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Nationwide surveillance of antimicrobial susceptibility patterns of pathogens isolated from surgical site infections (SSI) in Japan
J Infect Chemother (2012) 18:816–826 DOI 10.1007/s10156-012-0509-1
SURVEILLANCE
Nationwide surveillance of antimicrobial susceptibility patterns of pathogens isolated from surgical site infections (SSI) in Japan Yoshio Takesue • Akira Watanabe • Hideaki Hanaki • Shinya Kusachi • Tetsuro Matsumoto • Aikichi Iwamoto Kyoichi Totsuka • Keisuke Sunakawa • Morimasa Yagisawa • Junko Sato • Toyoko Oguri • Kunio Nakanishi • Yoshinobu Sumiyama • Yuko Kitagawa • Go Wakabayashi • Isamu Koyama • Katsuhiko Yanaga • Toshiro Konishi • Ryoji Fukushima • Shiko Seki • Shun Imai • Tsunehiro Shintani • Hiroki Tsukada • Kazuhiro Tsukada • Kenji Omura • Hiroshige Mikamo • Hiromitsu Takeyama • Masato Kusunoki • Shoji Kubo • Junzo Shimizu • Toshihiro Hirai • Hiroki Ohge • Akio Kadowaki • Kohji Okamoto • Katsunori Yanagihara
•
Received: 7 August 2012 / Accepted: 14 October 2012 / Published online: 10 November 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract To investigate the trends of antimicrobial resistance in pathogens isolated from surgical site infections (SSI), a Japanese surveillance committee conducted the first nationwide survey. Seven main organisms were collected from SSI at 27 medical centers in 2010 and were shipped to a central laboratory for antimicrobial suscepti-
bility testing. A total of 702 isolates from 586 patients with SSI were included. Staphylococcus aureus (20.4 %) and Enterococcus faecalis (19.5 %) were the most common isolates, followed by Pseudomonas aeruginosa (15.4 %) and Bacteroides fragilis group (15.4 %). Methicillinresistant S. aureus among S. aureus was 72.0 %. Vanco-
Y. Takesue A. Watanabe S. Kusachi T. Matsumoto A. Iwamoto K. Totsuka K. Sunakawa M. Yagisawa J. Sato T. Oguri K. Nakanishi Surveillance Committee of JSC, JAID and JSCM, Tokyo, Japan
I. Koyama Saitama Medical University International Medical Center, Saitama, Japan
Y. Takesue Hyogo College of Medicine Hospital, Hyogo, Japan Y. Takesue (&) Department of Infection Control and Prevention, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan e-mail: [email protected] H. Hanaki Kitasato University Institute, Tokyo, Japan S. Kusachi Toho University Medical Center Ohashi Hospital, Tokyo, Japan Y. Sumiyama Y. Kitagawa Japan Society for Surgical Infection, Tokyo, Japan Y. Sumiyama Toho University, Tokyo, Japan Y. Kitagawa Keio University Hospital, Tokyo, Japan G. Wakabayashi Iwate Medical University Hospital, Iwate, Japan
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K. Yanaga The Jikei University Hospital, Tokyo, Japan T. Konishi NTT Medical Center Tokyo, Tokyo, Japan R. Fukushima Teikyo University Hospital, Tokyo, Japan S. Seki National Hospital Organization Tokyo Medical Center, Tokyo, Japan S. Imai Hiratsuka City Hospital, Kanagawa, Japan T. Shintani Shizuoka Red Cross Hospital, Shizuoka, Japan H. Tsukada Niigata City General Hospital, Niigata, Japan K. Tsukada Toyama University Hospital, Toyama, Japan K. Omura Koseiren Takaoka Hospital, Toyama, Japan
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mycin MIC 2 lg/ml strains accounted for 9.7 %. In Escherichia coli, 11 of 95 strains produced extendedspectrum b-lactamase (Klebsiella pneumoniae, 0/53 strains). Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ) and 26.3 % to ciprofloxacin (CPFX). No P. aeruginosa strains produced metallo-b-lactamase. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem, cefepime, and CPFX, and 0 % to gentamicin. In the B. fragilis group, the rates were 28.6 % to clindamycin, 5.7 % to cefmetazole, 2.9 % to TAZ/PIPC and IPM, and 0 % to metronidazole (Bacteroides thetaiotaomicron; 59.1, 36.4, 0, 0, 0 %). MIC90 of P. aeruginosa isolated 15 days or later after surgery rose in TAZ/PIPC, CAZ, IPM, and CPFX. In patients with American Society of Anesthesiologists (ASA) score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than in patients with ASA B2. The data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI. Timing of isolation from surgery and the patient’s physical status affected the selection of resistant organisms.
Introduction
Keywords Surgical site infections Surveillance Antibiotic susceptibility Bacteroides fragilis group
Methods
H. Mikamo Aichi Medical University Hospital, Aichi, Japan H. Takeyama Nagoya City University Hospital, Aichi, Japan M. Kusunoki Mie University Hospital, Mie, Japan S. Kubo Osaka City University Hospital, Osaka, Japan J. Shimizu Toyonaka Municipal Hospital, Osaka, Japan T. Hirai Kawasaki Medical School Hospital, Okayama, Japan H. Ohge Hiroshima University Hospital, Hiroshima, Japan A. Kadowaki Sanin Rosai Hospital, Tottori, Japan K. Okamoto University of Occupational and Environmental Health, Kitakyushu, Japan K. Yanagihara Nagasaki University Hospital, Nagasaki, Japan
Surgical site infections (SSIs) are one of the most important causes of hospital-acquired infections. In a prevalence survey undertaken in 2010 by the Japanese HealthcareAssociated Infections Surveillance [1] (JHAIS), 7.6 % of patients who had undergone surgical procedures developed SSIs. The occurrence of an SSI results in reduced quality of life, increased length of hospital stay, increased likelihood of mortality, and markedly increased costs [2–5]. Appropriate antimicrobial therapy is mandatory not only to improve the prognosis of patients with SSIs but also to minimize the occurrence of antibiotic-resistant organisms. To use antibiotics appropriately, information on the antibiotic susceptibility of the organisms isolated from SSIs is of particular value. The purpose of this study was to investigate the antibiotic susceptibility of the organisms isolated from SSIs by a nationwide survey, and to reserve the data to compare with the subsequent incidence of the isolation of antibiotic-resistant organisms with periodic surveillance.
The Japanese surveillance committee, consisting of the Japanese Society of Chemotherapy, Japanese Association for Infectious Disease, and Japanese Society for Clinical Microbiology, conducted the first nationwide surveillance of antimicrobial susceptibility in organisms isolated from SSI. The study protocol was prepared by the working group and accepted by the governing board of the Japanese surveillance committee. Ethics approval was the responsibility of each study center. All patient data were reported anonymously to the study database. If necessary, investigators asked for formal approval of the protocol by the regional ethics committee. The diagnosis of SSI was made based on definitions stated in the guidelines issued by the National Nosocomial Infections Surveillance [6] (NNIS) system. The criterion for the diagnosis of SSI was an infection that occurred within 30 days after the operation. SSI was defined by any of the following clinical criteria: documentation by an attending trauma surgeon indicating the presence of an SSI, the administration of antibiotics specifically for a surgical site, and the opening or packing of a surgical wound based on its appearance. Site infections were further classified by CDC criteria into superficial incisional, deep incisional, or organ/space SSI. Superficial incisional SSI involved only the skin or subcutaneous tissues, whereas deep incisional SSI involved the deep soft tissues of the incision. Organ/ space infections involved any location beyond the incision that was manipulated during surgery.
