriate antibiotics remains the most important treatment for patients
Correspondence: Chih-Cheng Lai
Email [email protected] with HAP/VAP,2,3 the emergence of antibiotic resistance among causative pathogens—

Infection and Drug Resistance 2021:14 2251–2258 2251

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multidrug resistant organisms (MDROs)—has largely lim­ patients with VAP, pneumonia developed after receiving
ited therapeutic options. Gram-negative bacilli (GNB), such mechanical ventilation for more than 48 hours.3 In this
as Pseudomonas aeruginosa and Enterobacteriaceae, play study, primary dose of cefoperazone-sulbactam (1 gram/1
an important role in HAP/VAP,5–7 and many kinds of anti­ gram) was 4 g every 12 hours and piperacillin-tazobactam
biotic-resistance mechanism have been detected among these (2 gm/250 mg) was 4.5 g every 8 hours before dose adjust­
pathogens.8,9 Therefore, a combination of ß-lactam and ß- ment according to renal function. Data pertaining to the
lactamase inhibitor as a broad-spectrum antibiotic was demographic characteristics of the patients, their underlying
recommended as one of therapeutic options in the treatment disease/conditions, disease severity, microbiological infor­
of HAP/VAP. mation, antibiotic treatment, and clinical outcomes were
Cefoperazone-sulbactam is one of combinations of ß- retrospectively collected after obtaining approval from local
lactam and ß-lactamase inhibitors.10 Many studies have ethics committees or institutional review boards. Informed
demonstrated its potent in vitro activity against commonly consent was not required by the approving ethics committees
encountered respiratory pathogens and also MDROs, includ­ because all data were collected on a routine basis, and the
ing ESBL-producing Escherichia coli and Klebsiella analysis was conducted retrospectively. All methods, includ­
pneumoniae.10–15 However, very few clinical studies have ing patient data confidentiality, were performed in accor­
assessed the effectiveness of cefoperazone-sulbactam for the dance with the Declaration of Helsinki.
treatment of HAP/VAP.16,17 We conducted this study to
compare the clinical efficacy of cefoperazone-sulbactam Outcome
with that of piperacillin-tazobactam, which is another com­ The primary outcome measured was clinical cure rate, which
monly used ß-lactam and ß-lactamase inhibitor antibiotic in was defined as the proportion of patients in which the clinical
the treatment of HAP/VAP. symptoms or signs resolved or improved 7 days after the end of
treatment, and in which no additional antibiotics were required.
In contrast, clinical failure was defined as one of the following
Methods scenarios: clinical symptoms or signs deteriorated or persisted
Study Design and Data Collection during treatment and required additional antibiotics for man­
This study was based on retrospective analyses, using clinical agement; death due to pneumonia after 3 days of antibiotic
information extracted from BATTLE study, which investi­ treatment; or the development of complications, such as
gated the efficacy and safety of Brosym® (TTY Biopharm empyema or a lung abscess. An indeterminate outcome was
Company, Taiwan) in the treatment of adult patients with defined as one of the following: the patient was transferred to
severe community-acquired pneumonia (SCAP) and nosoco­ another hospital or refused further treatment; death due to
mial pneumonia. The patients enrolled in BATTLE study pneumonia within 2 days of antibiotic treatment; death due
were those receiving empirical cefoperazone-sulbactam or to a cause other than pneumonia during treatment; or incom­
piperacillin-tazobactam for treating SCAP, HAP and VAP, in plete treatment due to allergy, severe adverse events, or other
which study subjects were identified from the electronic personal reasons. The secondary outcomes measured were the
database in each study sites. BATTLE study was conducted clinical effective rate, the risk of adverse events, and in-
in eight medical centers and one regional hospital in Taiwan hospital mortality. Clinical effectiveness was defined as the
between March 2018 and May 2019. All three hospitals were improvement of clinical symptoms and signs; radiographic
located in north, central, and south Taiwan. The present study findings; or inflammation markers, such as white blood cell
evaluated the clinical efficacy of cefoperazone-sulbactam or counts, procalcitonin, or c-reactive protein levels.
piperacillin-tazobactam for the treatment of HAP or VAP. Ineffectiveness was defined as when any one of the three
The diagnosis of pneumonia was made based on the newly criteria listed above was not achieved. Indeterminate effective­
developed or progressive radiographic lung infiltration/con­ ness was defined as when the above three criteria could not be
solidation in patients with 2 or more of the following: cough, assessed.
fever, hypothermia, purulent sputum or respiratory secretion,
and characteristic physical signs.3 In each study site, respira­ Statistical Analysis
tory specimens and blood were routinely sampling for culture Continuous variables are reported as the mean and standard
before prescribing antibiotics. In patients with HAP, pneu­ deviation (SD). Categorical variables are presented as fre­
monia developed ≥ 48 hours after hospitalization; whereas in quency counts with percentages. The differences in baseline

