Ciprofloxacin treatment for cryptogenic Klebsiella pneumoniae liver abscesses

Accepted Manuscript Title: Ciprofloxacin treatment for cryptogenic Klebsiella pneumoniae liver abscesses Author: Se Yoon Park, Taeeum Kim, Min-Chul Kim, Heungsup Sung, Mi-Na Kim, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Jun Hee Woo, Yang Soo Kim, Yong Pil Chong PII: DOI: Reference:

S0163-4453(17)30317-1 https://doi.org/doi:10.1016/j.jinf.2017.10.004 YJINF 3999

To appear in:

Journal of Infection

Accepted date:

10-10-2017

Please cite this article as: Se Yoon Park, Taeeum Kim, Min-Chul Kim, Heungsup Sung, Mi-Na Kim, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Jun Hee Woo, Yang Soo Kim, Yong Pil Chong, Ciprofloxacin treatment for cryptogenic Klebsiella pneumoniae liver abscesses, Journal of Infection (2017), https://doi.org/doi:10.1016/j.jinf.2017.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Ciprofloxacin treatment for cryptogenic Klebsiella pneumoniae liver abscesses

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Se Yoon Park1,3, Taeeum Kim1, Min-Chul Kim1, Heungsup Sung2, Mi-Na Kim2, Sung-Han

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Kim1, Sang-Oh Lee1, Sang-Ho Choi1, Jun Hee Woo1, Yang Soo Kim1, and Yong Pil

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Chong1*

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Medicine, Seoul, Republic of Korea;

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Departments of Infectious Diseases, Asan Medical Center, University of Ulsan College of

Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine,

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Seoul, Republic of Korea;

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University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea

Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang

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*

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Yong Pil Chong, Department of Infectious Diseases, Asan Medical Centere, University of

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Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul, 138-736, Republic

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of Korea. E-mail: [email protected]

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Tel: 82-2-3010-3306, Fax: 82-2-3010-6970

Correspondence

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Running Title: Ciprofloxacin for Klebsiella liver abscess

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1 Page 1 of 15

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Words count of text: 993

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Number of Tables: 2

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Number of Figures: 0

(Number of Supplemental Tables: 1)

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Keywords. Klebsiella pneumoniae; Cryptogenic; Liver abscess; Ciprofloxacin; Treatment

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outcome.

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Highlights ·

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problem spreading globally. ·

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Treatment success rate of ciprofloxacin-based therapy was 91% (93/102) and infection-related mortality was 2% (2/102).

·

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Community-acquired cryptogenic K. pneumoniae liver abscess is an emerging

Anti-anaerobic coverage does not seem to be mandatory for treating cryptogenic K. pneumoniae liver abscess.

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Ciprofloxacin monotherapy can be an effective treatment option for K.

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pneumoniae liver abscess in non-critically ill patients to decrease the duration of

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intravenous therapy and hospital stay by changing to an oral formulation.

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We read with great interest the article: "First case of bacteremic liver abscess caused by an

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ST260-related (ST1861), hypervirulent Klebsiella pneumoniae".1 Pyogenic liver abscess

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caused by K. pneumoniae has been increasingly reported in Asian countries, especially in

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Taiwan and South Korea, over the past 30 years.2 Considering that K. pneumoniae strains

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isolated from liver abscesses are generally susceptible to fluoroquinolones,3-5 these drugs can

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be used as an effective alternative to cephalosporins, especially because they have a high oral

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bioavailability. However, there are few data on the clinical outcome of fluoroquinolone

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treatment for K. pneumoniae liver abscess.6

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A retrospective study was conducted at the Asan Medical Center, a 2700-bed, tertiary

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referral center in Seoul, Korea, where ciprofloxacin was a preferred empirical antibiotic for

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community-acquired liver abscess. All cases of cryptogenic K. pneumoniae liver abscess

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from 2004 to 2009 (n = 112) were included in our study. Our aim was to evaluate the

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outcome of ciprofloxacin treatment and to compare additional anti-anaerobic coverage and

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non-coverage in cryptogenic K. pneumoniae liver abscess. Cryptogenic liver abscess was

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defined as liver abscess not caused by biliary disease (cholangitis, biliary stone disease, and

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obstructing tumor), intraabdominal infection, or any hepatic penetrating trauma. K.

