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AAC Accepted Manuscript Posted Online 25 February 2019

Antimicrob. Agents Chemother. doi:10.1128/AAC.02495-18
Copyright © 2019 American Society for Microbiology. All Rights Reserved.

1 Antibiotic treatment duration for bacteremia due to

2 Enterobacteriaceae: A systematic review and meta-analysis

4 Giannoula S. Tansarli, MD1, Nikolaos Andreatos, MD1, Elina E. Pliakos, BSc1,

5 Eleftherios Mylonakis, MD, PhD, FIDSA1

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1
7 Division of Infectious Diseases, Warren Alpert Medical School of Brown

8 University, Providence, Rhode Island, United States of America

10 Corresponding author

11 Eleftherios Mylonakis, MD, PhD, FIDSA

12 Charles C.J. Carpenter Professor of Infectious Disease
13 Chief, Infectious Diseases Division,
14 Warren Alpert Medical School, Brown University
15 Rhode Island Hospital
16 593 Eddy Street
17 POB, 3rd Floor, Suite 328/330
18 Providence, RI, 02903
19 Tel: 401-444-7856 / Fax: 401-444-8179
20 Email: [email protected]
21

22 Running title: Treatment duration of Enterobacteriaceae bacteremia

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23 ABSTRACT
24 Background: The duration of antibiotic therapy for bacteremia due to

25 Enterobacteriaceae is not well-defined. We sought to evaluate the clinical outcomes

26 with shorter versus longer-course treatment.

27 Methods: We performed a systematic search of the PubMed and EMBASE databases

28 through May 2018. Studies presenting comparative outcomes between patients

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29 receiving antibiotic treatment for ≤10 days (“short-course”) and those treated for >10

30 days (“long-course”) were considered eligible.

31 Results: Four retrospective cohort studies and one randomized controlled trial

32 comprising 2,865 patients met the inclusion criteria. Short and long-course antibiotic

33 treatment did not differ in 30-day all-cause mortality (1,374 patients, RR= 0.99, 95%

34 CI (0.69-1.43)), 90-day all-cause mortality (1,750 patients, RR= 1.16 (95% CI, 0.81-

35 1.66)), clinical cure (1,080 patients, RR= 1.02 (95% CI, 0.96-1.08)), or relapse at 90

36 days (1,750 patients, RR= 1.08 95% CI (0.69-1.67)).

37 Conclusions: In patients with bacteremia due to Enterobacteriaceae, short and long-

38 course antibiotic treatment did not differ significantly in terms of clinical outcomes.

39 Further well-designed studies are needed before treatment for 10 days or less is

40 adopted in clinical practice.

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41 INTRODUCTION

42 Annually, nearly 2 million episodes of bloodstream infections (BSI) occur in North

43 America and Europe leading to around 250,000 deaths (1) and BSI is the 11th most

44 common cause of death in the U.S. (2)) BSI caused by Gram-negative bacteria

45 accounts for approximately 45% of all cases of community-acquired and almost one-

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46 third of all healthcare-associated cases of bacteremia, with Escherichia coli being the

47 most prevalent Gram-negative pathogen for both types of bacteremia (3). Timely

48 administration of the appropriate antibiotic treatment remains the cornerstone for

49 favorable clinical outcome in patients with BSI (4-6).

50 Determining the appropriate duration of therapy is included in the CDC

51 Strategic Priorities for Combating Antimicrobial Resistance (7) and is part of the

52 National Action Plan for Combating Antibiotic-Resistant Bacteria (8). However, the

53 optimal duration of antibiotic therapy is yet to be defined. The current Infectious

54 Diseases Society of America guidelines suggest that the duration of treatment for

55 intravascular catheter-related Gram-negative bacteremia should be between 7-14 days

56 (9), but there is no consensus on the optimal duration of the antimicrobial therapy for

57 non-catheter-related Gram-negative bacteremia. Recently published studies on non-

58 catheter-related bacteremia due to Enterobacteriaceae compared the outcomes of short

59 (≤10 days) with longer (>10 days) treatment in terms of clinical outcomes in an

60 attempt to define the optimal duration of therapy but their findings are controversial

61 (10, 11). The aim of the present study is to evaluate short versus longer courses of

62 antibiotic treatment for bacteremia due to Enterobacteriaceae in clinical outcomes.

