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International Journal of Infectious Diseases 38 (2015) 108–114
Contents lists available at ScienceDirect
International Journal of Infectious Diseases
jou rnal homepage: www.elsevier.com/locate/ijid
Cefepime combined with amoxicillin/clavulanic acid: a new choice for
the KPC-producing K. pneumoniae infection
a a a b a a
Shujuan Ji , Fangfang Lv , Xiaoxing Du , Zeqing Wei , Ying Fu , Xinli Mu ,
a a,b,
Yan Jiang , Yunsong Yu *
a
Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China
b
Key Laboratory of Infectious Diseases of the Public Health Ministry, First Affiliated Hospital, School of Medicine, Zhejiang University, China
A R T I C L E I N F O S U M M A R Y
Article history: Objective: Clinical treatment for blaKPC-positive Klebsiella pneumoniae isolates is challenging because the
Received 13 April 2015
recommended antibiotic options are limited and are extraordinarily expensive. This study aimed to
Received in revised form 24 July 2015
explore a new therapy for infection caused by KPC-producing K. pneumoniae.
Accepted 26 July 2015
Methods: Patients with blaKPC-positive K. pneumoniae infection, were prospectively screened and were
Corresponding Editor: Eskild Petersen,
categorised into two groups: patients in the study group received a combination-based therapy of
Aarhus, Denmark
cefepime and amoxicillin/clavulanic acid and the control group received tigecycline-based therapy. The
pathogen clearance rate, 28-day mortality and cost of the antibiotic treatment were compared between
Keywords: the two groups. Moreover, the checkerboard microdilution method was performed to determine the
Cefepime
synergy between cefepime and amoxicillin/clavulanic acid in vitro.
Amoxicillin/clavulanic acid
Results: Twenty-six and 25 cases were enrolled in the study and control groups. The mortality and the
Klebsiella pneumoniae
overall pathogen clearance rate showed no significant differences (P=0.311 and P=0.447). Both the total
KPC
cost and the portion of the cost not covered by insurance were higher for the control group compared to
Prospective study
Tigecycline the study group (both P<0.001). Consistently, synergy (65.4%) and partial synergy (26.9%) were the main
effects.
Conclusions: In contrast to the currently recommended tigecycline-based therapy, cefepime and
amoxicillin/clavulanic acid combination was an effective and economical option to KPC-KP infection in
China.
ß 2015 The Authors. 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/).
from 43% to 53%, particularly among patients with bloodstream
1. Introduction
infections. Thus, the treatment for KPC-producing K. pneumoniae
(KPC-KP) infection has been a major challenge because the
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has been a
recommended antibiotic options are limited and extraordinarily
major global health concern, as increasing CRKP infections have
6
1 expensive. Therefore, many studies have made clinical attempts
been reported, especially in the past 20 years. Many carbapene-
8,9
to explore new treatment options for KPC-KP.
mases are associated with carbapenem resistance in K. pneumo-
Therapy based on tigecycline, colistin E or fosfomycin has
niae, such as K. pneumoniae-producing carbapenemase (KPC),
10,11
shown therapeutic benefits against KPC-KP. Although tigecy-
metal-b lactamases (IMP, VIM and NDM-1) and OXA-48 carba-
2–5 cline has demonstrated an excellent spectrum of activity in vitro
penemase. Of these, KPC, a plasmid-mediated serine-carbape-
against KPC-producing organisms, it is expensive and is often
nemase, is still the most common carbapenemase encountered in
12
associated with high mortality when applied as a monotherapy.
K. pneumoniae. Of note, KPC-producing CRKP pathogens spread in a
Many experts suggest that a combination treatment based on
clonal fashion, disseminating from the eastern United States to
6,7 tigecycline could be a recommended choice for KPC-KP isolate
Greece and from Zhejiang province to Taiwan, China.
induced infection. This treatment program has been widely used in
KPC-producing K. pneumoniae isolates are often associated with
other countries; however, it is not so widely applied in China
severe healthcare-associated infection with high mortality ranging
because it is expensive and not covered by medical insurance.
Besides, a treatment option based on colistin is unavailable in our
country because it is still not approved for sale in Mainland China.
* Corresponding author. Tel./Fax: +86-571-86006142.