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Seven principal organisms (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Bacteroides fragilis group, Staphylococcus aureus, Enterococcus faecalis) isolated from SSI were collected in 27 medical centers in Japan between April 2010 and December 2010, and were referred to a central laboratory (Research Center for Anti-infective Drugs of Kitasato Institute) for testing. Shipped strains were kept at -80 °C until antimicrobial susceptibility testing was conducted. Re-identification and cultivation of the strains yielded evaluable strains. All isolates were susceptibility tested by the broth microdilution method as described by the Clinical and Laboratory Standards Institute [7, 8] (CLSI). In daptomycin, a frozen plate prepared by Eiken Chemicals was used. As culture medium, cation-adjusted Mueller–Hinton broth (CAMHB) was used (concentration of calcium was adjusted to 50 mg/l). The accuracy of determination of the minimum inhibitory concentrations (MICs) of antibacterial agents was controlled according to the recommendations of the CLSI. To detect b-lactamase production in gram-negative bacteria, a Nitrocefin disk (Cefinase; BD, Japan) was used according to the reference manual supplied by the manufacturer. The Cica-Beta Test (Kanto Chemical, Tokyo, Japan), a recently developed rapid method, was used to detect extendedspectrum b-lactamase (ESBL) and metallo-b-lactamase (MBL)-producing gram-negative bacteria by directly scraping the colony and applying it on the disk [9, 10]. Thirty-one different antibacterial agents were employed: especially, vancomycin, teicoplanin, linezolid, clindamycin, minocycline, erythromycin, sulfamethoxazole-trimethoprim, arbekacin, and rifampin for methicillin-resistant Staphylococcus aureus (MRSA), ceftazidime cefepime, piperacillin/tazobactam, imipenem, meropenem, doripenem, biapenem, panipenem, aztreonam, ciprofloxacin, levofloxacin, pazufloxacin, and gentamycin for P. aeruginosa, and metronidazole, clindamycin, cefmetazole, flomoxef, ampicillin/sulbactam, piperacillin/tazobactam, and five kinds of carbapenems for B. fragilis group). Because daptomycin was not commercially available at the start of this study, daptomycin was excluded from the initial protocol. Separately, the MIC of daptomycin against MRSA was determined afterward by the central laboratory using the same MRSA isolates. Survey items concerning each patient’s characteristics were as follows: type of surgery, type of SSI (incisional, organ/space), American Society of Anesthesiologists (ASA) physical status classification score, duration of therapeutic antibiotic use, and postoperative hospital stay until organism isolation. Statistical analysis was performed as follows: categorical variables were compared by the v2 test with Yates’ correction or Fisher’s exact test when necessary, using Microsoft Excel 2003.
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Results A total of 702 isolates (incisional 328, organ/space 374 strains) were included in the investigation. S. aureus (20.4 %) and E. faecalis (19.5 %) were the most common isolates. P. aeruginosa (15.4 %) and B. fragilis group (15.4 %) were next, with E. coli, Enterobacter cloacae, and K. pneumoniae accounting for 13.5, 8.8, and 7.7 % of isolates, respectively. Five organisms were isolated from pediatric patients. Incidences of S. aureus and P. aeruginosa isolated from incisional SSI were significantly higher than those of organ/space SSI. In contrast, the incidence of Enterobacteriaceae isolated from organ/space SSI was significantly higher than from incisional SSI (Table 1). Three hundred thirty-six strains were isolated from lower gastroenterological surgery, 190 strains from hepatobiliary and pancreatic surgery, 73 strains from upper gastroenterological surgery, 68 strains from general surgery including breast surgery, and 30 strains from thoracic surgery (cardiovascular and respiratory tract). As for the duration of antimicrobial prophylaxis, only 18.5 % of patients had their antimicrobial prophylaxis discontinued within 24 h. At 48 h after the end of surgery, 56.2 % of patients were still receiving prophylaxis, and 11.7 % continued to receive prophylaxis for more than 5 days. Leading isolates were S. aureus in upper gastroenterological surgery, general surgery, and thoracic surgery, E. faecalis in hepatobiliary and pancreatic surgery, and B. fragilis group in lower gastroenterological surgery. Antibiotic susceptibility of gram-positive organisms, including methicillin-sensitive S. aureus (MSSA), MRSA, and E. faecalis, gram-negative organisms, including E. coli, K. pneumoniae, E. cloacae, and P. aeruginosa, and B. fragilis group is shown in Table 2. MRSA was 72.0 % among S. aureus. Vancomycin MIC 2 lg/ml strains accounted for 9.7 % (Table 5). In E. coli, 11 of 95 strains Table 1 Isolated organisms according to types of surgical site infection (SSI) Organisms Staphylococcus aureus
Incisional SSI
Organ/space SSI
81 (24.7)
62 (16.6)
MRSA
53 (16.2)
50 (13.4)
MSSA
28 (8.5)
12 (3.2)
P value 0.008
Enterococcus faecalis
55 (16.8)
82 (21.9)
0.085
Enterobacteriaceae
84 (25.6)
122 (32.6)
0.042
Escherichia coli Klebsiella pneumoniae
37 (11.3) 17 (5.2)
58 (15.5) 36 (9.6)
Enterobacter cloacae
30 (9.1)
28 (7.5)
Pseudomonas aeruginosa
63 (19.2)
45 (12.0)
0.009
Bacteroides fragilis group
45 (13.7)
63 (16.8)
0.252
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Table 2 Antibiotic susceptibility in methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecalis Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Cefazolin
0.5
0.5
Cefmetazole Cefepime
1 2
1 2
Ampicillin
0.5
8
Range
Susceptible
Intermediate
Resistant
MSSA (40) 0.25–1
100
0
0
1–2 1–4
100 100
0 0
0 0
47.5
–
52.5
0.125–16
Oxacillin
0.25
0.5
0.125–0.5
100
0
0
Ampicillin/sulbactam
0.5
2
0.125–4
100
0
0
Piperacillin/tazobactam
1
2
0.5–2
100
0
0
Imipenem
0.06
0.06
0.06–0.125
100
0
0
Meropenem
0.06
0.125
0.06–0.125
100
0
0
Doripenem
0.06
0.06
0.06–0.06
–
–
–
Biapenem
0.06
0.06
0.06–0.125
–
–
–
Panipenem
0.06
0.06
0.06–0.125
–
–
-
Levofloxacin
0.25
0.5
95
0
5
Gentamycin
0.25
128
0.25–128
75
0
25
Minocycline
0.125
0.125
0.06–0.25
100
0
0
Clindamycin
0.25
0.25
0.25–0.5
100
0
0
Erythromycin MRSA (103)
0.5
0.5
0.5–128
81.6
0
18.4
Vancomycin
1
1
0.5–2
100
0
0
Teicoplanin
1
2
0.25–8
100
0
0
Gentamycin
0.5
64
0.25–256
52.4
0
47.6
Arbekacin
0.5
1
0.25–8
–
–
–
Minocycline
8
16
0.06–32
43.7
10.7
45.6
Clindamycin
128
128
0.25–128
9.3
–
90.7
Erythromycin
128
128
0.25–128
7.8
0
92.2
Linezolid
2
2
1–4
100
0
0
Daptomycin
0.25
0.5
Sulfamethoxazole/trimethoprim
0.063
0.063
Ampicillin
1
2
Piperacillin
4
4
0.125–8
0.25–0.75
100
0
0
0.031–0.125
100
0
0
E. faecalis (137) 0.5–8 2–128
100
0
0
–
–
–
Imipenem
2
2
0.5–16
–
–
–
Levofloxacin Vancomycin
2 1
64 2
1–128 0.5–8
83.9 98.5
2.2 1.5
13.9 0
(11.9 %) produced extended-spectrum b-lactamase (ESBL), and none of the strains produced ESBL in K. pneumoniae. Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ), 20.0 % to sulbactam-ampicillin, 37.9 % to cefazolin, and 26.3 % to ciprofloxacin (CPFX) (Table 3). None of the P. aeruginosa strains produced MBL. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/ piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem (MEPM), cefepime (CFPM), and CPFX, and 0 % to gentamicin (Table 3; Fig. 1). In
B. fragilis, the resistant rate was 28.6 % to clindamycin; however, the incidence remained 5.7 % to cefmetazole. In non-fragilis Bacteroides, including B. thetaiotaomicron, high resistance rates to clindamycin and cefmetazole were noted. Low rates of resistance to TAZ/PIPC, IPM, and metronidazole were observed in both B. fragilis and nonfragilis Bacteroides (Table 4). Antibiotic susceptibility of P. aeruginosa according to the duration of the postoperative hospital stay until isolation was analyzed. When compared with MIC90 of
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J Infect Chemother (2012) 18:816–826
Table 3 Antibiotic susceptibility in Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Range
Susceptible
Intermediate
Resistant
Cefazolin
1
C256
0.5 to C256
52.5
9.5
37.9
Cefmetazole
0.5
16
0.25 to 128
92.6
2.1
5.3
Escherichia coli (95)
Ceftazidime
0.125
8
B0.06 to 128
89.5
2.1
8.4
Cefepime
B0.06
4
B0.06 to 64
96.8
2.1
1.1
Ampicillin/sulbactam
4
32
1 to C256
56.8
23.2
20
Piperacillin/tazobactam Imipenem
1 0.25
4 0.5
0.5 to C256 B0.06 to 1
95.8 100
2.1 0
2.1 0
Meropenem
B0.06
B0.06
B0.06 to B0.06
100
0
0
Doripenem
B0.06
B0.06
B0.06 to B0.06
–
–
–
Biapenem
B0.06
B0.06