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63 METHODS

64 Literature search

65 We performed a systematic search of the available literature in the PubMed and

66 EMBASE databases through May 2018. The following search term was applied:

67 “(“bloodstream infection” OR bacteremia OR sepsis OR septicemia) AND treatment

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68 AND (short-course OR long-course OR prolonged) AND (cure OR failure OR

69 mortality)”. A year limit to 1990 was set and all articles published in English,

70 German, or French were evaluated.

71 Study Selection

72 We defined “short-course” treatment as treatment for ≤10 days and “long-course”

73 treatment as treatment for >10 days. As such, studies comparing the clinical outcomes

74 between patients who received antibiotic treatment for ≤10 days and those who

75 received treatment for >10 days were considered eligible for inclusion. Studies

76 assessing clinical outcomes between different treatment duration groups using a cut-

77 off other than 10 days were evaluated and discussed, but were not included in the

78 meta-analysis. Studies reporting only the mean or median without a minimum

79 duration of therapy were not eligible for inclusion. Also, studies reporting on

80 antibiotics that are not currently approved by the Food and Drug Administration were

81 excluded. Last, case reports and studies including pediatric patients were also

82 excluded.

83 Data Extraction and Quality assessment

84 Two investigators (GST and NA) independently performed the systematic search of

85 databases, study selection, and data extraction. Any discrepancies between the

86 investigators were resolved by consensus during meetings. The extracted data

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87 included the main characteristics of each study (first author name, year, and study

88 design), number of patients with bacteremia who received antibiotic treatment, source

89 of bacteremia, causative pathogen of bacteremia, aggregate Newcastle-Ottawa Scale

90 score, duration of antibiotic therapy in both arms, as well as the available clinical

91 outcomes in each treatment group.

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92 The methodological quality of the non-randomized studies that were included

93 in the meta-analysis was assessed with the “star-system” of the Newcastle-Ottawa

94 scale (12). The studies were evaluated according to the selection of study groups,

95 comparability of groups, and ascertainment of the outcome of interest.

96 Definitions and Outcomes

97 The primary outcome of the meta-analysis was all-cause mortality. Clinical cure, as

98 defined by the investigators of the individual studies, and relapse of bacteremia were

99 the secondary outcomes.

100 Meta-analysis

101 The meta-analysis was performed using Review Manager for Windows, v.5.3 (13).

102 Pooled risk ratios and 95% confidence intervals were calculated regarding the

103 outcomes of interest. We assessed statistical heterogeneity among studies by using a

104 χ2 test (P <0.10 was defined to indicate significant heterogeneity) and I2. When there

105 was no significant statistical heterogeneity (<40%) (14) between the studies, the

106 Mantel-Haenszel fixed effect model was used (15). Otherwise the random effects

107 model with the DerSimonian and Laird approach was used as appropriate (16). We

108 assessed publication bias by the funnel plot (16).

109

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110 RESULTS

111 Study selection and patient characteristics. The literature search process retrieved

112 3,462 articles: 2,139 from PubMed, 1,313 from EMBASE, and 10 from manual

113 review searching of referenced papers. Among them, 67 studies were assessed in full-

114 text. Of these, 24 studies were excluded due to ineligible comparisons of treatment

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115 duration, 5 were excluded because the mean/median instead of standard duration of

116 treatment was provided. Other reasons of exclusion comprised duplicates (12 studies),

117 data that could not be extracted (5 studies), study outcomes that were out of interest (2

118 studies), studies that were not found (2 studies), or ineligible language of publication

119 (1 study). Finally, 7 studies included eligible comparisons of duration but were

120 excluded because they referred to infections caused by Gram-negative or Gram-

121 positive pathogens, where the authors did not distinguish the outcomes according to

122 pathogen group (17-23). Among the remaining 9 studies, there was inconsistency in

123 treatment duration comparisons among published studies: 5 studies compared ≤10 vs.

124 >10 days (10, 11, 24-26), 1 study (178 patients) ≤7 vs. >7 days (27), 2 studies (56

125 patients) 7 vs. 14 days (28, 29), and 1 study (92 patients) <14 vs. ≥14 (30). Also, 3 of

126 those studies referred to bacteremia from specific sites of infections (acute

127 pyelonephritis (28, 29), acute cholangitis (30). We selected to focus our analysis on

128 studies that compared ≤10 vs. >10 days of treatment which included various sources

129 of bacteremia. The remaining studies were evaluated and discussed as part of the

130 systematic review, but they were not included in the meta-analysis (27-30). The

131 detailed study selection process is depicted in Figure 1.

132 Five studies reporting on 2,865 patients met the inclusion criteria of the meta-

133 analysis (4 studies that compared ≤10 vs. >10 days and 1 study that compared <14 vs.

134 ≥14) (10, 11, 24-26). The characteristics and outcomes of the studies included in the

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135 meta-analysis are presented in Table 1. Four studies were based on retrospective

136 cohort analyses (10, 11, 25, 26), and 1 study was an open-label non-inferiority

137 randomized controlled trial (24). On the Newcastle-Ottawa scale, 2 studies were

138 assigned with 7 stars (10, 11), 1 study was assigned with 8 stars (25), and another 1

139 was assigned with 4 stars (26).