E-mail address: [email protected] (Y. Yu). Therefore, it is high time to explore feasible antibiotic options to
http://dx.doi.org/10.1016/j.ijid.2015.07.024
1201-9712/ß 2015 The Authors. 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/).
S. Ji et al. / International Journal of Infectious Diseases 38 (2015) 108–114 109
fight this serious situation, especially given that our Zhejiang used as references to interpret the resistant tigecycline ( 8 mg/L)
13 15,16
province is an area that has been worst hit by KPC-KP. and colistin (>2 mg/L) results, respectively.
Our previous study has showed that b-lactamase inhibitors,
especially clavulanic acid, demonstrated affinity for the KPC-2 2.4. Data collection
13
enzyme and inhibitory activity toward KPC producers. Moreover,
a synergistic effect of cefepime and clavulanic acid against KPC-KP For all enrolled patients, the following data were collected: age,
in vitro was also illustrated. Thus, a prospective study was sex, prior ICU admission, comorbidities, risk factors, source of
designed to compare the clinical effects of cefepime in combina- bacteraemia, mixed infectious pathogens, hospital length of stay,
tion with amoxicillin/clavulanic with the currently recommended, duration of antibiotic therapy and Acute Physiologic and Chronic
tigecycline-based combination therapy for KPC-producing K. Health Evaluation (APACHE) II scores. The APACHE II scores were
pneumoniae. based on the data collected at admission that were to be involved
in our study during the first 24 hours.
2. Patients and methods
2.5. Statistical analysis
2.1. Definitions
Descriptive data were reported as the means SD, median
Healthcare-associated infection (HAI) was defined as an (interquartile range) or number and percentage. With respect to the
infection that occurred after exposure to hospitals or clinical differences in the 28-day mortality rates, pathogen clearance rates
facilities and that usually be evident within 48 hours or longer and cost of the antibiotic treatment between the two groups,
after admission. Definitive therapy was normally identified as categorical variables were compared using chi-square analysis.
continuous antibiotic treatment over 48 hours. Clinical efficacy of Continuous variables were compared using an independent Sample
the treatment was assessed at the sixth day of the definitive T test for normally distributed data, and the Mann-Whitney U test
therapy. The 28-day mortality rate was calculated from the first was used for non-normally distributed data. Statistical analysis was
day of the targeted definitive therapy when KPC-producing K. performed using SPSS 19.0 (Chicago, Ill, USA), and statistical
pneumoniae were identified. Pathogen clearance was defined as at significance was defined as P <0.05.
least three continuous negative cultures, or the inability to obtain
specimens within two weeks. 2.6. Combination effect of cefepime combined with amoxicillin/
clavulanic acid in vitro
2.2. Study design
The checkerboard microdilution method was used to determine
All patients with confirmed blaKPC-positive K. pneumoniae the in vitro activity of cefepime combined with amoxicillin/
17
infection, as shown by PCR amplification, from a tertiary hospital in clavulanic acid. The active components ratio of amoxicillin and
east China between March 2011 and December 2012 were clavulanic acid was 1:5 (amoxicillin vs clavulanic acid). The
prospectively screened to be involved in the study. The enrolled fractional inhibitory concentration (FIC) and FIC index (FICI) were
patients were randomly divided into two groups according to calculated for each combination, and interpretation of the FICI was
different definitive treatment options: the study group received as follows: 0.5, synergy; >0.5 to <1, partial synergy; 1, additive;
-1
normal doses of cefepime (1g q6h d ) in combination with >1 to <4, indifference; and 4, antagonism.
-1
amoxicillin/clavulanic acid (1.2g q6hd ), and the control group
received the currently recommended tigecycline-based treatment
-1
(loading dose, 100 mg, decreased to 50mg q12h d ). The specific 3. Results
infection types included pneumonia, intra-abdominal infection
bloodstream infection, and urinary tract infection. Fosfomycin was All CRE isolates collected between March 2011 and December
included in the treatment of some patients of the study group, and 2012 in our hospital were included in advance, and were submitted
the treatment was subdivided into two subgroups. While in the to sequencing of the blaKPC gene. Sixty-two patients were primarily
tigecycline group, six different combination programs were screened and randomly divided into the study and control groups
analysed, including tigecycline alone, tigecycline in combination after nucleotide sequencing. Fifty-one patients were enrolled in
with fosfomycin, tigecycline with amikacin and levofloxacin, the study. Of these patients, 26 received the cefepime combined
tigecycline with cefepime, tigecycline with cefoperazone/sulbac- with amoxicillin/clavulanic acid therapy, while 25 received the
tam, or tigecycline with meropenem (Table 2). tigecycline-based treatment (Fig. 1).