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pneumoniae liver abscess was diagnosed on the basis of clinical manifestations and

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microbiological evidence; clinical symptoms such as fever and abdominal pain; evidence

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from imaging studies; pus from liver aspirates with K. pneumoniae isolated or positive blood

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culture result(s) for K. pneumoniae. Polymicrobial liver abscess was excluded in the analysis.

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The study was approved by the Institutional Review Board and Ethics Committee. Informed

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consent was not obtained from study patients owing to the retrospective nature of the study.

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Of the 112 patients with cryptogenic K. pneumoniae liver abscess, 102 (91%) were treated

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with ciprofloxacin alone (n = 41) or ciprofloxacin + metronidazole (n = 61), and 10 were

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treated with β-lactam-based regimens. All 112 patients acquired the K. pneumoniae infection

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in the community, and all K. pneumoniae isolates were susceptible to ciprofloxacin. A

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serologic test for amoebic infection was performed in most patients (70%) to exclude

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amoebic liver abscess, although amoebic liver abscess is very rare, except in HIV-infected

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patients, in the Republic of Korea.7 The median age was 62 years (interquartile range [IQR],

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52-71 years) and 69% were male. Most patients had no underlying disease, but if they had,

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diabetes mellitus was most common (30%). Most patients (77%) underwent therapeutic

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intervention such as pigtail catheter drainage. Nineteen patients (17%) had a metastatic

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infection of which 18 (95%) were an early metastatic infection (≤3 days of admission). Late

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metastatic infection occurred in two patients with ciprofloxacin-based therapy. The most

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common metastatic lesion was in the lung (11%) followed by the eye (5%), and

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musculoskeletal system (3%). When the baseline characteristics were compared between the

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ciprofloxacin group and the ciprofloxacin + metronidazole group, there were no significant

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differences in demographic characteristics, underlying diseases, severity of infection, and

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radiological findings (Table 1). Patients treated with β-lactam antibiotics were more severely

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ill than patients treated with ciprofloxacin-based therapy.

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Treatment success was defined as having none of the followings: change of antibiotic or

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surgery because of a lack of antibiotic effect, reuse of antibiotics after treatment completion,

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recurrence within 6 months, and infection-related mortality. The treatment success of 112

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patients with cryptogenic K. pneumoniae liver abscess was 90%. The treatment success rate

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of the ciprofloxacin-based regimen was 91% (93/102) and infection-related mortality was 2%

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(2/102) (Table 2). In patients receiving ciprofloxacin-based therapy, the median duration of

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intravenous antibiotic therapy was 17 days (IQR 12-25 days) and the median hospital stay

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was 18 days (IQR 14-26 days). In previous studies, most K. pneumoniae liver abscesses were

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treated with β-lactam antibiotics such as cephalosporins with/without metronidazole or

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aminoglycosides.3, 5, 8-10 Although there is a substantial limitation in comparing across studies

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due to limited data on disease severity, the clinical severity determined by the APACHE II

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score and proportion of septic shock or metastatic infections of our patients treated with

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ciprofloxacin were comparable to those in previous studies of β-lactam therapy, and the

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treatment outcome of ciprofloxacin-based therapy was also comparable (2% versus 1.5%–10%

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mortality in previous studies) (Supplement Table 1).3, 5, 8-11 Prolonged intravenous antibiotic

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therapy may increase the hospital stay, resulting in the increase of economic burden and

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hospital-acquired infections such as Clostridium difficile infection. Because ciprofloxacin and

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metronidazole have a high oral bioavailability, ciprofloxacin-based therapy could be useful to

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decrease the duration of intravenous therapy, costs, and length of hospital stay by changing to

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oral formulations. Duration of intravenous therapy and hospital stay in our study patients

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receiving ciprofloxacin-based therapy were relatively shorter than those of previous studies

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(Supplement Table 1).3-5,8-11 These findings support the recommendation of the guidelines for