B0.06 to 0.125
–
–
–
Panipenem
0.125
0.25
B0.06 to 0.5
–
–
–
Aztreonam
B0.06
8
B0.06 to 64
87.4
6.3
6.3
Ciprofloxacin
B0.06
32
B0.06 to 128
73.7
0
26.3
Levofloxacin
0.125
16
B0.06 to 32
73.7
1
25.3
Pazufloxacin
B0.06
8
B0.06 to 16
–
–
–
Gentamycin
0.5
2
0.25 to 128
90.5
0
9.5
Cefazolin
1
2
1 to C256
81.1
9.4
9.4
Cefmetazole
0.5
4
0.5 to C256
94.3
0
5.7
Ceftazidime
0.125
0.5
B0.06 to 32
98.1
0
1.9
Cefepime Ampicillin/sulbactam
B0.06 4
0.125 16
B0.06 to 2 2 to 64
100 88.7
0 5.7
0 5.7
Piperacillin/tazobactam
2
8
0.5 to 32
96.2
3.8
0
K. pnemoniae (53)
Imipenem
0.25
1
0.125 to 2
100
0
0
Meropenem
B0.06
B0.06
B0.06 to 1
100
0
0
Doripenem
B0.06
0.125
B0.06 to 1
–
–
–
Biapenem
0.125
0.5
B0.06 to 1
–
–
–
Panipenem
0.25
0.5
B0.06 to 2
–
–
–
Aztreonam
B0.06
0.25
B0.06 to 2
100
0
0
Ciprofloxacin
B0.06
0.25
B0.06 to 1
100
0
0
Levofloxacin
0.125
1
B0.06 to 2
100
0
0
Pazufloxacin
B0.06
0.25
B0.06 to 1
–
–
–
Gentamycin
0.25
0.5
0.125 to 1
100
0
0
E. cloacae (58) Cefmetazole
C256
C256
64 to C256
0
0
100
Ceftazidime
0.5
64
B0.06 to 128
74.1
1.8
24.1
Cefepime Ampicillin/sulbactam
B0.06 32
1 64
B0.06 to 8 4 to 128
100 3.4
0 17.3
0 79.3
Piperacillin/tazobactam
2
64
0.5 to C256
81
13.8
5.2
Imipenem
1
2
0.25 to 2
100
0
0
Meropenem
B0.06
0.125
B0.06 to 2
100
0
0
Doripenem
B0.06
0.125
B0.06 to 1
–
–
–
Biapenem
0.125
0.25
B0.06 to 0.5
–
–
–
Panipenem
0.5
1
0.25 to 4
–
–
–
Aztreonam
0.25
32
B0.06 to 64
77.6
1.7
20.7
Ciprofloxacin
B0.06
2
B0.06 to 32
89.7
1.7
8.6
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Table 3 continued Organism (number tested) and antimicrobial agent
MIC (lg/ml) MIC50
% MIC90
Range
Susceptible
Intermediate
Resistant
Levofloxacin
0.125
2
B0.06 to 16
93.1
5.2
1.7
Pazufloxacin
B0.06
1
B0.06 to 16
–
–
–
Gentamycin
0.25
0.5
0.25 to 4
100
0
0 6.5
P. aeruginosa (108) Ceftazidime
2
16
0.5 to 64
89.8
3.7
Cefepime
2
8
0.25 to 32
91.7
5.5
2.8
Piperacillin/tazobactam
4
64
0.25 to C256
92.6
–
7.4
Imipenem
2
16
0.25 to 16
88
1.8
10.2
Meropenem Doripenem
0.25 0.25
4 4
B0.06 to 16 B0.06 to 16
93.5 –
3.7 –
2.8 –
Biapenem
0.5
8
0.125 to 32
–
–
–
Panipenem
8
16
0.25 to 64
–
–
–
Aztreonam
4
16
0.5 to 64
66.7
19.4
13.9
Ciprofloxacin
0.25
0.5
B0.06 to 128
95.4
1.8
2.8
Levofloxacin
1
2
0.125 to 128
91.7
5.5
2.8
Pazufloxacin
0.5
1
B0.06 to 32
–
–
–
Gentamycin
2
2
0.5 to 4
100
0
0
Fig. 1 Antibiotic resistance rate of Pseudomonas aeruginosa for each antibiotic
P. aeruginosa isolated within 7 days after surgery, that of P. aeruginosa isolated 15 days or later after surgery rose by eightfold in TAZ/PIPC and CAZ, by fourfold in IPM and MEPM, and by twofold in CPFX, GM, and CFPM (Fig. 2). In addition, the changes of antibiotic susceptibility according to the duration of therapeutic antibiotic use were evaluated. When compared with MIC90 of P. aeruginosa isolated within 2 days of therapeutic antibiotic use, that of P. aeruginosa with 8 days or more therapeutic antibiotic use revealed a similar tendency of the alteration of antibiotic susceptibility, which was observed in the analysis according to the duration of postoperative hospital stay until isolation (Fig. 3). Antibiotic susceptibility was also
analyzed from the patient’s physical status classification. In patients with ASA score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than those in patients with ASA B2 (Fig. 4).
Discussion In a prevalence survey by the JHAIS, the main organisms isolated from SSI were 2,182 strains (14.3 %) of Enterococcus faecalis, 2,167 strains (14.2 %) of Staphylococcus aureus (MRSA, 1351 strains), 1,557 strains (10.2 %) of Pseudomonas aeruginosa, 1,140 strains (7.5 %) of
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Table 4 Antibiotic susceptibility in Bacteroides fragilis group Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Range
Susceptible
Intermediate
Resistant
Cefmetazole
8
32
4–128
Flomoxef
1
64
0.25–256
82.9
11.4
5.7
–
–
–
Ampicillin/sulbactam
1
8
Piperacillin/tazobactam
0.25
2
0.5–256
90
5.7
4.3
0.06–256
95.7
1.4
Imipenem
0.25
2.9
2
0.125–128
95.7
1.4
Meropenem Doripenem
2.9
0.125 0.25
4 2
0.06–256 0.125–128
97.1 –
0 –
2.9 –
Biapenem
0.25
1
0.125–256
–
–
–
Panipenem
0.25
2
0.06–256
–
–
–
Clindamycin
0.5
256
0.06–256
70
1.4
28.6
Metronidazole
1
2
0.25–4
100
0
0 36.4
B. fragilis (70)
B. thetaiotaomicron (22) Cefmetazole
32
64
16–64
4.5
59.1
Flomoxef
16
256
4–256
–
–
–
Ampicillin/sulbactam
1
4
1–4
100
0
0
Piperacillin/tazobactam
8
16
1–16
100
0
0
Imipenem
0.5
1
0.25–2
100
0
0
Meropenem
0.25
0.5
0.125–1
100
0
0
Doripenem
0.5
1
0.25–1
–
–
–
Biapenem
0.25
1
0.25–1
–
–
–
Panipenem Clindamycin
0.5 256
2 256
0.25–2 0.5–256
– 31.8
– 9.1
– 59.1
Metronidazole
1
1
0.125–2
100
–
– 20
Other Bacteroides sp. (10) Cefmetazole
16
64
8–128
50
30
Flomoxef
8
256
0.5–256
–
–
–
Ampicillin/sulbactam
4
32
0.5–32
80
0
20
Piperacillin/tazobactam
2
4
0.5–4
100
0
0
Imipenem
1
2
0.25–8
90
10
0
Meropenem
0.25
2
0.125–4
100
0
0
Doripenem
0.5
2
0.125–8
–
–
–
Biapenem
0.5
1
0.25–1
–
–
–
Panipenem
1
4
0.5–4
–
–
–
Clindamycin
2
256
0.25–256
50
10
40
Metronidazole
1
2
0.06–1
100
0
0
Escherichia coli, 911 strains (6.0 %) of Enterobacter cloacae, 610 strains (4.0 %) of Staphylococcus epidermidis, 504 strains (3.3 %) of Bacteriodes fragilis group, and 446 strains (2.9 %) of Klebsiella pneumoniae [1]. We found only a few reports concerning the antimicrobial susceptibility of organisms isolated from SSI and, as far as we know, this is the largest survey. Schnu¨riger et al. [11] studied the microbiological profile and antimicrobial susceptibility in SSIs following hollow viscus injury. Susceptibility rates of E. coli and E. cloacae, respectively,
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were 38 and 8 % for ampicillin/sulbactam, 82 and 4 % for cefazolin, 96 and 92 % for cefoxitin, with both 92 % for PIPC/TAZ and 100 % for ertapenem. The members of the B. fragilis group are the most important anaerobic pathogens recovered from intraabdominal infections. Among the B. fragilis group isolates, B. fragilis accounts for 40–54 % of the Bacteroides isolates. Another important pathogen that belongs to the B. fragilis group isolates is B. thetaiotaomicron, which accounts for 13–23 % of the isolates. Other members of the
J Infect Chemother (2012) 18:816–826 Table 5 Distribution of minimum inhibitory concentrations (MIC) against anti-MRSA drugs in MRSA
Antimicrobial agents
823
% of organisms in each minimum inhibitory concentration 0.25 lg/ml
Vancomycin
0.5 lg/ml
1 lg/ml
2 lg/ml
4 lg/ml
8 lg/ml
1.9
88.3
9.8
Teicoplanin
2.9
42.7
37.9
14.6
2.0
Arbekacin
5.8
55.3
34.0
3.9
1.0
24.3
71.8
Linezolid Daptomycin
54.3
41.7
3.9
3.9
Fig. 2 MIC90 against Pseudomonas aeruginosa for each antibiotic according to the duration of postoperative hospital stay until isolation. MIC90 minimum inhibitory concentration required to inhibit the growth of 90 % of organisms
Fig. 3 MIC90 against Pseudomonas aeruginosa for each antibiotic according to the duration of therapeutic antibiotic use until isolation. MIC90 minimum inhibitory concentration required to inhibit the growth of 90 % of organisms
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824
J Infect Chemother (2012) 18:816–826
Fig. 4 Antibiotic resistance rate in Pseudomonas aeruginosa according to the American Society of Anesthesiologists (ASA) physical status classification score
B. fragilis group isolates account for 33–39 % [12, 13]. B. fragilis is generally the most susceptible, and B. thetaiotaomicron is generally the most resistant [14]. Marked increases in the resistance of the B. fragilis group relative to 20 years ago were observed for clindamycin [12]. Among second-generation cephalosporins, cefoxitin is the most effective against the B. fragilis group. Cefotetan and cefmetazole were equally effective to cefoxitin against B. fragilis but are inferior against other members of the B. fragilis group isolates [12–14]. In our study, a similar pattern was confirmed in the SSI isolates. Carbapenems, TAZ/PIPC, and metronidazole possess excellent activity against B. fragilis group. Compared with the organisms isolated from community-acquired intraabdominal infections, the antibiotic resistance rate of cefoxitine and clindamycin tended to be higher in isolates from nosocomial intraabdominal infections [15]. In the guideline for the diagnosis and management of complicated intraabdominal infection by the Infectious Diseases Society of America [16], ampicillin-sulbactam is not recommended because of high rates of resistance to this agent among E. coli, and quinolones should not be used unless surveys indicate [90 % susceptibility of E. coli. In our study, resistant E. coli strains were 20.0 % to sulbactam-ampicillin and 26.3 % to CPFX, and these antibiotics seem not to be recommended for the treatment of postoperative intraabdominal infections. Longer duration of antimicrobial prophylaxis may cause a high resistance rate of E. coli (37.9 %) isolated from SSI to cefazolin. At 48 h after the end of surgery, 56.2 % of patients were still receiving prophylaxis. Recently, ESBL-producing strains have become prevalent in the community setting in Japan [17]. In this survey, 11 of 95 E. coli strains (11.9 %) isolated from SSI produced ESBL, but none of the strains produced ESBL in K. pneumoniae. The low success rate of