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140 The source of bacteremia in the included studies accounted for urinary tract

141 (54.8%), biliary/gastrointestinal tract infection (13.8%), intra-abdominal (5%),

142 primary/central venous catheter-related bacteremia (4.8%), pneumonia (3.6%), soft

143 tissue infection (1.4%), or other/unknown sources. Overall, urinary tract was the most

144 prevalent source of bacteremia in all 5 studies comprising 71% (26), 69% (11), 68%

145 (24), 51.3% (25), and 36.1% (10) of the included infections. E. coli was the only

146 involved pathogen in 1 study (25) and the most common pathogen from the

147 Enterobacteriaceae family in the other 4 studies, representing 71.4% (26), 66% (11),

148 65% (24), and 46.9% (10) of the pathogens. Overall, the majority of bacteremia cases

149 in this meta-analysis came from urinary tract infections due to E. coli and 41.2%

150 (1,181 out of 2,865) of the patients were reported to have uncomplicated bacteremia.

151 K. pneumoniae was the second most common cause of bacteremia in three studies,

152 accounting for 32.6% (10),17% (26), and 14.8% (11) of the included cases. The

153 antibiotic treatment was not specified in any of these studies.

154 Studies included in the meta-analysis: treatment for ≤10 days vs. > 10 days. We

155 pooled studies that assessed mortality at 30 days (10, 24) and 90 (11, 24, 25) counting

156 from the completion of the antibiotic therapy. Pooling of the studies that assessed 30-

157 day mortality showed that there was no statistically significant difference in all-cause

158 mortality between short and long-course treatment (7.5% vs. 7.6%) [Figure 2; 1,374

159 patients, RR= 0.99, 95% CI (0.69-1.43)] and no heterogeneity was detected (I2= 0%).

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160 When we pooled data on 90-day mortality, again there was no significant difference

161 between short and long-course treatment (6.7% vs. 5.6%) [Figure 3; 1,750 patients,

162 RR= 1.16 (95% CI, 0.81-1.66)]. Mild statistical heterogeneity was detected in this

163 analysis (I2= 33%).

164 Concerning clinical cure, no significant difference between the two treatments

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165 was detected when those studies were pooled (81.6% vs. 81.4%) [Figure 4; 1,080

166 patients, RR= 1.02 (95% CI, 0.96-1.08)] and no statistical heterogeneity was detected

167 in this analysis (I2= 0%). Moreover, 4 of the studies provided data on relapse of

168 bacteremia (10, 11, 24, 25). Relapse was assessed within 30 (10) or 90 (11, 24, 25)

169 days from the completion of the antibiotic therapy. Pooling of the studies showed that

170 relapse at 90 days (11, 24, 25) was not significantly different between short and long-

171 course treatment, (4.5% vs 4.5%) [Figure 5; 1,750 patients, RR= 1.08 95% CI (0.69-

172 1.67), (I2= 0%)]. The relapse rate was also similar between short and long-course

173 treatment in one study that assessed relapse at 30 days from the completion of

174 treatment (1.2% vs. 2.3%) [RR= 0.56 (95% CI, 0.19-1.64)] (10).

175 Studies comparing other treatment durations. Table 2 presents four studies which

176 used a cut-off other than the 10 days for the classification of treatment as “short” or

177 “long” course. Two of them were double-blind randomized controlled trials (28, 29),

178 1 was a retrospective cohort study (30), and 1 was a retrospective case-control trial

179 (27). Three out of those studies included patients with bacteremia secondary to a

180 single source of infection. Among them, 2 included patients with acute pyelonephritis

181 (28, 29), and 1 included patients with acute cholangitis (30).

182 In the studies referring to acute pyelonephritis, only a small subset of patients

183 (56/503) had positive blood cultures (28, 29). The antibiotic treatment was

184 ciprofloxacin for 7 days (short course) vs. ciprofloxacin (28) or

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185 trimethoprim/sulfamethoxazole (29) for 14 days (long course). Clinical cure was not

186 different between the compared treatment groups in any of those studies [100% vs.

187 90%, p= NS (29); 94% vs. 96%, p= NS (28)]. Other clinical outcomes were not

188 provided in those studies.