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characteristics and clinical variables between the cefopera­ tazobactam, respectively. No significant difference was
zone-sulbactam and piperacillin-tazobactam groups were eval­ observed in terms of microbiologic distribution and the
uated using the Fisher’s exact test (for continuous variables) incidence of concomitant bacteremia (all p > 0.05).
and the Wilcoxon rank sum test (for categorical variables).
Significance was set at p <0.05 (two-tailed). Differences in the
Outcomes
crude relative risk (RR) and adjusted RR (adjusted for propen­
Cefoperazone-sulbactam group had their clinical cure rate of
sity score) of the outcomes between the cefoperazone-
80.9% and the clinical failure rate was 17.2%. Overall, these
sulbactam and piperacillin-tazobactam groups were calculated
clinical outcomes of cefoperazone-sulbactam group were
using Statistical Analysis System® (SAS) for Windows
similar to those of piperacillin-tazobactam group (p = 0.943).
(Version 9.4 or higher, SAS Institute, Cary, North
Regarding secondary outcomes, the cefoperazone-sulbactam
Carolina, USA).
group had a clinical effective rate of 80.9% and an ineffective
rate of 17.7%, which were similar to piperacillin-tazobactam
Results group (p = 0.711). The all-cause mortality of the cefoperazone-
Demographic Data sulbactam group and piperacillin-tazobactam was similar, too
During the study period, 410 patients (n = 345 in HAP, n = (23.9% vs 20.9%, p = 0.480). A similar trend was observed for
65 in VAP) were enrolled. Of these, 209 patients received pneumonia-related mortality (cefoperazone-sulbactam vs
cefoperazone-sulbactam and 201 patients received pipera­ piperacillin-tazobactam, 12.9% vs 9.0%, p = 0.304; Table 3).
cillin-tazobactam. The mean age of patients receiving Subgroup analysis based on the different study sites revealed
cefoperazone-sulbactam was 75.1 ± 14.8 years and 141 no significant differences in the primary outcome (the clinical
(67.5%) were male. The median treatment duration was cure rate) or secondary outcomes (the clinical effective rate,
9.0 days. Their Charlson, APACHE II, and SOFA scores in-hospital mortality, and pneumonia-related mortality)
were 6.5 (± 2.9), 21.4 (± 6.2), and 5.3 (± 2.9), respectively. between patients who received cefoperazone-sulbactam and
Patients who received cefoperazone-sulbactam had higher piperacillin-tazobactam in each hospital (data not shown, all
occurrences of myocardial infarction, stroke and dementia p > 0.05). However, one site only enrolled patients in the
than patients receiving piperacillin-tazobactam (all p < cefoperazone-sulbactam group. In addition, the clinical out­
0.05). In addition, the Charlson and APACHE II score come and mortality between patients receiving cefoperazone-
were significantly higher in cefoperazone-sulbactam sulbactam and piperacillin for HAP and VAP was similar
group than piperacillin-tazobactam group. In contrast, (Figures 1 and 2). Among HAP patients, patients receiving
there were no significant differences in age, sex, or cefoperazone-sulbactam had less requirement of mechanical
SOFA scores between patients receiving cefoperazone- ventilation (MV) and further ICU admission than those receiv­
sulbactam and piperacillin-tazobactam (Table 1). ing piperacillin-tazobactam (MV use: 18.0% versus 34.7%,
p = 0.0007; ICU admission: 15.1% versus 36.4%, p < 0.0001).
Microbiologic Distribution Moreover, the clinical cure rate between cefoperazone-
For all patients, blood and respiratory specimens were sulbactam and piperacillin-tazobactam group did not differ
sampled for culture to identify pathogens; however, only for causative pathogens, including E. coli (90.0% [9/10] vs
64.1% (n = 134) of cefoperazone-sulbactam group and 71.4% [5/7]), K. pneumoniae (81.3% [26/32] vs 76.9% [10/
39.3% (n = 79) of piperacillin-tazobactam group had iden­ 13]), P. aeruginosa (76.3% [29/38] vs 78.9% [15/19]) and
tified pathogens. In the cefoperazone-sulbactam group, Acinetobacter spp. (77.8% [28/36] vs 61.1% [11/18]) (all p >
P. aeruginosa (18.2%, n = 38) and Acinetobacter spp. 0.05). Regarding the adverse events, only one patient in cefo­
(17.6%, n = 36) were the most common bacteria, followed perazone-sulbactam group had skin rash and two patients in
by K. pneumoniae (17.2%, n = 32). Similar findings were piperacillin-tazobactam had diarrhea group. Among cefoper­
observed in patients receiving piperacillin-tazobactam; the azone-sulbactam group, only 30 patients had received interna­
most common bacteria were P. aeruginosa (9.5%), fol­ tional normalized ratio (INR) test during both pre- and post-
lowed by Acinetobacter spp. (9.0%) and K. pneumoniae treatment after one week. No significant difference between
(6.5%) (Table 2). In addition, concomitant bacteremia was the pre- and post-treatment INR was found in this population
found in 5.2% (n = 11) and 10.9% (n = 22) of patients (1.10 ± 0.15 versus 1.19 ± 0.21, p = 0.06) and no significant
receiving cefoperazone-sulbactam and piperacillin- bleeding was reported in both groups.