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vancomycin, and the poor prognosis of patients with MRSA bacteremia, were demonstrated in vancomycin MIC 2 lg/ml strains [18]. In this study, 2 lg/ml strains accounted for 9.7 %. Alternative therapy should be considered in the treatment of SSI if the vancomycin MIC is 2 lg/ml in MRSA. In P. aeruginosa isolates from SSI, antibiotic susceptibility tended to be superior to those from hospital-acquired respiratory infections [19] and urinary tract infections [20]. Susceptibility of P. aeruginosa isolates from hospitalacquired pneumonia and ventilator-associated pneumonia by the SENTRY antimicrobial surveillance study were 72 %/66 % for gentamicin, 60 %/58 % for levofloxacin, 70 %/65 % for cefepime, 72 %/66 % for meropenem, and 76 %/71 % for piperacillin/tazobactam, respectively[18]. Mathai et al. [19] reported that P. aeruginosa causing urinary tract infections in hospitalized patients was most susceptible to amikacin (97.3 %) [ piperacillin ± tazobactam (92.0–95.6 %) [ cefepime = imipenem (91.2 %) [ ceftazidime (85.8 %). Greatest resistance was observed to fluoroquinolone (24.8–39.8 %). Acquisition of intrinsically resistant organisms and selective pressure for resistance within a unit or hospital are of increasing concern. Unnecessarily prolonged antibiotic use and needlessly broad coverage cause resistant organisms. Mentzelopoulos et al. [21] reported that the sole independent predictor of pandrug-resistant P. aeruginosa ventilator-associated pneumonia (VAP) was the combined use of carbapenem for more than 20 days and colistin use for more than 13 days. Kusachi et al. [22] reported that the incidence of strains resistant to cephems and carbapenems increased as the number of different antimicrobial agents used for the treatment of SSI increased. In general, antimicrobial therapy of established intraabdominal infection should be limited to 4–7 days, unless it is difficult to
J Infect Chemother (2012) 18:816–826
achieve adequate source control [15]. A common practice in the treatment of incisional SSI is to open all infected wounds. If there is minimal surrounding evidence of invasive infection and systemic signs of infection, antibiotics are unnecessary. In cases indicated for antimicrobial therapy, a duration of 24–48 h may be indicated [23]. In our study, isolation of MRSA (p \ 0.001) and P. aeruginosa (p = 0.081) increased 8 days or later after surgery. Antibiotic susceptibility of P. aeruginosa isolated 15 days or later after surgery decreased in TAZ/PIPC, CAZ, IPM, and CPFX. MIC90 of P. aeruginosa with 8 days or more therapeutic antibiotic use revealed a similar tendency when compared with a shorter duration until isolation. In addition, the patient’s preoperative status affected the antibiotic susceptibility of organisms isolated from SSI. In patients with ASA score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than those in patients with ASA B2. A history of previous hospitalization for reasons of comorbidity or the necessity of prolonged antibiotic therapy in a compromised host with comorbidity may cause lower antibiotic susceptibility of isolates from SSI. In conclusion, the data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI, and the need for continuous monitoring was confirmed. Conflict of interest Yoshio Takesue has received a speaker’s honorarium from Taisho Toyama Pharm. Co., Ltd, MSD Japan, Astellas Pharma Inc. and Pfizer Japan Inc. Akira Watanabe is a consultant to Daiichi-Sankyo Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Toyama Chemical Co., Ltd, and Otsuka Pharmaceutical Co., Ltd. A.W. has received a speaker’s honorarium from MSD Japan, Glaxo SmithKline K.K., Shionogi & Co. Ltd., Daiichi-Sankyo Co., Ltd, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma Co., Ltd, and Pfizer Japan Inc. and grant support from Astellas Pharma Inc., Kyorin Pharmaceutical Co., Ltd, Shionogi & Co. Ltd., Taisho Pharmaceutical Co., Ltd, Toyama Chemical Co., Ltd, Daiichi Sankyo Co., Ltd, Dainippon Sumitomo Pharma Co., Ltd, Taiho Pharma Co., Ltd, and Meiji Seika Pharma Co., Ltd. Shinya Kusachi has received a speaker’s honorarium from Shionogi & Co., Ltd, MSD Japan, and Taisho Toyama Pharmaceutical Co., Ltd. Keisuke Sunakawa received a research grant from Meiji Seika Pharma Co., Ltd. and Taisho Toyama Pharmaceutical Co., Ltd. Yuko Kitagawa has received a speaker’s honorarium from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Shionogi & Co., Ltd, Coviden Japan Co., Ltd, and Ethicon Endo-Surgery, LLC. Y.K received a research grant from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Yakult Honsha Co., Ltd.
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825 3. Astagneau P, Rioux C, Golliot F, Brucker G. INCISCO Network Study Group: morbidity and mortality associated with surgical site infections: results from the 1997–1999 INCISO surveillance. J Hosp Infect. 2001;48:267–74. 4. Dimick JB, Chen SL, Taheri PA, Henderson WG, Khuri SF, Campbell DA Jr. Hospital costs associated with surgical complications: a report from the private-sector National Surgical Quality Improvement Program. J Am Coll Surg. 2004;199:531–7. 5. Kirkland KB, Briggs JP, Trivette S, Wilkinson WE, Sedon DJ. The impact of surgical-site infection in the 1990s: attribute mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20:725–30. 6. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32:470–85. 7. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial disk susceptibility tests; approved standards, 9th edn. M2-M9. Wayne: Clinical and Laboratory Standards Institute; 2006. 8. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 8th edn. M7-A8. Wayne: Clinical and Laboratory Standards Institute; 2009. 9. Hanaki H, Kubo R, Nakano T, Kurihara M, Sunagawa K. Characterization of HMRZ-86. a novel chromogenic cephalosporin for the detection of extended-spectrum beta-lactamases. J Antimicrob Chemother. 2004;53:888–9. 10. Colodner R, Rezik B, Gal V, Yamazaki H, Hanaki H, Kubo R. Evaluation of a novel kit for the rapid detection of extendedspectrum beta-lactamase. Eur J Clin Microb Infect Dis. 2006;25:49–51. 11. Schnu¨riger B, Inaba K, Eberle BM, Wu T, Talving P, Bukur M, et al. Microbiological profile and antimicrobial susceptibility in surgical site infections following hollow viscus injury. J Gastrointest Surg. 2010;14:1304–10. 12. Brook I. Antimicrobial treatment of anaerobic infections. Expert Opin. 2011;12:1691–707. 13. Goldstein EJ. Intra-abdominal anaerobic infections: bacteriology and therapeutic potential of newer antimicrobial carbapenem, fluoroquinolone, and desfluoroquinolone therapeutic agents. Clin Infect Dis. 2002;35(suppl 1):S106–11. 14. Snydman DR, Jacobus NV, McDermott LA, Golan Y, Hecht DW, Goldstein EJC, et al. Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005–2007). Clin Infect Dis. 2010;50(suppl 1):S26–33. 15. Montravers P, Lepape A, Dubreuil L, Gauzit R, Pean Y, Benchimol D, et al. Clinical and microbiological profiles of community-acquired and nosocomial intra-abdominal infections: results of the French prospective, observational EBIIA study. J Antimicrob Chemother. 2009;63:785–94. 16. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Disease Society of America. Clin Infect Dis. 2010;50:133–64. 17. Nakamura T, Komatsu M, Yamasaki K, Fukuda S, Miyamoto Y, Higuchi T, et al. Epidemiology of Escherichia coli, Klebsiella species, and Proteus mirabilis strains producing extended-spectrum b-lactamases from clinical samples in the Kinki Region of Japan. Am J Clin Pathol. 2012;137:620–6. 18. Takesue Y, Nakajima K, Takahashi Y, Ichiki K, Ishihara M, Wada Y, et al. Clinical characteristics of vancomycin minimum inhibitory concentration of 2 lg/ml methicillin-resistant Staphylococcus aureus strains isolated from patients with bacteremia. J Infect Chemother. 2011;17:52–7.
