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Uncomplicated Gram-Negative Bacteremia in Adults – with the Implications for Antimicrobial Stewardship, Is a Longer

Course of Antibiotics DESPICABLE?

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Cameron Stuart Pickard, Pharm.D. PGY1 Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health San Antonio

February 16th, 2018

Learning Objectives:

1. Provide a basic overview of antimicrobial stewardship and gram-negative bacteremia. 2. Describe the significance of gram-negative bacteremia. 3. Discuss the literature pertaining to the duration of antibiotic therapy for uncomplicated gram-

negative bloodstream infections. 4. Recommend optimal treatment duration in a patient with uncomplicated gram-negative

bacteremia given patient specific factors.

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Bloodstream Infection (BSI)

1. Definitions1,2 a. BSI: microorganism growth on a blood culture, excluding contamination, from a patient

exhibiting clinical signs of infection b. Bacteremia: BSI caused by bacteria c. Uncomplicated bacteremia

i. Methicillin-resistant Staphylococcus aureus (MRSA): positive blood culture results and the following:

1. Defervescence within 72 hours of appropriate antibiotic therapy 2. No MRSA growth on follow-up blood cultures obtained 2-4 days after

initial positive culture 3. Exclusions: endocarditis, implanted prostheses, evidence of metastatic

sites of infection 2. Epidemiology3-5

a. 2013 epidemiological study in the United States (US) found: i. BSI incidence rate: 174-204/100,000 person-years ii. Estimated annual number of BSIs: 535,920-628,320 iii. BSI estimated mortality rate: 23.5-27.5/100,000 person-years iv. Estimated annual number of deaths following BSI: 72,349-84,823

b. Septicemia i. 11th leading cause of death in the US in 2015 ii. Responsible for 40,773 deaths (1.5% of total deaths) iii. 9,549 death (0.2%) increase from 2000

3. Current Guideline Recommendation for Duration of Treatment in Bacteremia2 a. Infectious Diseases Society of America (IDSA) 2011 guidelines for treatment of MRSA

infections in adults and children i. For adults with uncomplicated MRSA bacteremia, ≥ 2 weeks of intravenous (IV)

therapy recommended ii. For adults with complicated MRSA bacteremia, 4-6 weeks of IV therapy

recommended Gram-Negative Bacteremia (GNB)

1. Definitions a. GNB: BSI caused by gram-negative (GN) organism b. Uncomplicated GNB

i. No universally accepted or utilized definition ii. Presenter’s proposed definition of uncomplicated GNB

1. Exclusion of endocarditis 2. Exclusion of osteomyelitis 3. Exclusion of prostatitis 4. Absence of implanted prostheses 5. No evidence of metastatic seeding 6. Defervescence within 72 hours of effective treatment

2. Epidemiology6-8 a. Incidence continues to increase

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i. 1750-bed hospital in Madrid, Spain: 1. 1985 GNB incidence 7.8/1000 admissions and 63.5/100,000 population 2. 2006 GNB incidence increased to 16.2/1000 admissions and

141.9/100,000 population a. 2006 gram-positive BSIs incidence 138.3/100,000 population

3. 43.7% (11,987 out of 27,419) of BSIs due to GN organisms ii. Retrospective, population-based, cohort study from Olmsted County, Minnesota:

1. January 1, 2003 to December 31, 2005, incidence of GN BSI 80.9/100,000 person-years

2. 43.2% (281 out of 650) of BSIs due to GN organisms 3. Incidence increased with age (male > females, beginning at age 60)

b. Mortality i. 1500-bed hospital in Seoul, Korea, BSIs due to antibiotic-resistant GN bacilli

yielded an overall mortality rate of 33.2% (95 out of 286) 1. Mortality per resistant GN organism:

Figure 1

2. Mortality per therapy group (P = 0.049): a. Appropriate empiric: 27.4% b. Inappropriate empiric: 38.4%

3. Etiology6,9,10 a. Source

i. Primary: no focus ii. Secondary

• Urinary tract • Respiratory • Skin and soft tissue • Intravascular catheter • Biliary • Intra-abdominal • Bone and joint • Cardiac

b. Organism i. 2006 GN microbiology breakdown of 1,055 BSIs from Madrid, Spain:

Figure 2: GNB Distribution

Escherichia coli: 21.3%

(13 of 61)

Klebsiella pneumoniae:

32.3% (21 of 65)

Enterobacter species (spp.):

33.7% (29 of 86)

Pseudomonas aeruginosa:

43.2% (32 of 74)

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ii. Distribution by GN organism from 3015 BSIs in the US from 2002-2003 Table 1: Microbiology by Acquisition Location

Organism Community (n = 1,233)

Healthcare-Associated (n = 1,603)

Nosocomial (n = 179)