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Table 1 Demographic Characteristics of the Patients Receiving Cefoperazone-Sulbactam and Piperacillin-Tazobactam

Variable Cefoperazone-Sulbactam, n = 209 Piperacillin-Tazobactam, n = 201 p

Age 75.1±14.8 74.6±16.6 0.794

Sex 0.671
Male 141 (67.5) 140 (69.7)
Female 68 (32.5) 61 (30.3)

Type of infection 0.344

Hospital-acquired pneumonia 172 (82.3) 173 (86.1)
Ventilator-associated pneumonia 37 (17.7) 28 (13.9)

Underlying disease
Dementia 91 (43.5) 38 (18.9) <0.001
Diabetes mellitus 65 (31.1) 80 (39.8)) 0.079
Chronic pulmonary disease 56 (26.8) 48 (23.9) 0.570
Congestive heart failure 45 (21.5) 32 (15.9) 0.165
Stroke 40 (19.1) 14 (7.0) <0.001
Peptic ulcer disease 33 (15.8) 23 (11.4) 0.250
Myocardial infarction 31 (14.8) 13 (6.5) 0.007
Chronic kidney disease 27 (12.9) 31 (15.4) <0.001
Solid cancer 18 (8.6) 17 (8.5) >0.999
Chronic liver disease 18 (8.6) 11 (5.5) 0.250
Peripheral vascular disease 11 (5.3) 4 (2.0) 0.113
Charlson score 6.5±2.9 5.7±2.7 <0.001
APACHE II score 21.4±6.2 (n = 171) 19.3±6.0 (n = 109) 0.002
SOFA score 5.3±2.9 (n = 171) 5.8±3.5 (n = 112) 0.257