The institutional review board of Sir Run Run Shaw Hospital Patients’ symptoms and inflammation index, and each patient
approved the study protocol. Written informed consents were with at least twice positive culture results, supported that all
obtained from all patients or from their legally representatives. blaKPC-positive K. pneumoniae isolates were the real pathogens
associated with infections. Thirteen patients (8+5) whose patho-
2.3. Pathogen identification and MIC detection gens were isolated from sputum met the diagnosis criteria of
Hospital Associated Pneumonia (HAP) by CT scan or X-ray results
The isolates were first identified using the VITEK compact (Table 1). There were no significant differences in the baseline
2 system (AB bioMe´rieux, France), and the minimum inhibitory characteristics between the two groups, except that more patients
concentrations (MICs) of 13 antibiotics were determined by the in the tigecycline group had a history of surgery (88% vs 57.7%,
Etest method (AB bioMe´rieux, France), which included ceftriaxone, P=0.046) (Table 1).
cefepime, amoxicillin/clavulanic acid, piperacillin/tazobactam,
cefoperazone/sulbactam, aztreonam, imipenem, meropenem, ami- 3.1. MIC distribution
kacin, levofloxacin, fosfomycin, colistin and tigecycline. Suscepti-
bility to a drug was interpreted according to the CLSI guideline Most isolates presented typical features of KPC-KP pathogens,
14
(2013). The resistance breakpoints of cefepime and amoxicillin/ being highly resistant to both carbapenems and broad-spectrum
clavulanic acid were 32 mg/L and 32/16 mg/L, respectively. Due cephalosporins, except for colistin and tigecycline. The MICs of
to the absence of CLSI criteria, FDA and EUCAST guidelines were tigecycline were distributed from 0.25 to 1 mg/L in all isolates.
110 S. Ji et al. / International Journal of Infectious Diseases 38 (2015) 108–114
Figure 1. Study profile.
3.2. Mortality and pathogen clearance of patients treated with they were used alone (Supplementary Table 1). Furthermore, the
cefepime combined with amoxicillin/clavulanic acid and tigecycline checkerboard results indicated that the MIC of cefepime was
dramatically decreased when amoxicillin/clavulanic acid was
The overall 28-day mortality rate was 29.0%, and the mortality of combined. Consistently, synergy was the main effect in 65.4%
the study group was lower than that of the tigecycline group (23.1% patients, followed by partial synergy (26.9%) and then indifference
vs 36.0%, respectively), although this difference was not significant (7.7%). Of note, antagonism was not found in any of the tests
(P=0.311). The pathogen clearance rate was 62.7% (32/51), with (Fig. 2). The MIC of cefepime was drastically reduced 2 32 times
57.7% (15/26) and 68.0% (17/25) for two groups, respectively after combination, and the MIC of amoxicillin/clavulanic acid was
(P=0.447) (Table 2). When compared to the tigecycline mono- even reduced 2 256 times. The combination treatment was
therapy, the cefepime and amoxicillin/clavulanic acid treatment significantly different from both the cefepime and amoxicillin/
tended to have lower mortality (20.8% vs 60%, P=0.075) and a similar clavulanic acid treatment alone (P =0.013 and <0.001, respective-
pathogen clearance rate (53.8% vs 60.0%, P=0.945). ly), which implies a powerful combinatorial effect between