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SURVEILLANCE
Nationwide surveillance of antimicrobial susceptibility patterns of pathogens isolated from surgical site infections (SSI) in Japan Yoshio Takesue • Akira Watanabe • Hideaki Hanaki • Shinya Kusachi • Tetsuro Matsumoto • Aikichi Iwamoto Kyoichi Totsuka • Keisuke Sunakawa • Morimasa Yagisawa • Junko Sato • Toyoko Oguri • Kunio Nakanishi • Yoshinobu Sumiyama • Yuko Kitagawa • Go Wakabayashi • Isamu Koyama • Katsuhiko Yanaga • Toshiro Konishi • Ryoji Fukushima • Shiko Seki • Shun Imai • Tsunehiro Shintani • Hiroki Tsukada • Kazuhiro Tsukada • Kenji Omura • Hiroshige Mikamo • Hiromitsu Takeyama • Masato Kusunoki • Shoji Kubo • Junzo Shimizu • Toshihiro Hirai • Hiroki Ohge • Akio Kadowaki • Kohji Okamoto • Katsunori Yanagihara
•
Received: 7 August 2012 / Accepted: 14 October 2012 / Published online: 10 November 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract To investigate the trends of antimicrobial resistance in pathogens isolated from surgical site infections (SSI), a Japanese surveillance committee conducted the first nationwide survey. Seven main organisms were collected from SSI at 27 medical centers in 2010 and were shipped to a central laboratory for antimicrobial suscepti-
bility testing. A total of 702 isolates from 586 patients with SSI were included. Staphylococcus aureus (20.4 %) and Enterococcus faecalis (19.5 %) were the most common isolates, followed by Pseudomonas aeruginosa (15.4 %) and Bacteroides fragilis group (15.4 %). Methicillinresistant S. aureus among S. aureus was 72.0 %. Vanco-
Y. Takesue A. Watanabe S. Kusachi T. Matsumoto A. Iwamoto K. Totsuka K. Sunakawa M. Yagisawa J. Sato T. Oguri K. Nakanishi Surveillance Committee of JSC, JAID and JSCM, Tokyo, Japan
I. Koyama Saitama Medical University International Medical Center, Saitama, Japan
Y. Takesue Hyogo College of Medicine Hospital, Hyogo, Japan Y. Takesue (&) Department of Infection Control and Prevention, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan e-mail: [email protected] H. Hanaki Kitasato University Institute, Tokyo, Japan S. Kusachi Toho University Medical Center Ohashi Hospital, Tokyo, Japan Y. Sumiyama Y. Kitagawa Japan Society for Surgical Infection, Tokyo, Japan Y. Sumiyama Toho University, Tokyo, Japan Y. Kitagawa Keio University Hospital, Tokyo, Japan G. Wakabayashi Iwate Medical University Hospital, Iwate, Japan
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K. Yanaga The Jikei University Hospital, Tokyo, Japan T. Konishi NTT Medical Center Tokyo, Tokyo, Japan R. Fukushima Teikyo University Hospital, Tokyo, Japan S. Seki National Hospital Organization Tokyo Medical Center, Tokyo, Japan S. Imai Hiratsuka City Hospital, Kanagawa, Japan T. Shintani Shizuoka Red Cross Hospital, Shizuoka, Japan H. Tsukada Niigata City General Hospital, Niigata, Japan K. Tsukada Toyama University Hospital, Toyama, Japan K. Omura Koseiren Takaoka Hospital, Toyama, Japan
J Infect Chemother (2012) 18:816–826
817
mycin MIC 2 lg/ml strains accounted for 9.7 %. In Escherichia coli, 11 of 95 strains produced extendedspectrum b-lactamase (Klebsiella pneumoniae, 0/53 strains). Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ) and 26.3 % to ciprofloxacin (CPFX). No P. aeruginosa strains produced metallo-b-lactamase. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem, cefepime, and CPFX, and 0 % to gentamicin. In the B. fragilis group, the rates were 28.6 % to clindamycin, 5.7 % to cefmetazole, 2.9 % to TAZ/PIPC and IPM, and 0 % to metronidazole (Bacteroides thetaiotaomicron; 59.1, 36.4, 0, 0, 0 %). MIC90 of P. aeruginosa isolated 15 days or later after surgery rose in TAZ/PIPC, CAZ, IPM, and CPFX. In patients with American Society of Anesthesiologists (ASA) score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than in patients with ASA B2. The data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI. Timing of isolation from surgery and the patient’s physical status affected the selection of resistant organisms.
Introduction
Keywords Surgical site infections Surveillance Antibiotic susceptibility Bacteroides fragilis group
Methods
H. Mikamo Aichi Medical University Hospital, Aichi, Japan H. Takeyama Nagoya City University Hospital, Aichi, Japan M. Kusunoki Mie University Hospital, Mie, Japan S. Kubo Osaka City University Hospital, Osaka, Japan J. Shimizu Toyonaka Municipal Hospital, Osaka, Japan T. Hirai Kawasaki Medical School Hospital, Okayama, Japan H. Ohge Hiroshima University Hospital, Hiroshima, Japan A. Kadowaki Sanin Rosai Hospital, Tottori, Japan K. Okamoto University of Occupational and Environmental Health, Kitakyushu, Japan K. Yanagihara Nagasaki University Hospital, Nagasaki, Japan
Surgical site infections (SSIs) are one of the most important causes of hospital-acquired infections. In a prevalence survey undertaken in 2010 by the Japanese HealthcareAssociated Infections Surveillance [1] (JHAIS), 7.6 % of patients who had undergone surgical procedures developed SSIs. The occurrence of an SSI results in reduced quality of life, increased length of hospital stay, increased likelihood of mortality, and markedly increased costs [2–5]. Appropriate antimicrobial therapy is mandatory not only to improve the prognosis of patients with SSIs but also to minimize the occurrence of antibiotic-resistant organisms. To use antibiotics appropriately, information on the antibiotic susceptibility of the organisms isolated from SSIs is of particular value. The purpose of this study was to investigate the antibiotic susceptibility of the organisms isolated from SSIs by a nationwide survey, and to reserve the data to compare with the subsequent incidence of the isolation of antibiotic-resistant organisms with periodic surveillance.
The Japanese surveillance committee, consisting of the Japanese Society of Chemotherapy, Japanese Association for Infectious Disease, and Japanese Society for Clinical Microbiology, conducted the first nationwide surveillance of antimicrobial susceptibility in organisms isolated from SSI. The study protocol was prepared by the working group and accepted by the governing board of the Japanese surveillance committee. Ethics approval was the responsibility of each study center. All patient data were reported anonymously to the study database. If necessary, investigators asked for formal approval of the protocol by the regional ethics committee. The diagnosis of SSI was made based on definitions stated in the guidelines issued by the National Nosocomial Infections Surveillance [6] (NNIS) system. The criterion for the diagnosis of SSI was an infection that occurred within 30 days after the operation. SSI was defined by any of the following clinical criteria: documentation by an attending trauma surgeon indicating the presence of an SSI, the administration of antibiotics specifically for a surgical site, and the opening or packing of a surgical wound based on its appearance. Site infections were further classified by CDC criteria into superficial incisional, deep incisional, or organ/space SSI. Superficial incisional SSI involved only the skin or subcutaneous tissues, whereas deep incisional SSI involved the deep soft tissues of the incision. Organ/ space infections involved any location beyond the incision that was manipulated during surgery.