Table 2 Microbiological Distribution of Major Pathogens

Pathogens No (%) of Pathogen

All Hospital-Acquired Pneumonia Ventilator-Associated

Pneumonia

Cefoperazone- Piperacillin- Cefoperazone- Piperacillin- Cefoperazone- Piperacillin-

Sulbactam, Tazobactam, Sulbactam, Tazobactam, Sulbactam, Tazobactam,
n = 209 n = 201 n = 172 n = 173 n = 37 n = 28

Pseudomonas 38 (18.2) 19 (9.5) 34 (19.8) 14 (8.1) 4 (10.8) 5 (17.9)

aeruginosa

Acinetobacter spp. 36 (17.2) 18 (9.0) 22 (12.8) 17 (9.8) 14 (37.8) 1 (3.6)

Klebsiella pneumoniae 32 (15.3) 13 (6.5) 29 (16.9) 10 (5.8) 3 (3.0) 3 (10.7)

Escherichia coli 10 (4.8) 7 (3.5) 10 (5.8) 7 (4.0) 0 (0) 0 (0)

Streptococcus spp. 7 (3.3) 12 (6.0) 5 (2.9) 12 (6.9) 2 (5.4) 0 (0)

Outcome Analysis rate of cefoperazone-sulbactam remained comparable to

Because different comorbidities and disease severity were that of piperacillin-tazobactam (adjusted RR [aRR], 0.93;
found between the cefoperazone-sulbactam and piperacil­ 95% confidence interval [95% CI], 0.82–1.05) in the over­
lin-tazobactam groups, we used propensity score method all population (Table 3). No significant difference was
to adjust for these two confounding factors. After adjust­ observed in terms of the clinical cure rate of cefoperazone-
ing the APACHE II and Charlson scores, the clinical cure sulbactam and piperacillin-tazobactam in the treatment

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Table 3 Clinical Outcomes Between Cefoperazone-Sulbactam and Piperacillin-Tazobactam Groups

Variable Cefoperazone-Sulbactam, n = 209 Piperacillin-Tazobactam, n = 201 p

Primary outcome 0.943

Clinical cure 169 (80.9) 161 (80.1)
Failure 36 (17.2) 37 (18.4)
Indeterminate 4 (1.9) 3 (1.5)

Secondary outcome 0.711

Effective 169 (80.9) 162 (80.6)
Ineffective 37 (17.7) 38 (18.9)
Indeterminate 3 (1.4) 1 (0.5)

In-hospital mortality
All-cause mortality 50 (23.9) 42 (20.9) 0.480
Pneumonia related 27 (12.9) 18 (9.0) 0.304

patients with HAP (aRR, 0.89; 95% CI, 0.77–1.03), and Discussion
VAP (aRR, 1.33; 95% CI, 0.33–1.92) (Table 4). Regarding This retrospective study determined the clinical efficacy of
secondary outcomes, cefoperazone-sulbactam was com­ cefoperazone-sulbactam for treating patients with HAP/VAP;
parable to piperacillin in terms of clinical efficacy rate, in- it was comparable to piperacillin-tazobactam in terms of both
hospital mortality, and pneumonia-related mortality, which primary and secondary outcomes. First, the clinical cure and
remained unchanged in the overall population, HAP, and failure rate of cefoperazone-sulbactam were similar to those of
VAP groups (Table 3). piperacillin-tazobactam. Moreover, there was no statistically

Figure 1 Clinical outcome of patients receiving cefoperazone-sulbactam and piperacillin-tazobactam for hospital-acquired pneumonia (HAP) (A) and ventilator-associated
pneumonia (VAP) (B).

Figure 2 All-cause mortality (A) and pneumonia-related mortality (B) of patients receiving cefoperazone-sulbactam and piperacillin-tazobactam for hospital-acquired
pneumonia (HAP) and ventilator associated pneumonia (VAP).