cefepime and amoxicillin/ clavulanic acid (Supplementary
3.3. Susceptibility results and in vitro activity of cefepime in Table 1).
combination with amoxicillin/clavulanic acid
3.4. Antibiotic cost for KPC-KP treatment
The KPC-producing isolates appeared to present higher MIC
values to both amoxicillin/clavulanic acid and cefepime. The MIC As shown in Table 3, the total antibiotic cost was extremely
ranges of cefepime and amoxicillin/clavulanic acid in the 26 tested higher for the tigecycline group ($3465 vs $1109, P<0.001)
isolates were 1 4096 mg/L and 64 4096 mg/L, respectively, when compared to that of the study group. Given that tigecycline is
S. Ji et al. / International Journal of Infectious Diseases 38 (2015) 108–114 111
Table 1
acid group) was tended to be lower than that of the control group
Patient Baseline Demographics Treated with Cefepime in combination with
(tigecycline-based treatment group) (23.1% vs 36.0%, P=0.311). The
Amoxicillin/ Clavulanic Acid Group vs Tigecycline Group
pathogen clearance rate was 57.7% and 68.0% for the two groups,
Baseline Demographics Cefepime combined Tigecycline P value
respectively (P=0.447). With respect to the financial burden, both
with amoxicillin/ group
the total antibiotic cost and the portion not covered by medical
clavulanic acid (n=25)
insurance were by far higher for the tigecycline-based treatment
group (n=26)
group compared to the study group ($3465 vs $1109, and $3221 vs
Age, y, 67.1 16.1 63.6 17.8 0.457
$222; both P<0.001). Moreover, synergy (65.4%) and partial
Sex, Male, n (%) 18 (69.2%) 13 (52%) 0.208
synergy (26.9%) were the main effects when cefepime was
Prior ICU admission, n (%) 19(73%) 18 (72.0%) 0.931
Comorbidities, n (%) combined with amoxicillin/clavulanic acid in the checkerboard
Diabetes mellitus 4 (15.4%) 1 (4.0%) 0.172
microdilution test. Therefore, compared to the currently recom-
Congestive heart disease 13 (50.0%) 8 (32.0%) 0.049
mended tigecycline-based therapy, cefepime and amoxicillin/
Chronic obstructive 2 (7.7%) 4 (16.0%) 0.246
clavulanic acid combination therapy was an effective and
pulmonary disease
Chronic liver disease 1 (3.8%) 3 (12.0%) 0.26 economical option to control KPC-producing K. pneumoniae
Cholelithiasis 6 (23.1%) 3(12.0%) 0.269 infection.
Hematological 1 (3.8%) 0 (0%) 0.322
KPC-producing K. pneumoniae shows wide hydrolytic activity
malignancies
toward multiple classes of antibiotics, such as carbapenems,
Risk factors, n (%)
cephalosporins, penicillins and the monobactam aztreonam,
Surgery 15 (57.7%) 22 (88.0%) 0.046
Central venous catheter 15 (57.7%) 24 (96.0%) 0.564 rendering them ineffective. This organism is also associated with
Mechanical ventilation 12 (46.2%) 16 (64.0%) 0.2
severe infections with high mortality. Unfortunately, the optimal
Urinary catheter 6 (23.1%) 6 (24.0%) 0.251
antimicrobial therapy for KPC-KP infection is not well established,
Carbapenem Exposures 22 (84.6%) 21 (84.0%) 0.952 1
and the clinical outcome data remains sparse. Of note, our
Hemodialysis 1(3.8%) 2(8.0%) 0.529
Source of bacteria, n (%) previous study has demonstrated that KPC-KP isolates have widely
Sputum 8 (31%) 5 (20%) 0.177 spread around China and have become a particularly worrisome
Peritoneal fluid 3 (12%) 10 (40%) 7,13
problem due to the location of its plasmid. However, clinical
Blood 4 (15%) 2 (8%)
and efficacy data for KPC-KP infection treatment are still lacking.
Urine 1 (4%) 0
Therefore, it is very necessary to explore effective therapy options
Cerebrospinal fluid 0 1 (4%)
Two or more sources 10 (38%) 7 (28%) to control infection caused by KPC-KP.