189 Another study evaluated treatment for ≤7 days vs. >7 days for the treatment of

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190 bacteremia due to Enterobactericeae (27). The authors assessed clinical cure and

191 bacteriological eradication among the compared treatment groups and found that there

192 was no significant difference in either cure or eradication (78.6% vs. 86.8%, p= NS

193 and 83.3% vs.89.7%, p=NS, respectively). Finally, 1 study referred to patients treated

194 for bacteremia due to Enterobacteriaceae secondary to acute cholangitis for either <14

195 days or ≥14 days (30). No difference was found in mortality between the compared

196 treatment groups in that study (0% vs. 5.7%, p= NS), but relapse was higher among

197 patients who were treated for ≥14 days than those treated for <14 days (13.3% vs. 0%,

198 p<0.05). The antibiotics administered were not determined in either of these two

199 studies (27, 30).

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200 DISCUSSION

201 Prolonged courses of antibiotics have been associated with increased adverse events

202 (31) and emergence of antibiotic-resistant strains (32-34), while inadequate courses

203 lead to ineffective treatment and relapse of the infection (35). In this meta-analysis,

204 we evaluated short versus longer courses of antibiotic for the treatment of bacteremia

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205 due to Enterobacteriaceae in terms of all-cause mortality, clinical cure, and relapse of

206 bacteremia. We found that shorter courses of antibiotics (≤10 days) did not result in

207 inferior clinical outcomes as compared to longer courses of treatment. Notably, the

208 included studies did not differ in terms of patient population and source of bacteremia

209 and patient characteristics between the compared treatment groups. The lack of

210 statistical heterogeneity from all analyses further strengthens these findings.

211 There is scarcity of evidence regarding the optimal duration of antibiotic

212 therapy for non-catheter-related Gram-negative bacteremia and the limited studies

213 presented controversial findings (10, 11). As a result, there is wide variation in

214 treatment duration among clinicians, with a general tendency to more prolonged

215 courses (36). For example, according to a survey among infectious diseases and

216 critical care physicians, the most common response was 14 days of treatment for BSI,

217 irrespectively of its source. However, in terms of range of treatment, the majority of

218 respondents recommended treatment for 7-10 days for all bacteremic syndromes, such

219 as bacteremic urinary tract infection and bacteremic pneumonia (36). On the contrary,

220 herein we found that antibiotic treatment for 10 days or less for bacteremia due to

221 Enterobacteriaceae was not associated with improved outcomes and cannot replace

222 yet the standard of care with treatment for over 10 days.

223 The impact of treatment duration on antimicrobial resistance is another factor

224 taken into account in the selection of the treatment regimen. Emergence of multidrug

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225 resistance during therapy was evaluated in one of the included studies in which 4.4%

226 vs. 7.3% cases of multidrug-resistant bacteria occurred in the short and long-course

227 group, respectively, without significant difference between the compared arms (10).

228 Likewise, no significant difference in the emergence of resistance was found between

229 short and long-course group in the randomized controlled trial (10.8% vs. 9.8%, p=

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230 NS) (24). On the other hand, antibiotic use is associated with Clostridioides

231 (Clostridium) difficile infection (CDI) (37). Two of the included studies assessed the

232 development of CDI between short and long-course groups and both found that there

233 was no significant difference between the compared treatments (10, 24).

234 Moreover, appropriateness of empiric therapy is another important factor that

235 affects treatment outcome and should be assessed as a potential confounder in the

236 results of the included studies (38). Two studies provided information on the empiric

237 therapy with the one showing no difference in the occurrence of inappropriate empiric

238 therapy between short and long-course treatment (11) and the other showing higher

239 more common inappropriate therapy in the short-course group (25). Besides the

240 difference in the appropriateness of therapy noted in the latter study, clinical cure,

241 relapse or mortality did not differ significantly between short and long-course

242 treatment (25).

243 The present study bears certain limitations that should be considered in the

244 interpretation of the findings. First, all but 1 included study were retrospective cohort

245 meaning that the quality of the data may be suboptimal or the data are prone to

246 confounding factors. To eliminate confounding by indication, the authors of 1 study

247 excluded patients in whom antimicrobial duration of treatment was dictated by

248 outcome (in-hospital mortality) or clinical response to therapy (prolonged

249 hospitalization) (11). In order to address this issue, another study included propensity

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250 score matching (10), while a third study utilized a propensity score of receiving short-

251 course treatment using multivariate logistic regression (25). The randomized

252 controlled trial did not bear confounding by indication due to randomization.

253 However, it should be noted that the authors excluded hemodynamically unstable

254 patients who tend to receive antibiotic treatment for longer periods (24). Moreover, in

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255 non-randomized studies survival bias might occur (39). In 3 out of 4 non-randomized

256 studies that were included in our meta-analysis, the authors addressed this concern.