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implementing an antibiotic stewardship program that the timely switch from intravenous to

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oral antibiotics should be encouraged.12

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Treatment outcomes were similar between the ciprofloxacin group and the ciprofloxacin +

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metronidazole group. Therefore, it seems that the anti-anaerobic coverage is not necessary in

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the treatment of cryptogenic K. pneumoniae liver abscess. Although patients treated with β-

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lactam antibiotics were more severely ill, treatment failure was not significantly more

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frequent than those treated with ciprofloxacin-base therapy. Adverse events of ciprofloxacin

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were gastrointestinal discomfort (2.9% [3/102]), pruritus (1% [1/102]), and rash (1% [1/102]).

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Two patients discontinued ciprofloxacin therapy; one was because of nausea and vomiting

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(ciprofloxacin for 13 days) and the other was because of pruritus (ciprofloxacin for 26 days).

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In conclusion, ciprofloxacin monotherapy can be an effective treatment option for K.

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pneumoniae liver abscess in non-critically ill patients, along with a possible reduction in the

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duration of intravenous antibiotic use and hospitalization by the early switch from

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intravenous to oral ciprofloxacin. In critically ill patients, initial cephalosporin therapy

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followed by ciprofloxacin therapy after stabilization of clinical condition can be a good

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treatment option. A prospective, randomized controlled trial is warranted to confirm our

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observations. It seems that anti-anaerobic coverage is not mandatory in the treatment of

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cryptogenic K. pneumoniae liver abscess.

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Funding

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This work was supported by a grant from the Korea Healthcare Technology R&D Project,

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Ministry for Health and Welfare, Republic of Korea (grant number: HI17C2052).

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Conflict of interest

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None declared.

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Acknowledgements

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We sincerely thank Mi Young Kim and Kyung-Mi Bang for support with data collection.

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References

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1. Arena F, Spanu T, Henrici De Angelis L, Liotti FM, D'Andrea MM, Menchinelli G, et al.

138

First case of bacteremic liver abscess caused by an ST260-related (ST1861), hypervirulent

139

Klebsiella pneumoniae. J Infect. 2016;73(1):88-91.

140

http://dx.doi.org/10.1016/j.jinf.2016.04.006

141

2. Siu LK, Yeh KM, Lin JC, Fung CP, Chang FY. Klebsiella pneumoniae liver abscess: a new

142

invasive syndrome. Lancet Infect Dis. 2012;12(11):881-7.

143

http://dx.doi.org/10.1016/S1473-3099(12)70205-0

144

3. Chung DR, Lee SS, Lee HR, Kim HB, Choi HJ, Eom JS, et al. Emerging invasive liver

145

abscess caused by K1 serotype Klebsiella pneumoniae in Korea. J Infect. 2007;54(6):578-

146

83. http://dx.doi.org/10.1016/j.jinf.2006.11.008

147

4. Yoon JH, Kim YJ, Jun YH, Kim SI, Kang JY, Suk KT, et al. Liver abscess due to

148

Klebsiella pneumoniae: risk factors for metastatic infection. Scand J Infect Dis.

149

2014;46(1):21-6. http://dx.doi.org/10.3109/00365548.2013.851414

150

5. Kim HA, Chung DR, Yeom JS, Ki HK, Cheong HS, Son JS, et al. Anti-anaerobic coverage

151

is not necessary for Klebsiella pneumoniae liver abscess: a propensity score-matched

152

cohort study. Diagn Microbiol Infect Dis. 2015;81(1):60-5.

153

http://dx.doi.org/10.1016/j.diagmicrobio.2014.10.002

154

6. Chen YW, Chen YS, Lee SS, Yen MY, Wann SR, Lin HH, et al. A pilot study of oral

155

fleroxacin once daily compared with conventional therapy in patients with pyogenic liver

156

abscess. J Microbiol Immunol Infect. 2002;35(3):179-83.