Escherichia, n (%) 635 (51.5) 723 (45.1) 32 (17.9) Klebsiella, n (%) 146 (11.8) 231 (14.4) 29 (16.2) Proteus, n (%) 67 (5.4) 132 (8.2) 2 (1.1) Pseudomonas, n (%) 57 (4.6) 117 (7.3) 15 (8.4) Other GN, n (%) 328 (26.6) 400 (25.0) 101 (56.4)

4. Clinical Presentation11 a. Fever b. Chills/rigors c. Signs and symptoms of source infection d. Disorientation, hypotension, and respiratory failure

5. Risk Factors12-18 a. Immunocompromised: human immunodeficiency virus, solid organ transplant, stem cell

transplant, treatment with glucocorticoids b. Diabetes mellitus c. Liver failure d. Serum albumin < 3 g/dL e. Pulmonary disease f. Chronic hemodialysis g. Urinary retention, surgery involving urogenital tract, prostate biopsy, and endoscopic

retrograde cholangiopancreatography 6. Diagnosis

a. GN bacillus growth on blood culture 7. Management

a. Empiric, broad spectrum antibiotic therapy b. Source control c. Supportive care d. Monitoring e. Definitive antibiotic therapy

Table 2: Potential Antimicrobial Options for GNB IV Oral – High Bioavailability

Ceftriaxone Piperacillin-tazobactam Ciprofloxacin Ciprofloxacin Ceftazidime Carbapenem Levofloxacin Levofloxacin Cefepime Aztreonam Aminoglycoside Trimethoprim-sulfamethoxazole

8. Current Guideline Recommendation19 a. IDSA 2009 guidelines for diagnosis and management of intravascular catheter-related

infection i. 7-14 days of antibiotic therapy suggested in the absence of complications ii. Recommendation graded C-III

1. C: “Poor evidence to support a recommendation” 2. III: “Evidence from opinions of respected authorities, based on clinical

experience, descriptive studies, or reports of expert committees”

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Cons

eque

nces

Development and spread of antimicrobial resistance

Selection of pathogenic organisms (e.g. Clostridium difficile)

Increased risk of antimicrobial organ toxicity

Decreased compliance

Increased costs

Antimicrobial Stewardship

1. Historic Reasons for Prolonged Antibiotic Course Prescribing20,21 a. Deficient knowledge of effect on intestinal microbiome and downstream consequences b. Lack comparative evidence, as longer durations of therapy often used by default in trials c. Limited recognition of the incidence and impact of antimicrobial resistance

2. Consequences of Unnecessary Prolonged Course Therapy20-22

Figure 3 3. Proposed Mechanism for Reducing Antimicrobial-Related Consequences22,23

a. Up to 50% of antimicrobial use inappropriate b. At the 45th Annual Meeting of the IDSA in 2007, Louis Rice, MD, recommended reducing

the length of antimicrobial regimens as the “safest” and “most palatable” method to combat antimicrobial resistance

4. Infections with Recent Recommendations in Favor of Reducing Treatment Durations24-26 a. Community-acquired pneumonia (CAP): minimum treatment duration of 5 days b. Ventilator-associated pneumonia: 7-day antimicrobial course

i. Note, non-lactose-fermenting GN bacilli associated with recurrent infection with shorter courses (i.e. 7-8 days) of therapy

c. Pyelonephritis: 7 days of therapy with fluoroquinolone appropriate

Clinical Controversy: Optimal Duration of Antibiotic Therapy for Uncomplicated GNB in Adults

Figure 4: Ideal Duration of Therapy Balance

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Past Literature Review

Table 3: Background Literature Author Overview Conclusion

Havey et al.27 2011 systematic review and meta-analysis that investigated optimal duration of antibiotic therapy for bacteremia • 24 trials met eligibility criteria – only 1 trial,

regarding intensive care unit (ICU) neonates, dedicated to bacteremia

• 227 patients with bacteremia in 13 trials allocated to short duration (SD) (5-7 days) vs. long duration (LD) (7-21 days) antibiotic therapy o 155 bacteremic patients with outcomes

data – 66 neonatal bacteremias, 40 secondary to intra-abdominal infection, 40 secondary to pneumonia, and 9 secondary to pyelonephritis

• Results o Clinical cure: SD 45/52 vs. LD 47/49; RR,

0.88; 95% confidence interval (CI), 0.77-1.01

o Microbiologic cure: SD 28/28 vs. LD 30/32; RR, 1.05; 95% CI, 0.91-1.21

o Survival: SD 15/17 vs. LD 26/29; RR, 0.97; 95% CI, 0.76-1.23

Shorter durations (≤ 7 days) of antibiotic therapy may successfully treat non-S. aureus bacteremia due to mild to moderate intra-abdominal infection, CAP, or pyelonephritis • Not specific to GNB • Variation in duration of

treatment amongst trials • Low rates of blinding • Clinical improvement

prior to randomization required by some trials

• Post-randomization exclusions or per-protocol analyses meant potentially excluding bacteremic patients that failed therapy