257 More specifically, in 1 study the authors mentioned that in order to reduce the risk of

258 survival bias they excluded patients who did not survive initial hospitalization for

259 bloodstream infection (11). Also, in 2 other studies the authors excluded from the

260 analyses all patients that died while receiving antibiotic treatment for bloodstream

261 infection (10, 25). Second, mortality was assessed at either 30 (10) or 90 (11, 24, 25).

262 Given that bacteremia is associated with long-term mortality (40), assessment of the

263 effectiveness of the definitive treatment at 90 rather than 30 days may be preferable.

264 In addition, clinical outcomes (such as the source or severity of bacteremia, the

265 presence of co-morbidities, and the antimicrobial resistance profile of the involved

266 pathogens) were not available and clearer conclusions could not be drawn. Third, the

267 impact of treatment duration on outcomes may depend on the type of antibiotic;

268 however, data on the specific antibiotics used were not provided in the included

269 studies. Interestingly, according to a previously published study which assessed the

270 effectiveness of oral antibiotics in the treatment of Gram-negative bacteremia, clinical

271 outcomes improve with oral antibiotics of high bioavailability as compared to

272 antibiotics of moderate or low bioavailability (such as cephalosporins or penicillins)

273 (41).

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274 In conclusion, in patients with bacteremia due to Enterobacteriaceae treatment

275 for ≤10 days did not result in inferior clinical outcomes as compared to treatment for

276 >10 days. The current practice for the treatment of Gram-negative bacteremia varies

277 widely (36). Further well-designed studies that will compare effectiveness, safety and

278 emergence of resistance between short and long-course treatment are necessary in

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279 order to assess whether shortening of treatment duration in specific sources of

280 bacteremia would be beneficial. Also, future studies that include patients with

281 bacteremia of urinary source should investigate whether clinical outcomes with short

282 versus long-course treatment differ based on gender. Lastly, cost-effectiveness

283 analyses should be performed to evaluate whether differences in the duration of

284 antibiotic treatment for bacteremia impact healthcare cost.

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285 Figure legends

286 Figure 1. Flow diagram of the search process and study selection

287 Figure 2. Forest plot depicting the risk ratios of 30-day mortality among patients

288 receiving antibiotic treatment for ≤10 days vs. >10 days. Vertical line indicates ‘no

289 difference’ point between the two regimens; horizontal lines indicate the 95%

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290 confidence interval (CI). ■, risk ratios; ♦, pooled risk ratios for all studies.

291 Figure 3. Forest plot depicting the risk ratios of 90-day mortality among patients

292 receiving antibiotic treatment for ≤10 days vs. >10 days. The vertical line indicates

293 the ‘no difference’ point between the two regimens. The horizontal lines indicate the

294 95% confidence interval (CI). ■, risk ratios; ♦, pooled risk ratios for all studies.

295 Figure 4. Forest plot depicting the risk ratios of clinical cure of patients receiving

296 antibiotic treatment for ≤10 days vs. >10 days. The vertical line indicates the ‘no

297 difference’ point between the two regimens. The horizontal lines indicate the 95%

298 confidence interval (CI). ■, risk ratios; ♦, pooled risk ratios for all studies.

299 Figure 5. Forest plot depicting the risk ratios of relapses of patients receiving

300 antibiotic treatment for ≤10 days vs. >10 days. The vertical line indicates the ‘no

301 difference’ point between the two regimens. The horizontal lines indicate the 95%

302 confidence interval (CI). ■, risk ratios; ♦, pooled risk ratios for all studies.

303

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304 REFERENCES

305 1. Goto M, Al-Hasan MN. 2013. Overall burden of bloodstream infection and
306 nosocomial bloodstream infection in North America and Europe. Clin Microbiol
307 Infect 19:501-9.
308 2. Anonymous. Deaths: Final Data for 2015. National Vital Statistics Reports (NVSS).
309 https://www.cdc.gov/nchs/data/nvsr/nvsr66/nvsr66_06.pdf. Last accessed on
310 6/5/2018. Accessed
311 3. Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. 2003.
312 Epidemiology and outcome of nosocomial and community-onset bloodstream
313 infection. J Clin Microbiol 41:3655-60.