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Table 4 Outcome Analysis

All Hospital-Acquired Pneumonia Ventilator-Associated Pneumonia

Variable Crude RR Adjust RR* Crude RR Adjust RR* Crude RR Adjust RR*
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

Clinical cure 1.01 (0.92, 1.11) 0.93 (0.82, 1.05) 1.00 (0.90, 1.10) 0.89 (0.77, 1.03) 1.10 (0.82, 1.46) 1.33 (0.93, 1.92)

Clinical effectiveness 1.00 (0.91, 1.10) 0.90 (0.80, 1.03) 0.98 (0.89, 1.09) 0.84 (0.73, 0.98) 1.14 0.86, 1.50) 1.33 (0.93, 1.92)

In-hospital mortality
All-cause mortality 1.14 (0.80, 1.64) 1.10 (0.65, 1.84) 1.15 (0.77, 1.70) 1.31 (0.75, 2.30) 1.14 (0.46, 2.82) 0.60 (0.17, 2.14)
Pneumonia related 1.26 (0.82, 1.94) 1.01 (0.51, 2.00) 1.19 (0.77, 1.84) 0.76 (0.40, 1.47) 2.67 (0.39, 18.42) 1.67 (0.16, 17.89)
Note: *Adjusted APACHE II and Charlson score using propensity score matching.

significant difference between the clinical effective and inef­ the treatment of HAP/VAP, to ensure they act against these
fective rates of cefoperazone-sulbactam and piperacillin- prevalent pathogens. An in vitro study22 showed that the
tazobactam. Second, the all-cause and pneumonia-related susceptibility rates of E. coli, K. pneumoniae, Citrobacter
mortality of patients receiving cefoperazone-sulbactam was freundii, Serratia marcescens, and Proteus mirabilis to
similar to that of patients receiving piperacillin-tazobactam. cefoperazone-sulbactam were all ≥90%, and only ≤15%
Third, cefoperazone-sulbactam was found to be comparable to of P. aeruginosa, Acinetobacter spp., and Enterobacter
piperacillin-tazobactam in all analyses, including the subgroup cloacae strains were resistant to cefoperazone-sulbactam.
analysis based on the study sites, causative pathogens and the Even for MDROs, the susceptibility rates of ESBL-
HAP and VAP groups. Finally, after adjustment for Charlson E. coli, ESBL- K. pneumoniae, carbapenem-resistant
and APACHE II scores, cefoperazone-sulbactam exhibited E. coli, and carbapenem-resistant A. baumannii to cefoper­
similar clinical outcomes compared with piperacillin- azone-sulbactam were 97.0%, 75.8%, 67.6% and 68%,
tazobactam in the HAP/VAP, HAP, and VAP groups. respectively.23 Only carbapenem-resistant P. aeruginosa
Furthermore, the mortality rate of HAP/VAP, when treated displayed high resistance against cefoperazone-
with cefoperazone-sulbactam, was 23.9%, which was consis­ sulbactam.11,23 Therefore, cefoperazone-sulbactam could
tent with the findings of previous studies.7,18,19 Similar to the be an appropriate antibiotic for patients the treatment of
findings of the ASPECT-NP trial,7 the rates of 28-day all- patients with HAP/VAP caused by most GNBs.
cause mortality in patients with nosocomial pneumonia were Safety, especially in the context of coagulopathy, is
24.0% (87/362) and 25.3% (92/364) among the ceftolozane- a serious concern for clinicians prescribing cefoperazone-
tazobactam and meropenem groups, respectively. A similar sulbactam.24–26 No significant difference in pre- and
finding was shown in another retrospective analysis of patients post-treatment INR was observed in 30 patients receiving
with HAP/VAP, in which the 30-day mortality was 18.1%– cefoperazone, but most of the patients did not have the assess­
22.8%.18 Therefore, our results suggest that cefoperazone- ment of coagulation disorder in this study. According to retro­
sulbactam, like piperacillin-tazobactam, could be an effective spective review of medical chart, no patients receiving
therapeutic option for the management of patients with cefoperazone-sulbactam had significant bleeding. In addition,
HAP/VAP. only one patient reported skin rash during the use of cefoper­
In this study, P. aeruginosa, Acinetobacter spp., and azone-sulbactam, but no serious adverse events related to
K. pneumoniae were found to be the most common patho­ cefoperazone-sulbactam were reported in this retrospective
gens causing HAP/VAP, which was in line with previous study. Therefore, based on the present findings, cefoperazone-
studies.7,19–21 In the REPROVE trial,6 P. aeruginosa and sulbactam was well tolerated.
K. pneumoniae were the most common GNBs causing This study had several limitations. First, unlike
nosocomial pneumonia, followed by Enterobacter cloacae a randomized controlled study, this retrospective study
and E. coli, whereas, in the ASPECT-NP trial,7 could not ensure that baseline characteristics and disease
Enterobacteriaceae and P. aeruginosa were the predomi­ severity were equal between the cefoperazone-sulbactam
nant gram-negative pathogens. Together, these findings and piperacillin-tazobactam groups. Therefore, we used pro­
suggest that broad-spectrum antibiotics should be used in pensity score method to adjust the baseline characteristics