• Treatment outcomes for bacteremic patients determined post hoc

Coats et al.28 2013 systematic review analyzed the evidence base for duration of antibiotic therapy in GNB secondary to urinary tract infection (UTI) • Focused on GNB due to pyelonephritis and

urosepsis • Canadian survey of critical care and infectious

diseases specialists revealed that 56.6% recommended < 10 days of treatment for GNB secondary to UTI purely based on expert consensus

• Included Havey et al. systematic review and meta-analysis and four RCTs

Limited current evidence suggests short-course (5-7 days) antibiotic therapy effective in treatment of E. coli bacteremia due to pyelonephritis • Literature limited to E.

coli • Studies with lack of focus

on bacteremia • Limited patient number • Potential bias

Hill et al.29 2012 poster abstract assessed efficacy of SD antibiotic therapy for GNB in critically ill trauma patients • Retrospective analysis at Presley Regional

Trauma Center in Memphis, Tennessee • January 2008 to December 2010 • Inclusion: critically ill trauma patients with GNB

7 days of antibiotic therapy resulted in acceptable clinical and microbiological success rates • Not exclusive to GNB • LD group sicker

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• Exclusion: immunocompromised, < 48 hours of antibiotics

• 72 patients received SD (≤ 7 days) vs. 48 patients LD (> 7 days) antibiotic therapy

• Mean age 44 ± 18 years, 77% male, 87% blunt injuries

• LD significantly more likely to have abdominal trauma, lungs as source or bacteremia, gram-positive concurrent bacteremia, and multiple antibiotics

• Results: o No significant difference in clinical success:

SD 72/78 (92%) vs. LD 48/51 (94%) o No significant difference in microbiologic

success: SD 34/36 (94%) vs. LD 27/33 (82%)

• Clinical success accounted for excluded patients

• Lacked definition of clinical success

Uno et al.30 2017 single center, retrospective cohort study aimed at validating the practice of < 2 weeks of antimicrobial treatment in patients with GN bacillary bacteremia secondary to acute cholangitis • Kameda Medical Center in Japan • July 2012 to March 2014 • Prior to May 2013, 40 patients received ≥ 2

weeks of antimicrobial therapy vs. 52 patients received < 2 weeks after May 2013

• Inclusion: acute cholangitis diagnosis with positive GN blood culture

• Exclusion: malignant biliary obstruction, presence of cholecystitis or hepatic abscesses, drainage procedures not performed, contraction of another illness during treatment

• Before May 2013, patients were older (81.7 vs. 76.0 years; P = 0.007) and less likely to receive appropriate empiric therapy (75.0% vs. 90.4%; P = 0.045)

• Results: o 30-day mortality rate: before May 2013

2/35 (5.7%) vs. after May 2013 0/47 (0.0%); P = 0.179

o 90-day recurrence: before May 2013 4/30 (13.3%) vs. after May 2013 0/37 (0.0%); P = 0.036

< 2 weeks of antimicrobial therapy may be adequate for GN bacillary bacteremia secondary to acute cholangitis with source control • Generalizability • Age and appropriate

empiric treatment favor < 2-week treatment group

• 20 patients lost to follow-up at 90 days

• No mention of power • Potentially unaccounted-

for outcomes due to 30-day limitation

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Cohort Studies

Swamy S, Sharma R. Duration of treatment of gram-negative bacteremia: are shorter courses of antimicrobial therapy feasible? Infect Dis Clin Pract. 2016;24(3):155-160.31

Introduction Objective Determine if short-course (SC) antimicrobial therapy was noninferior to intermediate-

course (IC) and long-course (LC) therapy for uncomplicated GNB Methods Study Design Single center, retrospective, case-cohort study

• Maimonides Medical Center in Brooklyn, New York • August 2006 to November 2013 • SC (≤ 7 days) vs. IC (8-14 days) and LC (> 14 days) appropriate therapy • GNB defined as GN organism in ≥ 1 blood culture with signs and symptoms of

infection • Uncomplicated bacteremia excluded endocarditis, osteomyelitis, necrotizing

fasciitis, uncontrolled abscess, central nervous system infection, central venous catheter infection without catheter removal, infection secondary to Haemophilus spp., Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, Salmonella spp., and Brucella spp.