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818
Seven principal organisms (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Bacteroides fragilis group, Staphylococcus aureus, Enterococcus faecalis) isolated from SSI were collected in 27 medical centers in Japan between April 2010 and December 2010, and were referred to a central laboratory (Research Center for Anti-infective Drugs of Kitasato Institute) for testing. Shipped strains were kept at -80 °C until antimicrobial susceptibility testing was conducted. Re-identification and cultivation of the strains yielded evaluable strains. All isolates were susceptibility tested by the broth microdilution method as described by the Clinical and Laboratory Standards Institute [7, 8] (CLSI). In daptomycin, a frozen plate prepared by Eiken Chemicals was used. As culture medium, cation-adjusted Mueller–Hinton broth (CAMHB) was used (concentration of calcium was adjusted to 50 mg/l). The accuracy of determination of the minimum inhibitory concentrations (MICs) of antibacterial agents was controlled according to the recommendations of the CLSI. To detect b-lactamase production in gram-negative bacteria, a Nitrocefin disk (Cefinase; BD, Japan) was used according to the reference manual supplied by the manufacturer. The Cica-Beta Test (Kanto Chemical, Tokyo, Japan), a recently developed rapid method, was used to detect extendedspectrum b-lactamase (ESBL) and metallo-b-lactamase (MBL)-producing gram-negative bacteria by directly scraping the colony and applying it on the disk [9, 10]. Thirty-one different antibacterial agents were employed: especially, vancomycin, teicoplanin, linezolid, clindamycin, minocycline, erythromycin, sulfamethoxazole-trimethoprim, arbekacin, and rifampin for methicillin-resistant Staphylococcus aureus (MRSA), ceftazidime cefepime, piperacillin/tazobactam, imipenem, meropenem, doripenem, biapenem, panipenem, aztreonam, ciprofloxacin, levofloxacin, pazufloxacin, and gentamycin for P. aeruginosa, and metronidazole, clindamycin, cefmetazole, flomoxef, ampicillin/sulbactam, piperacillin/tazobactam, and five kinds of carbapenems for B. fragilis group). Because daptomycin was not commercially available at the start of this study, daptomycin was excluded from the initial protocol. Separately, the MIC of daptomycin against MRSA was determined afterward by the central laboratory using the same MRSA isolates. Survey items concerning each patient’s characteristics were as follows: type of surgery, type of SSI (incisional, organ/space), American Society of Anesthesiologists (ASA) physical status classification score, duration of therapeutic antibiotic use, and postoperative hospital stay until organism isolation. Statistical analysis was performed as follows: categorical variables were compared by the v2 test with Yates’ correction or Fisher’s exact test when necessary, using Microsoft Excel 2003.
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J Infect Chemother (2012) 18:816–826
Results A total of 702 isolates (incisional 328, organ/space 374 strains) were included in the investigation. S. aureus (20.4 %) and E. faecalis (19.5 %) were the most common isolates. P. aeruginosa (15.4 %) and B. fragilis group (15.4 %) were next, with E. coli, Enterobacter cloacae, and K. pneumoniae accounting for 13.5, 8.8, and 7.7 % of isolates, respectively. Five organisms were isolated from pediatric patients. Incidences of S. aureus and P. aeruginosa isolated from incisional SSI were significantly higher than those of organ/space SSI. In contrast, the incidence of Enterobacteriaceae isolated from organ/space SSI was significantly higher than from incisional SSI (Table 1). Three hundred thirty-six strains were isolated from lower gastroenterological surgery, 190 strains from hepatobiliary and pancreatic surgery, 73 strains from upper gastroenterological surgery, 68 strains from general surgery including breast surgery, and 30 strains from thoracic surgery (cardiovascular and respiratory tract). As for the duration of antimicrobial prophylaxis, only 18.5 % of patients had their antimicrobial prophylaxis discontinued within 24 h. At 48 h after the end of surgery, 56.2 % of patients were still receiving prophylaxis, and 11.7 % continued to receive prophylaxis for more than 5 days. Leading isolates were S. aureus in upper gastroenterological surgery, general surgery, and thoracic surgery, E. faecalis in hepatobiliary and pancreatic surgery, and B. fragilis group in lower gastroenterological surgery. Antibiotic susceptibility of gram-positive organisms, including methicillin-sensitive S. aureus (MSSA), MRSA, and E. faecalis, gram-negative organisms, including E. coli, K. pneumoniae, E. cloacae, and P. aeruginosa, and B. fragilis group is shown in Table 2. MRSA was 72.0 % among S. aureus. Vancomycin MIC 2 lg/ml strains accounted for 9.7 % (Table 5). In E. coli, 11 of 95 strains Table 1 Isolated organisms according to types of surgical site infection (SSI) Organisms Staphylococcus aureus
Incisional SSI
Organ/space SSI
81 (24.7)
62 (16.6)
MRSA
53 (16.2)
50 (13.4)
MSSA
28 (8.5)
12 (3.2)
P value 0.008
Enterococcus faecalis
55 (16.8)
82 (21.9)
0.085
Enterobacteriaceae
84 (25.6)
122 (32.6)
0.042
Escherichia coli Klebsiella pneumoniae
37 (11.3) 17 (5.2)
58 (15.5) 36 (9.6)
Enterobacter cloacae
30 (9.1)
28 (7.5)
Pseudomonas aeruginosa
63 (19.2)
45 (12.0)
0.009
Bacteroides fragilis group
45 (13.7)
63 (16.8)
0.252
J Infect Chemother (2012) 18:816–826
819
Table 2 Antibiotic susceptibility in methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecalis Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Cefazolin
0.5
0.5
Cefmetazole Cefepime
1 2
1 2
Ampicillin
0.5
8
Range
Susceptible
Intermediate
Resistant
MSSA (40) 0.25–1
100
0
0
1–2 1–4
100 100
0 0
0 0
47.5
–
52.5
0.125–16
Oxacillin
0.25
0.5
0.125–0.5
100
0
0
Ampicillin/sulbactam
0.5
2
0.125–4
100
0
0
Piperacillin/tazobactam
1
2
0.5–2
100
0
0
Imipenem
0.06
0.06
0.06–0.125
100
0
0
Meropenem
0.06
0.125
0.06–0.125
100
0
0
Doripenem
0.06
0.06
0.06–0.06
–
–
–
Biapenem
0.06
0.06
0.06–0.125
–
–
–
Panipenem
0.06
0.06
0.06–0.125
–
–
-
Levofloxacin
0.25
0.5
95
0
5
Gentamycin
0.25
128
0.25–128
75
0
25
Minocycline
0.125
0.125
0.06–0.25
100
0
0
Clindamycin
0.25
0.25
0.25–0.5
100
0
0
Erythromycin MRSA (103)
0.5
0.5
0.5–128
81.6
0
18.4
Vancomycin
1
1
0.5–2
100
0
0
Teicoplanin
1
2
0.25–8
100
0
0
Gentamycin
0.5
64
0.25–256
52.4
0
47.6
Arbekacin
0.5
1
0.25–8
–
–
–
Minocycline
8
16
0.06–32
43.7
10.7
45.6
Clindamycin
128
128
0.25–128
9.3
–
90.7
Erythromycin
128
128
0.25–128
7.8
0
92.2
Linezolid
2
2
1–4
100
0
0
Daptomycin
0.25
0.5
Sulfamethoxazole/trimethoprim
0.063
0.063
Ampicillin
1
2
Piperacillin
4
4
0.125–8
0.25–0.75
100
0
0
0.031–0.125
100
0
0
E. faecalis (137) 0.5–8 2–128
100
0
0
–
–
–
Imipenem
2
2
0.5–16
–
–
–
Levofloxacin Vancomycin
2 1
64 2
1–128 0.5–8
83.9 98.5
2.2 1.5
13.9 0
(11.9 %) produced extended-spectrum b-lactamase (ESBL), and none of the strains produced ESBL in K. pneumoniae. Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ), 20.0 % to sulbactam-ampicillin, 37.9 % to cefazolin, and 26.3 % to ciprofloxacin (CPFX) (Table 3). None of the P. aeruginosa strains produced MBL. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/ piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem (MEPM), cefepime (CFPM), and CPFX, and 0 % to gentamicin (Table 3; Fig. 1). In