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Dovepress Chen et al

and disease severity and showed that the clinical efficacy of Funding
cefoperazone-sulbactam remained comparable to piperacil­ No funding was received.
lin-tazobactam. Second, because the in vitro activity of cefo­
perazone-sulbactam was not assessed in most study sites,
Disclosure
only 18 clinical isolates had results of cefoperazone-
The authors declare that they have no competing interests.
sulbactam susceptibility tests, and two of them, including
one P. aeruginosa and one K. pneumoniae isolates were not
susceptible to cefoperazone-sulbactam. Therefore, we were
References
unable to evaluate the cefoperazone-sulbactam resistance 1. Magill SS, Edwards JR, Bamberg W, et al. Multistate
point-prevalence survey of health care-associated infections. N Engl
rate of causative pathogens and their impact on the clinical J Med. 2014;370:1198–11208. doi:10.1056/NEJMoa1306801
outcome. In addition, susceptibility of GNB could vary 2. Kalil AC, Metersky ML, Klompas M, et al. Management of adults
with hospital-acquired and ventilator-associated pneumonia: 2016
according to different sites, so the results of this comparison Clinical Practice Guidelines by the Infectious Diseases Society of
should be different and empirical treatment of late HAP/VAP America and the American Thoracic Society. Clin Infect Dis.
should be made based on the local epidemiology. Third, 2016;63:e61–e111.
3. Chou CC, Shen CF, Chen SJ, et al. Infectious Diseases Society of
although the risk of adverse events was evaluated in this Taiwan; Taiwan Society of Pulmonary and Critical Care Medicine,
study, some mild adverse events which may not have been Medical Foundation in Memory of Dr. Deh-Lin Cheng;; Foundation
of Professor Wei-Chuan Hsieh for Infectious Diseases Research and
recorded in the chart could have been missed. Thus, the risk Education;; CY Lee’s Research Foundation for Pediatric Infectious
of adverse events might have been underestimated. Forth, Diseases and Vaccines,; 4th Guidelines Recommendations for
this study did not further classify the type of VAP – early or Evidence-based Antimicrobial agents use in Taiwan (GREAT) work­
ing group. Recommendations and guidelines for the treatment of
late VAP and did not measure the microbiological eradication pneumonia in Taiwan. J Microbiol Immunol Infect.
rate. Further large-scale study is warranted to investigate 2019;52:172–99. doi:10.1016/j.jmii.2018.11.004
4. Kollef MH, Hamilton CW, Ernst FR. Economic impact of
these issues. Finally, most of subgroup analyses were based ventilator-associated pneumonia in a large matched cohort. Infect
on small number, which might contribute to non-difference Control Hosp Epidemiol. 2012;33:250–256. doi:10.1086/664049
on the treatment outcome. 5. Jones RN. Microbial etiologies of hospital-acquired bacterial pneu­