Downloaded from http://aac.asm.org/ on February 26, 2019 by guest

314 4. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. 2000. The influence of
315 inadequate antimicrobial treatment of bloodstream infections on patient outcomes
316 in the ICU setting. Chest 118:146-55.
317 5. MacArthur RD, Miller M, Albertson T, Panacek E, Johnson D, Teoh L, Barchuk W.
318 2004. Adequacy of early empiric antibiotic treatment and survival in severe sepsis:
319 experience from the MONARCS trial. Clin Infect Dis 38:284-8.
320 6. Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E, LaPlante KL.
321 2017. The Effect of Molecular Rapid Diagnostic Testing on Clinical Outcomes in
322 Bloodstream Infections: A Systematic Review and Meta-analysis. Clin Infect Dis
323 64:15-23.
324 7. Anonymous. CDC Strategic Priorities for Combating Antimicrobial Resistance. URL:
325 https://www.cdc.gov/drugresistance/pdf/cdc-priorities-combating-ar-infections-
326 report-workshop.pdf. Last accessed on 9/29/2018.
327 8. Anonymous. National Action Plan for Combating Antibiotic-Resistant Bacteria.
328 March 2015. URL:
329 https://www.cdc.gov/drugresistance/pdf/national_action_plan_for_combating_anti
330 botic-resistant_bacteria.pdf. Last accessed on 9/29/2018.
331 9. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, Raad, II, Rijnders BJ,
332 Sherertz RJ, Warren DK. 2009. Clinical practice guidelines for the diagnosis and
333 management of intravascular catheter-related infection: 2009 Update by the
334 Infectious Diseases Society of America. Clin Infect Dis 49:1-45.
335 10. Chotiprasitsakul D, Han JH, Cosgrove SE, Harris AD, Lautenbach E, Conley AT,
336 Tolomeo P, Wise J, Tamma PD, Antibacterial Resistance Leadership G. 2018.
337 Comparing the Outcomes of Adults With Enterobacteriaceae Bacteremia Receiving
338 Short-Course Versus Prolonged-Course Antibiotic Therapy in a Multicenter,
339 Propensity Score-Matched Cohort. Clin Infect Dis 66:172-177.
340 11. Nelson AN, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. 2017. Optimal
341 duration of antimicrobial therapy for uncomplicated Gram-negative bloodstream
342 infections. Infection 45:613-620.
343 12. Anonymous. Wells G, Shea B, O'Connell J, Robertson J, et al. The Newcastle-Ottawa
344 Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis.
345 2011.
346 13. Anonymous. Review Manager (RevMan) [Computer program]. Version 5.3.
347 Copenhagen, Denmark: The Nordic Cochrane Centre TCC; 2014.
348 14. Anonymous. Heterogeneity and subgroup analyses in Cochrane Consumers and
349 Communication Group reviews: lanning the analysis at protocol stage. Cochrane
350 Consumers and Communication. December 2016. http://cccrg.cochrane.org. Last
351 accessed on 6/11/2018.
352 15. Mantel N, Haenszel W. 1959. Statistical aspects of the analysis of data from
353 retrospective studies of disease. J Natl Cancer Inst 22:719-48.

15
 Made with Xodo PDF Reader and Editor

354 16. DerSimonian R, Laird N. 1986. Meta-analysis in clinical trials. Control Clin Trials
355 7:177-88.
356 17. Daneman N, Rishu AH, Xiong W, Bagshaw SM, Dodek P, Hall R, Kumar A,
357 Lamontagne F, Lauzier F, Marshall J, Martin CM, McIntyre L, Muscedere J, Reynolds
358 S, Stelfox HT, Cook DJ, Fowler RA, Canadian Critical Care Trials G. 2016. Duration of
359 Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients. Crit Care
360 Med 44:256-64.
361 18. Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K, Cirillo I, Kimko H,
362 Redman R. 2012. A randomized trial of 7-day doripenem versus 10-day imipenem-
363 cilastatin for ventilator-associated pneumonia. Crit Care 16:R218.
364 19. Doi A, Morimoto T, Iwata K. 2018. Shorter duration of antibiotic treatment for acute