B. fragilis, the resistant rate was 28.6 % to clindamycin; however, the incidence remained 5.7 % to cefmetazole. In non-fragilis Bacteroides, including B. thetaiotaomicron, high resistance rates to clindamycin and cefmetazole were noted. Low rates of resistance to TAZ/PIPC, IPM, and metronidazole were observed in both B. fragilis and nonfragilis Bacteroides (Table 4). Antibiotic susceptibility of P. aeruginosa according to the duration of the postoperative hospital stay until isolation was analyzed. When compared with MIC90 of
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820
J Infect Chemother (2012) 18:816–826
Table 3 Antibiotic susceptibility in Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Range
Susceptible
Intermediate
Resistant
Cefazolin
1
C256
0.5 to C256
52.5
9.5
37.9
Cefmetazole
0.5
16
0.25 to 128
92.6
2.1
5.3
Escherichia coli (95)
Ceftazidime
0.125
8
B0.06 to 128
89.5
2.1
8.4
Cefepime
B0.06
4
B0.06 to 64
96.8
2.1
1.1
Ampicillin/sulbactam
4
32
1 to C256
56.8
23.2
20
Piperacillin/tazobactam Imipenem
1 0.25
4 0.5
0.5 to C256 B0.06 to 1
95.8 100
2.1 0
2.1 0
Meropenem
B0.06
B0.06
B0.06 to B0.06
100
0
0
Doripenem
B0.06
B0.06
B0.06 to B0.06
–
–
–
Biapenem
B0.06
B0.06
B0.06 to 0.125
–
–
–
Panipenem
0.125
0.25
B0.06 to 0.5
–
–
–
Aztreonam
B0.06
8
B0.06 to 64
87.4
6.3
6.3
Ciprofloxacin
B0.06
32
B0.06 to 128
73.7
0
26.3
Levofloxacin
0.125
16
B0.06 to 32
73.7
1
25.3
Pazufloxacin
B0.06
8
B0.06 to 16
–
–
–
Gentamycin
0.5
2
0.25 to 128
90.5
0
9.5
Cefazolin
1
2
1 to C256
81.1
9.4
9.4
Cefmetazole
0.5
4
0.5 to C256
94.3
0
5.7
Ceftazidime
0.125
0.5
B0.06 to 32
98.1
0
1.9
Cefepime Ampicillin/sulbactam
B0.06 4
0.125 16
B0.06 to 2 2 to 64
100 88.7
0 5.7
0 5.7
Piperacillin/tazobactam
2
8
0.5 to 32
96.2
3.8
0
K. pnemoniae (53)
Imipenem
0.25
1
0.125 to 2
100
0
0
Meropenem
B0.06
B0.06
B0.06 to 1
100
0
0
Doripenem
B0.06
0.125
B0.06 to 1
–
–
–
Biapenem
0.125
0.5
B0.06 to 1
–
–
–
Panipenem
0.25
0.5
B0.06 to 2
–
–
–
Aztreonam
B0.06
0.25
B0.06 to 2
100
0
0
Ciprofloxacin
B0.06
0.25
B0.06 to 1
100
0
0
Levofloxacin
0.125
1
B0.06 to 2
100
0
0
Pazufloxacin
B0.06
0.25
B0.06 to 1
–
–
–
Gentamycin
0.25
0.5
0.125 to 1
100
0
0
E. cloacae (58) Cefmetazole
C256
C256
64 to C256
0
0
100
Ceftazidime
0.5
64
B0.06 to 128
74.1
1.8
24.1
Cefepime Ampicillin/sulbactam
B0.06 32
1 64
B0.06 to 8 4 to 128
100 3.4
0 17.3
0 79.3
Piperacillin/tazobactam
2
64
0.5 to C256
81
13.8
5.2
Imipenem
1
2
0.25 to 2
100
0
0
Meropenem
B0.06
0.125
B0.06 to 2
100
0
0
Doripenem
B0.06
0.125
B0.06 to 1
–
–
–
Biapenem
0.125
0.25
B0.06 to 0.5
–
–
–
Panipenem
0.5
1
0.25 to 4
–
–
–
Aztreonam
0.25
32
B0.06 to 64
77.6
1.7
20.7
Ciprofloxacin
B0.06
2
B0.06 to 32
89.7
1.7
8.6
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J Infect Chemother (2012) 18:816–826
821
Table 3 continued Organism (number tested) and antimicrobial agent
MIC (lg/ml) MIC50
% MIC90
Range
Susceptible
Intermediate
Resistant
Levofloxacin
0.125
2
B0.06 to 16
93.1
5.2
1.7
Pazufloxacin
B0.06
1
B0.06 to 16
–
–
–
Gentamycin
0.25
0.5
0.25 to 4
100
0
0 6.5
P. aeruginosa (108) Ceftazidime
2
16
0.5 to 64
89.8
3.7
Cefepime
2
8
0.25 to 32
91.7
5.5
2.8
Piperacillin/tazobactam
4
64
0.25 to C256
92.6
–
7.4
Imipenem
2
16
0.25 to 16
88
1.8
10.2
Meropenem Doripenem
0.25 0.25
4 4
B0.06 to 16 B0.06 to 16
93.5 –
3.7 –
2.8 –
Biapenem
0.5
8
0.125 to 32
–
–
–
Panipenem
8
16
0.25 to 64
–
–
–
Aztreonam
4
16
0.5 to 64
66.7
19.4
13.9
Ciprofloxacin
0.25
0.5
B0.06 to 128
95.4
1.8
2.8
Levofloxacin
1
2
0.125 to 128
91.7
5.5
2.8
Pazufloxacin
0.5
1
B0.06 to 32
–
–
–
Gentamycin
2
2
0.5 to 4
100
0
0
Fig. 1 Antibiotic resistance rate of Pseudomonas aeruginosa for each antibiotic
P. aeruginosa isolated within 7 days after surgery, that of P. aeruginosa isolated 15 days or later after surgery rose by eightfold in TAZ/PIPC and CAZ, by fourfold in IPM and MEPM, and by twofold in CPFX, GM, and CFPM (Fig. 2). In addition, the changes of antibiotic susceptibility according to the duration of therapeutic antibiotic use were evaluated. When compared with MIC90 of P. aeruginosa isolated within 2 days of therapeutic antibiotic use, that of P. aeruginosa with 8 days or more therapeutic antibiotic use revealed a similar tendency of the alteration of antibiotic susceptibility, which was observed in the analysis according to the duration of postoperative hospital stay until isolation (Fig. 3). Antibiotic susceptibility was also
analyzed from the patient’s physical status classification. In patients with ASA score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than those in patients with ASA B2 (Fig. 4).
Discussion In a prevalence survey by the JHAIS, the main organisms isolated from SSI were 2,182 strains (14.3 %) of Enterococcus faecalis, 2,167 strains (14.2 %) of Staphylococcus aureus (MRSA, 1351 strains), 1,557 strains (10.2 %) of Pseudomonas aeruginosa, 1,140 strains (7.5 %) of
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822
J Infect Chemother (2012) 18:816–826
Table 4 Antibiotic susceptibility in Bacteroides fragilis group Organism (number tested) and antimicrobial agent
MIC (lg/ml)
%
MIC50
MIC90
Range
Susceptible
Intermediate
Resistant
Cefmetazole
8
32
4–128
Flomoxef
1
64
0.25–256
82.9
11.4
5.7
–
–
–
Ampicillin/sulbactam
1
8
Piperacillin/tazobactam
0.25
2
0.5–256
90
5.7
4.3
0.06–256
95.7
1.4
Imipenem
0.25
2.9
2
0.125–128
95.7
1.4
Meropenem Doripenem
2.9
0.125 0.25
4 2
0.06–256 0.125–128
97.1 –
0 –
2.9 –
Biapenem
0.25
1
0.125–256
–
–
–
Panipenem
0.25
2
0.06–256
–
–
–
Clindamycin
0.5
256
0.06–256
70
1.4
28.6
Metronidazole
1
2
0.25–4
100
0
0 36.4
B. fragilis (70)
B. thetaiotaomicron (22) Cefmetazole
32
64
16–64
4.5
59.1
Flomoxef
16
256
4–256
–
–
–
Ampicillin/sulbactam
1
4
1–4
100
0
0
Piperacillin/tazobactam
8
16
1–16
100
0
0
Imipenem
0.5
1
0.25–2
100
0
0
Meropenem
0.25
0.5
0.125–1
100
0
0
Doripenem
0.5
1
0.25–1
–
–
–
Biapenem
0.25
1
0.25–1
–
–
–
Panipenem Clindamycin
0.5 256
2 256
0.25–2 0.5–256
– 31.8
– 9.1
– 59.1
Metronidazole
1
1
0.125–2
100
–
– 20
Other Bacteroides sp. (10) Cefmetazole
16
64
8–128
50
30
Flomoxef
8
256
0.5–256
–
–
–
Ampicillin/sulbactam
4
32
0.5–32
80
0
20
Piperacillin/tazobactam
2
4
0.5–4
100
0
0
Imipenem
1
2
0.25–8
90
10
0
Meropenem
0.25
2
0.125–4
100
0
0
Doripenem
0.5
2
0.125–8
–
–
–
Biapenem
0.5
1
0.25–1
–
–
–
Panipenem
1
4
0.5–4
–
–
–
Clindamycin
2
256
0.25–256
50
10
40
Metronidazole
1
2
0.06–1
100
0
0
Escherichia coli, 911 strains (6.0 %) of Enterobacter cloacae, 610 strains (4.0 %) of Staphylococcus epidermidis, 504 strains (3.3 %) of Bacteriodes fragilis group, and 446 strains (2.9 %) of Klebsiella pneumoniae [1]. We found only a few reports concerning the antimicrobial susceptibility of organisms isolated from SSI and, as far as we know, this is the largest survey. Schnu¨riger et al. [11] studied the microbiological profile and antimicrobial susceptibility in SSIs following hollow viscus injury. Susceptibility rates of E. coli and E. cloacae, respectively,
123
were 38 and 8 % for ampicillin/sulbactam, 82 and 4 % for cefazolin, 96 and 92 % for cefoxitin, with both 92 % for PIPC/TAZ and 100 % for ertapenem. The members of the B. fragilis group are the most important anaerobic pathogens recovered from intraabdominal infections. Among the B. fragilis group isolates, B. fragilis accounts for 40–54 % of the Bacteroides isolates. Another important pathogen that belongs to the B. fragilis group isolates is B. thetaiotaomicron, which accounts for 13–23 % of the isolates. Other members of the
J Infect Chemother (2012) 18:816–826 Table 5 Distribution of minimum inhibitory concentrations (MIC) against anti-MRSA drugs in MRSA
Antimicrobial agents
823
% of organisms in each minimum inhibitory concentration 0.25 lg/ml