157 158 159

7. Park WB, Choe PG, Jo JH, Kim SH, Bang JH, Kim HB, et al. Amebic liver abscess in HIV-infected patients, Republic of Korea. Emerg Infect Dis. 2007;13(3):516-7. 8. Lee SS, Chen YS, Tsai HC, Wann SR, Lin HH, Huang CK, et al. Predictors of septic

8

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160

metastatic infection and mortality among patients with Klebsiella pneumoniae liver

161

abscess. Clin Infect Dis. 2008;47(5):642-50. http://dx.doi.org/10.1086/590932

162

9. Chan DS, Archuleta S, Llorin RM, Lye DC, Fisher D. Standardized outpatient management

163

of Klebsiella pneumoniae liver abscesses. Int J Infect Dis. 2013;17(3):e185-8.

164

http://dx.doi.org/10.1016/j.ijid.2012.10.002

165

10. Cheng HP, Siu LK, Chang FY. Extended-spectrum cephalosporin compared to cefazolin

166

for treatment of Klebsiella pneumoniae-caused liver abscess. Antimicrob Agents

167

Chemother. 2003;47(7):2088-92.

168 169 170

11. Shen DX, Wang J, Li DD. Klebsiella pneumoniae liver abscesses. Lancet Infect Dis. 2013;13(5):390-1. http://dx.doi.org/10.1016/S1473-3099(13)70068-9. 12. Barlam TF, Cosqrove SE, Abbo LM, MacDouqall C, Schuetz AN, Septimus EJ, et al.

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Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases

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Society of America and the Society for Healthcare Epidemiology of America. Clin Infect

173

Dis. 2016;62(10):e51-77.

174 175

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Table 1. Baseline and clinical characteristics of patients with cryptogenic Klebsiella pneumoniae liver abscess

Characteristic

Ciprofloxacin (n = 41)

Ciprofloxacin + Ciprofloxacinmetronidazole (n = based therapy (n 61)a =102)

Age, median (IQR)

59 (48–70)

60 (52–69)

61 (50–70)

Male gender

32 (78)

39 (63.9)

71 (69.6)

1 (2.4)

2 (3.3)

0 (0–1)

β-lactam-based therapy (n = 10)b

P valuec

67 (62–72)

.96

6 (60)

.13

3 (2.7)

0

.81

0 (0–1)

0 (0–1)

1 (0–1)

.65

14 (34.1)

17 (27.9)

31 (30.4)

4 (40)

.28

Pitt bacteremia score, median (IQR)

0 (0–1)

0 (0–1)

0 (0–2)

1 (0–3)

.22

APACHE II score, median (IQR)

8 (4–14)

9 (6–12)

9 (6–12)

12 (7–14)

.11

ICU care

4 (9.8)

9 (14.8)

13 (12.7)

7 (70)

.46

Fever

38 (92.7)

55 (90.2)

93 (91.2)

6 (60)

.66

Abdominal pain

26 (63.4)

38 (62.3)

64 (62.7)

8 (80)

.91

McCabe and Jackson criteria Ultimately or rapidly fatal Charlson comorbidity index, median (IQR) Severe sepsis or septic shock

Clinical presentation

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RUQ tenderness

28 (68.3)

42 (68.9)

70 (68.6)

10 (100)

.95

4 (9.8)

6 (9.8)

10 (9.8)

4 (40)

.99

20 (48.8)

28 (45.9)

48 (47.1)

4 (40)

.78

8 (19.5)

9 (14.8)

17 (16.7)

4 (40)

.53

5.8 ± 2.6

6.7 ± 2.7

6.3 ± 2.7

7.2 ± 2.3

.73

4 (9.8)

10 (16.4)

14 (13.7)

5 (50)

.34

Lung

2 (4.9)

6 (9.8)

8 (7.8)

4 (40)

.36

Eye

2 (4.9)

2 (3.3)

4 (3.9)

1 (10)

.68

Central nervous system

0

0

0

1 (10)

NA

Musculoskeletal systemd

0

3 (4.9)

3 (2.9)

0

.24

Otherse

1 (2.4)

1 (1.6)

2 (2.0)

0

.53

7 (17.1)

15 (24.6)

22 (21.6)

6 (60)

.67

Acute kidney injury

5 (12.2)

9 (14.8)

14 (13.7)

2 (20)