Downloaded from http://aac.asm.org/ on February 26, 2019 by guest

365 bacteraemic cholangitis with successful biliary drainage: a retrospective cohort
366 study. Clin Microbiol Infect doi:10.1016/j.cmi.2018.01.021.
367 20. Havey TC, Fowler RA, Pinto R, Elligsen M, Daneman N. 2013. Duration of antibiotic
368 therapy for critically ill patients with bloodstream infections: A retrospective cohort
369 study. Can J Infect Dis Med Microbiol 24:129-37.
370 21. Pereira JM, Goncalves-Pereira J, Ribeiro O, Baptista JP, Froes F, Paiva JA. 2018.
371 Impact of antibiotic therapy in severe community-acquired pneumonia: Data from
372 the Infauci study. J Crit Care 43:183-189.
373 22. Runyon BA, McHutchison JG, Antillon MR, Akriviadis EA, Montano AA. 1991. Short-
374 course versus long-course antibiotic treatment of spontaneous bacterial peritonitis.
375 A randomized controlled study of 100 patients. Gastroenterology 100:1737-42.
376 23. Siegel RE, Alicea M, Lee A, Blaiklock R. 1999. Comparison of 7 versus 10 days of
377 antibiotic therapy for hospitalized patients with uncomplicated community-acquired
378 pneumonia: a prospective, randomized, double-blind study. Am J Ther 6:217-22.
379 24. Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A,
380 Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A,
381 Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C,
382 Mussini C, Leibovici L, Paul M, Bacteremia Duration Study G. 2018. Seven versus
383 fourteen Days of Antibiotic Therapy for uncomplicated Gram-negative Bacteremia: a
384 Non-inferiority Randomized Controlled Trial. Clin Infect Dis doi:10.1093/cid/ciy1054.
385 25. Giannella M, Pascale R, Toschi A, Ferraro G, Graziano E, Furii F, Bartoletti M,
386 Tedeschi S, Ambretti S, Lewis RE, Viale P. 2018. Treatment duration for Escherichia
387 coli bloodstream infection and outcomes: retrospective single-centre study. Clin
388 Microbiol Infect doi:10.1016/j.cmi.2018.01.013.
389 26. Mercuro NJ, Stogsdill P, Wungwattana M. 2018. Retrospective analysis comparing
390 oral stepdown therapy for enterobacteriaceae bloodstream infections:
391 fluoroquinolones versus beta-lactams. Int J Antimicrob Agents 51:687-692.
392 27. Swamy S, Sharma R. 2016. Duration of Treatment of Gram-Negative Bacteremia: Are
393 Shorter Courses of Antimicrobial Therapy Feasible? Infectious Diseases in Clinical
394 Practice 24.
395 28. Sandberg T, Skoog G, Hermansson AB, Kahlmeter G, Kuylenstierna N, Lannergard A,
396 Otto G, Settergren B, Ekman GS. 2012. Ciprofloxacin for 7 days versus 14 days in
397 women with acute pyelonephritis: a randomised, open-label and double-blind,
398 placebo-controlled, non-inferiority trial. Lancet 380:484-90.
399 29. Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, Reuning-Scherer J,
400 Church DA. 2000. Comparison of ciprofloxacin (7 days) and trimethoprim-
401 sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in
402 women: a randomized trial. JAMA 283:1583-90.

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403 30. Uno S, Hase R, Kobayashi M, Shiratori T, Nakaji S, Hirata N, Hosokawa N. 2017.
404 Short-course antimicrobial treatment for acute cholangitis with Gram-negative
405 bacillary bacteremia. Int J Infect Dis 55:81-85.
406 31. Meropol SB, Chan KA, Chen Z, Finkelstein JA, Hennessy S, Lautenbach E, Platt R,
407 Schech SD, Shatin D, Metlay JP. 2008. Adverse events associated with prolonged
408 antibiotic use. Pharmacoepidemiol Drug Saf 17:523-32.
409 32. Barbosa TM, Levy SB. 2000. The impact of antibiotic use on resistance development
410 and persistence. Drug Resist Updat 3:303-311.
411 33. Canton R, Morosini MI. 2011. Emergence and spread of antibiotic resistance
412 following exposure to antibiotics. FEMS Microbiol Rev 35:977-91.
413 34. Ventola CL. 2015. The antibiotic resistance crisis: part 1: causes and threats. P T

Downloaded from http://aac.asm.org/ on February 26, 2019 by guest

414 40:277-83.
415 35. Chong YP, Moon SM, Bang KM, Park HJ, Park SY, Kim MN, Park KH, Kim SH, Lee SO,
416 Choi SH, Jeong JY, Woo JH, Kim YS. 2013. Treatment duration for uncomplicated
417 Staphylococcus aureus bacteremia to prevent relapse: analysis of a prospective
418 observational cohort study. Antimicrob Agents Chemother 57:1150-6.
419 36. Daneman N, Shore K, Pinto R, Fowler R. 2011. Antibiotic treatment duration for
420 bloodstream infections in critically ill patients: a national survey of Canadian
421 infectious diseases and critical care specialists. Int J Antimicrob Agents 38:480-5.
422 37. Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. 2012. Time interval of increased
423 risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob
424 Chemother 67:742-8.
425 38. Hanon FX, Monnet DL, Sorensen TL, Molbak K, Pedersen G, Schonheyder H. 2002.
426 Survival of patients with bacteraemia in relation to initial empirical antimicrobial
427 treatment. Scand J Infect Dis 34:520-8.
428 39. van Walraven C, Davis D, Forster AJ, Wells GA. 2004. Time-dependent bias was
429 common in survival analyses published in leading clinical journals. J Clin Epidemiol
430 57:672-82.
431 40. Nielsen SL, Lassen AT, Gradel KO, Jensen TG, Kolmos HJ, Hallas J, Pedersen C. 2015.
432 Bacteremia is associated with excess long-term mortality: a 12-year population-
433 based cohort study. J Infect 70:111-26.
434 41. Kutob LF, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. 2016.
435 Effectiveness of oral antibiotics for definitive therapy of Gram-negative bloodstream
436 infections. Int J Antimicrob Agents 48:498-503.
437