monia and ventilator-associated bacterial pneumonia. Clin Infect Dis.
2010;51:S81–7. doi:10.1086/653053
Conclusions 6. Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus
meropenem in nosocomial pneumonia, including
In the management of adult patients with HAP/VAP, cefoper­ ventilator-associated pneumonia (REPROVE): a randomised,
azone-sulbactam is as effective as piperacillin-tazobactam. double-blind, Phase 3 non-inferiority trial. Lancet Infect Dis.
2018;18:285–295. doi:10.1016/S1473-3099(17)30747-8
7. Kollef MH, Nováček M, Kivistik Ü, et al. Ceftolozane-tazobactam
Ethical Approval versus meropenem for treatment of nosocomial pneumonia
This study was approved by the ethics committee of Taipei (ASPECT-NP): a randomised, controlled, double-blind, phase 3,
non-inferiority trial. Lancet Infect Dis. 2019;19:1299–1311.
Veterans General Hospital (2019-08-006AC), Mackay doi:10.1016/S1473-3099(19)30403-7
Memorial Hospital (19MMHIS282e), Chung Shan 8. MacVane SH. Antimicrobial resistance in the intensive care unit:
Medical University Hospital (CS18126), Taichung a focus on gram-negative bacterial infections. J Intensive Care
Med. 2017;32:25–37. doi:10.1177/0885066615619895
Veterans General Hospital (CE18223A#2), National 9. Kaye KS, Pogue JM. Infections caused by resistant gram-negative
Taiwan University Hospital (201805123RINB), bacteria: epidemiology and management. Pharmacotherapy.
2015;35:949–962. doi:10.1002/phar.1636
Kaohsiung Chang Gung Memorial Hospital 10. Lai CC, Chen CC, Lu YC, Lin TP, Chuang YC, Tang HJ. Appropriate
(201900932B0C501), Chi Mei Medical Center (10806- composites of cefoperazone-sulbactam against multidrug-resistant
008) and Chi Mei Medical Center, Liouying (10808-L01). organisms. Infect Drug Resist. 2018;11:1441–1445. doi:10.2147/
IDR.S175257
11. Lai CC, Chen CC, Lu YC, Chuang YC, Tang HJ. In vitro activity of
Acknowledgments cefoperazone and cefoperazone-sulbactam against carbapenem-resistant
Acinetobacter baumannii and Pseudomonas aeruginosa. Infect Drug
The abstract of this paper was presented at 2020 Annual Resist. 2019;12:25–29. doi:10.2147/IDR.S181201
Congress of Taiwan Society of Pulmonary and Critical Care 12. Sheu MJ, Chen CC, Lu YC, et al. In vitro antimicrobial activity of
various cefoperazone/sulbactam products. Antibiotics (Basel). 2020;9
Medicine and Taiwan Society of Thoracic Surgeons,
(2):77. doi:10.3390/antibiotics9020077
Taiwan Association of Thoracic & Cardiovascular Surgery 13. Patankar M, Sukumaran S, Chhibba A, Nayak U, Sequeira L.
Joint Conference – Cefoperazone-sulbactam versus piper­ Comparative in-vitro activity of cefoperazone-tazobactam and
cefoperazone-sulbactam combinations against ESBL pathogens in
acillin-tazobactam in the treatment of nosocomial pneumo­ respiratory and urinary infections. J Assoc Physicians India.
nia with interim findings. 2012;60:22–24.