Vancomycin
0.5 lg/ml
1 lg/ml
2 lg/ml
4 lg/ml
8 lg/ml
1.9
88.3
9.8
Teicoplanin
2.9
42.7
37.9
14.6
2.0
Arbekacin
5.8
55.3
34.0
3.9
1.0
24.3
71.8
Linezolid Daptomycin
54.3
41.7
3.9
3.9
Fig. 2 MIC90 against Pseudomonas aeruginosa for each antibiotic according to the duration of postoperative hospital stay until isolation. MIC90 minimum inhibitory concentration required to inhibit the growth of 90 % of organisms
Fig. 3 MIC90 against Pseudomonas aeruginosa for each antibiotic according to the duration of therapeutic antibiotic use until isolation. MIC90 minimum inhibitory concentration required to inhibit the growth of 90 % of organisms
123
824
J Infect Chemother (2012) 18:816–826
Fig. 4 Antibiotic resistance rate in Pseudomonas aeruginosa according to the American Society of Anesthesiologists (ASA) physical status classification score
B. fragilis group isolates account for 33–39 % [12, 13]. B. fragilis is generally the most susceptible, and B. thetaiotaomicron is generally the most resistant [14]. Marked increases in the resistance of the B. fragilis group relative to 20 years ago were observed for clindamycin [12]. Among second-generation cephalosporins, cefoxitin is the most effective against the B. fragilis group. Cefotetan and cefmetazole were equally effective to cefoxitin against B. fragilis but are inferior against other members of the B. fragilis group isolates [12–14]. In our study, a similar pattern was confirmed in the SSI isolates. Carbapenems, TAZ/PIPC, and metronidazole possess excellent activity against B. fragilis group. Compared with the organisms isolated from community-acquired intraabdominal infections, the antibiotic resistance rate of cefoxitine and clindamycin tended to be higher in isolates from nosocomial intraabdominal infections [15]. In the guideline for the diagnosis and management of complicated intraabdominal infection by the Infectious Diseases Society of America [16], ampicillin-sulbactam is not recommended because of high rates of resistance to this agent among E. coli, and quinolones should not be used unless surveys indicate [90 % susceptibility of E. coli. In our study, resistant E. coli strains were 20.0 % to sulbactam-ampicillin and 26.3 % to CPFX, and these antibiotics seem not to be recommended for the treatment of postoperative intraabdominal infections. Longer duration of antimicrobial prophylaxis may cause a high resistance rate of E. coli (37.9 %) isolated from SSI to cefazolin. At 48 h after the end of surgery, 56.2 % of patients were still receiving prophylaxis. Recently, ESBL-producing strains have become prevalent in the community setting in Japan [17]. In this survey, 11 of 95 E. coli strains (11.9 %) isolated from SSI produced ESBL, but none of the strains produced ESBL in K. pneumoniae. The low success rate of
123
vancomycin, and the poor prognosis of patients with MRSA bacteremia, were demonstrated in vancomycin MIC 2 lg/ml strains [18]. In this study, 2 lg/ml strains accounted for 9.7 %. Alternative therapy should be considered in the treatment of SSI if the vancomycin MIC is 2 lg/ml in MRSA. In P. aeruginosa isolates from SSI, antibiotic susceptibility tended to be superior to those from hospital-acquired respiratory infections [19] and urinary tract infections [20]. Susceptibility of P. aeruginosa isolates from hospitalacquired pneumonia and ventilator-associated pneumonia by the SENTRY antimicrobial surveillance study were 72 %/66 % for gentamicin, 60 %/58 % for levofloxacin, 70 %/65 % for cefepime, 72 %/66 % for meropenem, and 76 %/71 % for piperacillin/tazobactam, respectively[18]. Mathai et al. [19] reported that P. aeruginosa causing urinary tract infections in hospitalized patients was most susceptible to amikacin (97.3 %) [ piperacillin ± tazobactam (92.0–95.6 %) [ cefepime = imipenem (91.2 %) [ ceftazidime (85.8 %). Greatest resistance was observed to fluoroquinolone (24.8–39.8 %). Acquisition of intrinsically resistant organisms and selective pressure for resistance within a unit or hospital are of increasing concern. Unnecessarily prolonged antibiotic use and needlessly broad coverage cause resistant organisms. Mentzelopoulos et al. [21] reported that the sole independent predictor of pandrug-resistant P. aeruginosa ventilator-associated pneumonia (VAP) was the combined use of carbapenem for more than 20 days and colistin use for more than 13 days. Kusachi et al. [22] reported that the incidence of strains resistant to cephems and carbapenems increased as the number of different antimicrobial agents used for the treatment of SSI increased. In general, antimicrobial therapy of established intraabdominal infection should be limited to 4–7 days, unless it is difficult to
J Infect Chemother (2012) 18:816–826
achieve adequate source control [15]. A common practice in the treatment of incisional SSI is to open all infected wounds. If there is minimal surrounding evidence of invasive infection and systemic signs of infection, antibiotics are unnecessary. In cases indicated for antimicrobial therapy, a duration of 24–48 h may be indicated [23]. In our study, isolation of MRSA (p \ 0.001) and P. aeruginosa (p = 0.081) increased 8 days or later after surgery. Antibiotic susceptibility of P. aeruginosa isolated 15 days or later after surgery decreased in TAZ/PIPC, CAZ, IPM, and CPFX. MIC90 of P. aeruginosa with 8 days or more therapeutic antibiotic use revealed a similar tendency when compared with a shorter duration until isolation. In addition, the patient’s preoperative status affected the antibiotic susceptibility of organisms isolated from SSI. In patients with ASA score C3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than those in patients with ASA B2. A history of previous hospitalization for reasons of comorbidity or the necessity of prolonged antibiotic therapy in a compromised host with comorbidity may cause lower antibiotic susceptibility of isolates from SSI. In conclusion, the data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI, and the need for continuous monitoring was confirmed. Conflict of interest Yoshio Takesue has received a speaker’s honorarium from Taisho Toyama Pharm. Co., Ltd, MSD Japan, Astellas Pharma Inc. and Pfizer Japan Inc. Akira Watanabe is a consultant to Daiichi-Sankyo Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Toyama Chemical Co., Ltd, and Otsuka Pharmaceutical Co., Ltd. A.W. has received a speaker’s honorarium from MSD Japan, Glaxo SmithKline K.K., Shionogi & Co. Ltd., Daiichi-Sankyo Co., Ltd, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma Co., Ltd, and Pfizer Japan Inc. and grant support from Astellas Pharma Inc., Kyorin Pharmaceutical Co., Ltd, Shionogi & Co. Ltd., Taisho Pharmaceutical Co., Ltd, Toyama Chemical Co., Ltd, Daiichi Sankyo Co., Ltd, Dainippon Sumitomo Pharma Co., Ltd, Taiho Pharma Co., Ltd, and Meiji Seika Pharma Co., Ltd. Shinya Kusachi has received a speaker’s honorarium from Shionogi & Co., Ltd, MSD Japan, and Taisho Toyama Pharmaceutical Co., Ltd. Keisuke Sunakawa received a research grant from Meiji Seika Pharma Co., Ltd. and Taisho Toyama Pharmaceutical Co., Ltd. Yuko Kitagawa has received a speaker’s honorarium from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Shionogi & Co., Ltd, Coviden Japan Co., Ltd, and Ethicon Endo-Surgery, LLC. Y.K received a research grant from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Yakult Honsha Co., Ltd.
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