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Table 1. Studies comparing for ≤10 vs. >10 days of antibiotic treatment for bacteremia due to Enterobacteriaceae

Clinical cure All-cause mortality Relapse

Author Study design; study Number of pts received abx; Aggregate Short- Long- Short- Long- Short- Long-
Year period; country pathogen; source of bacteremia NOS score course course course course course course
770; Enterobacteriaceae (46.9%
Escherichia coli); uncomplicated;
Retrospective 36.1% urinary tract, 19.9%
propensity-score gastrointestinal tract, 16.2% biliary 30-day 30-day 30-day 30-day
Chotiprasitsakul matched cohort; 2008- tract, 13.8% catheter-associated, 9%
201810 2014; USA pneumonia, 4% skin and soft tissue ******* NR NR 37/385 39/385 5/385 9/385

856; E. coli; 51.3% urinary tract,

15.4% primary, 13.7% biliary tract,
11.1% intra-abdominal, 3.9% lower 90-day 90-day 90-day 90-day 90-day 90-day
Giannella Retrospective cohort; respiratory tract, 2.1% CVC, 1.1%
201825 2013-2016; Italy skin and soft tissue ******** 344/426 341/430 11/426 13/430 23/426 19/430

MC open-label non- 90-day 90-day 90-day 90-day

Yahav inferiority RCT; Israel, 604; 90% Enteobacteriaceae (65% E.
201824 Italy coli); 68% urinary tract NA NR NR 36/306 32/298 8/306 8/298

224; Enterobacteriaceae (71.4% E.

coli); 71% urinary tract, 21.4% intra-
abdominal, skin and soft tissue, 30-day 30-day
Mercuro Retrospective cohort; pneumonia, catheter-related,
201726 2013-2016; USA unknown source **** 45/51 150/173 NR NR NR NR
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411; Enterobacteriaceae (66% E. 90-day 90-day 90-day 90-day
Nelson Retrospective cohort; coli); uncomplicated; 69% urinary
201711 2010-2013; USA tract ******* NR NR 8/91 §
7/199 §
6/91 §
15/199§

Abbreviations
NOS: Newcastle-Ottawa scale, NR: not reported, NA: non-applicable, MC: multi-center, RCT: randomized clinical trial
§
The data provided by the authors of the study after request were the following: 13 and 19 treatment failures (defined as mortality + relapse) in the short and long-course
group, respectively, and 26 and 95 patients lost to follow-up at day 90 in each group; 91 and 199 patients were evaluable at day 90 in the short and long-course group,
respectively; treatment failures comprised of 8 deaths + 6 recurrences (1 patient died after recurrence) in the short-course group and 7 deaths + 15 recurrences (3 patients died
after recurrence) in the long-course group.
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Table 2. Studies comparing treatment durations among patients with bacteremia mostly due to Enterobacteriaceae using a cut-off other than 10 days

Duration Clinical cure All-cause mortality Relapse

Number of pts received
Author Study design; study abx; causative pathogen; Short- Long- Short- Long- Short- Long-
Year period; country source of bacteremia Short-course Long-course course course course course course course

Uno Retrospective cohort; 82; mostly Enterobacteriaceae; 0/47 2/35 0/37 4/30
201730 2012-2014; Japan acute cholangitis <14 days ≥14 days NR NR (0%) (5.7%) (0%) (13.3%)

178; mostly Enterobacteriaceae;

Retrospective case- urinary tract, catheter-related,
Swamy control; 2006-2013; intra-abdominal, respiratory 33/42 118/136
201627 USA tract, skin and soft tissue, other ≤7 days >7 days (78.6%) (86.8%) NR NR NR NR

Non-inferiority double-
Sandberg blind RCT; 2006- Ciprofloxacin Ciprofloxacin 15/16 25/26
201228 2008; Sweden 42; E. coli; acute pyelonephritis for 7 days for 14 days (93.8%) (96.2%) NR NR NR NR

Trimethoprim/
Talan Double-blind RCT; Ciprofloxacin sulfamethoxaz 4/4 9/10
200029 1994-1997; USA 14; E. coli; acute pyelonephritis for 7 days ole for 14 days (100%) (90%) NR NR NR NR
Abbreviations
NR: not reported, RCT: randomized clinical trial