Infection and Drug Resistance 2021:14 https://doi.org/10.2147/IDR.S313828

2257
DovePress
Chen et al Dovepress

14. Sader HS, Carvalhaes CG, Streit JM, Castanheira M, Flamm RK. 21. Ismail B, Shafei MN, Harun A, Ali S, Omar M, Deris ZZ. Predictors
Antimicrobial activity of cefoperazone-sulbactam tested against of polymyxin B treatment failure in Gram-negative
Gram-Negative organisms from Europe, Asia-Pacific, and Latin healthcare-associated infections among critically ill patients.
America. Int J Infect Dis. 2020;91:32–37. doi:10.1016/j. J Microbiol Immunol Infect. 2018;51:763–769. doi:10.1016/j.
ijid.2019.11.006 jmii.2017.03.007
15. Xia J, Zhang D, Xu Y, Gong M, Zhou Y, Fang X. A retrospective 22. Jean SS, Liao CH, Sheng WH, Lee WS, Hsueh PR. Comparison of
analysis of carbapenem-resistant Acinetobacter baumannii-mediated commonly used antimicrobial susceptibility testing methods for eval­
nosocomial pneumonia and the in vitro therapeutic benefit of uating susceptibilities of clinical isolates of Enterobacteriaceae and
cefoperazone/sulbactam. Int J Infect Dis. 2014;23:90–93. nonfermentative gram-negative bacilli to cefoperazone-sulbactam.
doi:10.1016/j.ijid.2014.01.017 J Microbiol Immunol Infect. 2017;50:454–463. doi:10.1016/j.
16. Liu JW, Chen YH, Lee WS, et al. Randomized noninferiority trial of jmii.2015.08.024
cefoperazone-sulbactam versus cefepime in the treatment of 23. Chang PC, Chen CC, Lu YC, et al. The impact of inoculum size on
hospital-acquired and healthcare-associated pneumonia. Antimicrob the activity of cefoperazone-sulbactam against multidrug resistant
Agents Chemother. 2019;63:e00023–19. doi:10.1128/AAC.00023-19 organisms. J Microbiol Immunol Infect. 2018;51:207–213.
17. Xin X, Jian L, Xia X, et al. A multicentre clinical study on the doi:10.1016/j.jmii.2017.08.026
injection of ceftriaxone/sulbactam compared with cefoperazone/sul­ 24. Cai Z, Yang W, He Y, et al. Cefoperazone/sulbactam-induced abdom­
bactam in the treatment of respiratory and urinary tract infections. inal wall hematoma and upper gastrointestinal bleeding: a case report
Ann Clin Microbiol Antimicrob. 2013;12:38. doi:10.1186/1476-0711- and review of the literature. Drug Saf Case Rep. 2016;3:2.
12-38 doi:10.1007/s40800-016-0025-9
18. Liu WD, Shih MC, Chuang YC, Wang JT, Sheng WH. Comparative 25. Hu HR. Fatal Vitamin K-dependent coagulopathy associated with
efficacy of doripenem versus meropenem for hospital-acquired and cefoperazone/sulbactam: a case report. Drug Saf Case Rep.
ventilator-associated pneumonia. J Microbiol Immunol Infect. 2019;6:6. doi:10.1007/s40800-019-0100-0
2019;52:788–795. doi:10.1016/j.jmii.2019.04.008 26. Wang W, Liu Y, Yu C, et al. Cefoperazone-sulbactam and risk of
19. Chao CM, Chen CC, Huang HL, Chuang YC, Lai CC, Tang HJ. coagulation disorders or bleeding: a retrospective cohort study.
Clinical experience of patients receiving doripenem-containing regi­ Expert Opin Drug Saf. 2020;19:339–347. doi:10.1080/
mens for the treatment of healthcare-associated infections. PLoS One. 14740338.2020.1713090
2016;11:e0167522. doi:10.1371/journal.pone.0167522
20. Chung DR, Song JH, Kim SH, et al. High prevalence of
multidrug-resistant nonfermenters in hospital-acquired pneumonia in
Asia. Am J Respir Crit Care Med. 2011;184:1409–1417. doi:10.1164/
rccm.201102-0349OC

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