Mixed infectious pathogens Although KPC-KP isolates are non-susceptible to carbapenems
A. baumannii 1 (4%) 5 (20%) 0.337
in most cases, some researchers have still argued that carbape-
E. coli 1 (4%) 1 (4%)
nems could be used as treatment against KPC-KP by prolonging the
E. faecalis 1 (4%) 1 (4%)
S. maltophila 0 1 (4%) infusion time or increasing the drug dose, especially in conditions
18
Median length of hospital 9.0(4.8-15.5) 9.0 (6.5-14.5) 0.397 of intermediate MICs (meropenem MICs of 4 mg/L). In fact,
stay, days
supported by a series of retrospective analyses and in vitro synergy
APACHE II scores 16.0 8.8 17.1 9.3 0.683
susceptibility tests, some researchers have claimed that clinical
Mean duration of antibiotic 10.3 7.2 10.6 5.5 0.339
efficacy and outcome are highly dependent on the MIC levels of
therapy, day
18
carbapenems. Carbapenem regimens were inapplicable as
definitive treatment options in our study because most of our
KPC-KP isolates showed high MIC levels to these antibiotics (over
7
not covered by medical insurance in China, in contrast to 80% of the 32 mg/L). Therefore, anti-infectious treatment based on several
other antibiotics used in this study, including cefepime and other antibiotics, such as colistin, tigecycline and fosfomycin, have
amoxicillin/clavulanic acid, the difference in total antibiotic cost been widely applied. However, these regimens are always
that was not covered by insurance (paid by patients) between the relatively limited in their clinical application, especially when
two groups was significantly different ($3221 vs $222, P<0.001). administered as a monotherapy. For example, a series of
systematic reviews and clinical trials have emphasised that
4. Discussion tigecycline monotherapy is pooled with safety and efficacy, and
clinicians should avoid tigecycline monotherapy for the treatment
19,20
In this study, we treated two groups of patients infected by KPC- of severe infection. According to a previous report, the most
KP, and the overall 28-day mortality was 29.0%. The mortality of common successful combination regimens used in KPC-KP
the study group (cefepime combined with amoxicillin/clavulanic bacteraemia were either colistin-polymyxin B or tigecycline in
Table 2
Mortality and pathogen clearance of patients treated with cefepime combined with amoxicillin/ clavulanic acid and tigecycline
Definitive treatment Mortality, n (%) Pathogen clearance, n (%) Total, n
#
Cefepime + Amoxicillin/ clavulanic acid based antimicrobial therapy 6(23.1%) 15 (57.7%) 26
y
Cefepime + Amoxicillin/clavulanic acid 5 (20.8%) 14(58.8%) 24 (92.3%)
Cefepime + Amoxicillin/clavulanic acid + fosfomycin 1 (50%) 1(50.0%) 2 (7.7%)
##
Tigecycline based antimicrobial therapy 9 (36.0%) 17(68.0%) 25
yy
Tigecycline monotherapy 3 (60%) 3(60.0%) 5 (20%)
Tigecycline + fosfomycin 3 (25%) 9(75.0%) 12 (48%)
Tigecycline+Amikacin+Levofloxacin 1 (33.3%) 3(100.0%) 3 (25%)
Tigecycline+Cefepime 1 (50%) 1(50.0%) 2 (8%)
Tigecycline+Cefoperazone/sulbactam 1 (100%) 0 (0%) 1 (4%)
Tigecycline+ Meropenem 0 (0%) 1(100.0%) 1 (4%) a
P 0.311 0.447 b
P 0.075 0.945
a # ## b y yy
P , group vs group; P , group vs group.
112 S. Ji et al. / International Journal of Infectious Diseases 38 (2015) 108–114
Figure 2. In vitro activity of cefepime in combination with amoxicillin/ clavulanic acid.
Table 3
Antibiotic cost for KPC-producing K. pneumoniae infection
Cost ($) Cefepime in combination Tigecycline P value
with amoxicillin/ clavulanic group (n=25)
acid group (n=26)
Total antibiotic cost 1109 767 3465 2082 <0.001
Antibiotic cost per day 108 5 321 34 <0.001
Total antibiotic cost not covered by insurance 222 153 3221 1540 <0.001
Antibiotic cost not covered by insurance per day 22 1 302 7 <0.001
1 23
combination with a carbapenem regimen. It has been confirmed pneumonia. With increasing application, more clinical trials have
that combined therapies with two or more drugs in vivo are found increased mortality in patients receiving cefepime therapy,
beneficial for improving survival rate and for avoiding pathogen but the combination of this antibiotic with other antibiotic agents
24
resistance. Recent studies have revealed that the polymyxins might be an effective way to improve its efficacy. Cardile et al. also
[polymyxin B and polymyxin E (colistin)] have low success rate reported a successful treatment case where using high doses of
when used alone, but they exhibit higher activity when used in cefepime and levofloxacin to treat KPC-expressing Enterobacter
21,22
combination. The most frequently utilised combinations cleacae empyema showed an intermediate effect to that of cefepime
25
include tigecycline with colistin, colistin with aminoglycosides and levofloxacin (MIC=16 mg/L).