.71

Septic shock

6 (14.6)

10 (16.4)

16 (15.7)

6 (60)

.81

ARDS

0

1 (1.6)

1 (1.0)

0

.41

Altered mental status Bacteremia Radiologic findings Multiple abscesses Size of abscess (cm), mean ± SD Metastatic infection

Severe complications

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Data are presented as number of patients (%), unless otherwise specified. 11

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IQR, interquartile range; APACHE, Acute Physiologic and Chronic Health Evaluation; ICU, intensive care unit; RUQ, right upper quadrant;

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SD, standard deviation; ARDS, acute respiratory distress syndrome; NA, not applicable.

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a

Patients who received metronidazole for >7 days were classified as the ciprofloxacin + metronidazole group.

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b

Cefotaxime (or ceftriaxone) + metronidazole (n = 8), cefotaxime (n = 1), and carbapenem (n = 1).

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c

P value for comparison between the ciprofloxacin group and the ciprofloxacin + metronidazole group.

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d

Thigh pyomyositis (n = 1), psoas muscle abscess with vertebral osteomyelitis (n = 1), and buttock abscess (n = 1).

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e

Renal abscess (n = 1) and prostate abscess (n = 1).

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Table 2. Treatment and outcomes of patients with cryptogenic Klebsiella pneumoniae liver abscess

Treatment/Outcome

Ciprofloxacin (n = 41)

Ciprofloxacin + metronidazole (n = 61)a

Ciprofloxacinbased therapy (n =102)

β-lactam-based therapy (n = 10)b

P valuec

Intervention Therapeutic intervention

30 (73.2)

48 (78.7)

78 (76.5)

8 (80)

.52

Diagnostic interventiond

6 (14.6)

6 (9.8)

12 (11.8)

1 (10)

.46

Pigtail catheter drainage

32 (78.0)

47 (77.0)

79 (77.5)

6 (60)

.79

6 (14.6)

14 (23.0)

20 (19.6)

2 (20)

.30

Aspiration Duration of antibiotics (days), median (IQR) Total duration of antibiotic use

47 (39–59)

46 (37–56)

47 (38–56)

58 (47–111)

.66

Total duration of intravenous antibiotic use

16 (13–24)

18 (12–25)

17 (12–25)

34 (16–40)

.73

27 (17-43)

12 (5-29)

10 (7-27)

ND

17 (13–24)

18 (14–26)

18 (14–26)

37 (18–44)

.70

4 (3–6)

4 (2–6)

4 (3–6)

3 (2–7)

.79

37 (90.2)

56 (91.8)

93 (91.2)

7 (70)

.79

Duration of metronidazole therapy Hospital stay (days), median (IQR) Time to defeverence (days), median (IQR)

4 (3-6)

Clinical outcome Treatment success

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Treatment failure

4 (9.8)

5 (8.2)

9 (8.8)

3 (30)

.79

Change of antibioticse

0

4 (6.6)

4 (3.9)

0

.09

Reuse of antibiotics after completion of

3 (7.3)

0

3 (2.9)

0

.04

Surgical operation

1 (2.4)

2 (3.3)

3 (2.9)

2 (20)

.81

Recurrence

1 (2.4)

0

1 (1.0)

1 (10)

.09

Infection-related mortality

0

2 (3.3)

2 (2.0)

0

.24

In-hospital mortality

0

2 (3.3)

2 (2.0)

0

.24

3-month mortality

0

2 (3.3)

2 (2.0)

0

.24

therapy

187

Data are presented as number of patients (%), unless otherwise specified.

188

IQR, interquartile range; ND, not determined.

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a

Patients who received metronidazole for >7 days were classified as the ciprofloxacin + metronidazole group.

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b

Cefotaxime (or ceftriaxone) + metronidazole (n = 8), cefotaxime (n = 1), and carbapenem (n = 1).

191

c

P value for comparison between the ciprofloxacin group and the ciprofloxacin + metronidazole group.

192

d

Performed as only diagnostic procedure (diagnostic aspiration or liver biopsy).

193

e

Change of antibiotics because of a poor clinical response.

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194 195

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