or tigecycline/colistin with fosfomycin. Unfortunately, polymyxins Clavulanic acid is an irreversible ‘suicide’ inhibitor of intracel-
are still unavailable in Mainland China, while tigecycline is not lular and extracellular b-lactamases that is effective against a wide
included in the National Health Insurance price listing, which have variety of these enzymes and protects amoxicillin from inactiva-
made the choice of antibiotics for KPC-KP infection in China very tion by many b-lactamases. As a consequence, studies on the
limited. antibacterial activity of amoxicillin/clavulanic acid have been
Cefepime is a semi-synthetic, broad-spectrum, fourth-genera- restored at a time when the spread of resistance due to b-
tion cephalosporin that has been widely used since its approval for lactamase production severely threatens its usefulness. However,
23
clinical use in 1997. It is currently recommended in several little evidence is available regarding the clinical efficacy of
guidelines for the empirical treatment of febrile neutropenia, severe clavulanic acid toward KPC carbapenemases. Our previous study
community-acquired pneumonia, and late-onset hospital-acquired found that cefepime in combination with amoxicillin/clavulanic
S. Ji et al. / International Journal of Infectious Diseases 38 (2015) 108–114 113
acid is effective toward KPC-KP isolates (data not shown). Supported In conclusion, our study explores the clinical treatment efficacy
by evidence from the checkerboard microdilution method, we aim to of amoxicillin/clavulanic acid in combination with cefepime
use the combination therapy to treat patients infected by KPC-KP. toward KPC-positive K. pneumoniae isolates. By comparing the
The checkerboard microdilution test showed a significant synergis- results with those of a group treated with tigecycline, we found
tic effect for amoxicillin/clavulanic acid and cefepime, therefore, it that patients who received amoxicillin/clavulanic acid with
seems that clavulanic acid has a higher hydrolytic activity than KPC cefepime treatment showed no difference in clinical efficacy.
carbapenems in vitro, which is different from results of previous Therefore, we suggest that amoxicillin/clavulanic acid in combi-
studies. We further evaluated the clinical efficacies of these drugs by nation with cefepime could be recommended as a treatment choice
comparing the 28-day mortality and pathogen clearance of patients in special situations, such as when no drugs are available or for
treated with these drugs to those treated with tigecycline. Because infection of special sites (e.g. CNS, bloodstream or urinary tract).
many reports have proven the effectiveness of tigecycline in
controlling KPC-KP infection, treatment options based on tigecycline Acknowledgements
were utilised as a control in this study.
In our study, most patients in the control group had received This study was supported by the National Natural Science
multiple antibiotics before tigecycline was used. The higher Foundation of China (no. 81171615) and the Ministry of Health of
mortality of tigecycline monotherapy (60%) also supported that the People’s Republic of China (no. 201002021). We thank all the
combination programs would be more effective and safe in the patients who participated in the study, as well as the healthcare
control group (Table 2). Therefore, a combination program — personnel for their assistance in conducting the study.
tigecycline combined with at least one drug to which the isolate Ethical standards: The study was approved by the Medical Ethics
was susceptible, was utilized in our study. Committee of Sir Run Run Shaw Hospital. Patients were included
As shown in our study, the pathogen clearance rate was 62.7% after written informed consent was obtained.
(32/51), with 57.7% (15/26) and 68.0% (17/25) for two groups, Conflict of interest: The authors declare that there are no
respectively (P=0.447), which suggested that the cefepime competing interests.
combined with amoxicillin/clavulanic acid treatment might be a
superior treatment option when compared with tigecycline-based
treatment in regard to clinical safety and efficacy (Table 2).
Appendix A. Supplementary data
However, relatively lower microbiological clearance was observed
in the study group compared to the control group (57.7% vs 68%),
Supplementary data associated with this article can be found, in
which indicated that the cefepime combined with amoxicillin/
the online version, at http://dx.doi.org/10.1016/j.ijid.2015.07.024.
clavulanic acid treatment might be inferior to the tigecycline
treatment in microbiological eradication. Furthermore, cefepime
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