Population Inclusion: • GNB documented • ≥ 18 years old

Exclusion: • Pregnancy • Immunocompromised • Polymicrobial bacteremia • Complicated bacteremia • Inappropriate antimicrobial therapy

Outcome(s) Primary: Proportion of patients with clinical response (resolution of infection signs and symptoms, defervescence to < 100.4 °F, and white blood cell count < 11,000 cells/mm3) at end of therapy Secondary: Proportion of patients who achieved microbiological cure (sustained clearance of microbiologic organism from blood), indeterminate microbiological outcome (lack of repeat blood cultures), and microbiologic failure (regrowth of infecting organism in bloodstream) at end of therapy Subgroup analyses: Stratify clinical response in each treatment group based on causative organism (E. coli vs. K. pneumoniae vs. other), bacteremia source (urinary vs. non-urinary), and time to defervescence (≤ 72 hours vs. > 72 hours)

Statistical Methods

• Sample size of 715 patients required for 80% power to identify differences between treatment groups assuming clinical response rates of 85% SC, 90% IC, and 95% LC and prevalence of 30% SC, 50% IC, and 20% LC

• Student t test for continuous variables • Fisher’s exact test for nominal variables • Subgroup analyses utilized Fisher’s exact test and logistic regression

Results Baseline Characteristics

• 178 patients out of 406 met eligibility criteria Table 4: Patient Characteristics

Variable SC Therapy

(n = 42) IC Therapy (n = 100)

LC Therapy (n = 36) P Value

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Age, y, mean (StD) 65.1 (16.9) 62.2 (18.8) 61.6 (14.6) 0.6 Female, n (%) 28 (66) 68 (68) 24 (66) 0.9 SAPS II score, mean (StD) 36.7 (10.8) 33.1 (16.5) 34.75 (10.5) 0.4 Length of stay, days, mean (StD)

11.9 (10.9) 16.0 (16.2) 21.1 (21.6) 0.05

Source of bacteremia (urinary), n (%)

23 (55) 54 (54) 18 (50) 0.9

Source of bacteremia (catheters), n (%)

3 (7) 16 (16) 6 (16) 0.3

Infecting pathogen (E. coli), n (%)

25 (57) 43 (43) 22 (61) 0.07

Infecting pathogen (K. pneumoniae), n (%)

10 (24) 23 (23) 6 (17) 0.7

Time to defervescence ≤ 72 hours, n (%)

33 (79) 69 (69) 13 (36) 0.0002

StD = standard deviation; SAPS II = Simplified Acute Physiology Score II Table 5: Infecting Pathogens

Bacteria Percent of Isolates, (%) E. coli 48 K. pneumoniae 21 Klebsiella oxytoca 4 Enterobacter cloacae 7 Enterobacter aerogenes 1 P. aeruginosa 7 Serratia marcescens 4 Acinetobacter baumanii 4 Proteus mirabilis 4

Table 6: Source of Bacteremia Source Percent, (%)

Respiratory tract infections 6 Intra-abdominal infections 12 UTIs 53 Catheter related infection 14 Skin and soft tissue infection 1 Other/indeterminate 14

Endpoints Primary: • End of therapy clinical response rates: 78.6% SC therapy, 89.0% IC therapy, and

80.6% LC therapy; P = 0.2 Secondary: • Microbiological cure rates at end of therapy: 83.3% SC therapy, 89.0% IC

therapy, and 91.7% LC therapy; P = 0.7 • Indeterminate microbiological outcome rates at end of therapy: 9.5% SC

therapy, 7.0% IC therapy, and 2.8% LC therapy • Microbiologic failure rates at end of therapy: 7.1% SC therapy, 4.0% IC therapy,

and 5.6% LC therapy Subgroup analyses:

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• Fisher’s exact test: o No difference in clinical response at end of therapy among treatment

groups when stratified by pathogen or source of bacteremia o Significant difference in clinical response rate at end of therapy among

treatment groups when stratified for time to defervescence > 72 hours (11% SC therapy, 65% IC therapy, and 70% LC therapy; P = 0.03)

• Logistic regression: organism, bacteremia source, and defervescence time not predictive of clinical response at end of therapy

Author’s Conclusion

Clinical response rates and microbiological cure rates appeared similar when comparing SC therapy to IC and LC therapy for the treatment of GNB

Discussion Critique Strengths:

• Excluded patients who did not receive appropriate antimicrobial therapy (coverage, penetration, and dose)

• Insight into clinical response with shorter durations of therapy

• Nearly 20% of BSIs caused by non-lactose fermenting organisms

Limitations: • Retrospective – selection bias • Failed to meet power • Failed to assess mortality or recurrence • Lacked breakdown of IV/oral therapy • No actual presentation of number of

patients with source control • No breakdown of non-lactose fermenting

organisms by treatment group • Minimum treatment duration not limited • Results summarized without detailed

breakdown Take Home Point(s)

No insight into recommended initial duration for GNB, but reinforced importance of tailoring therapy based on clinical response

Nelson AN, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. Optimal duration of antimicrobial

therapy for uncomplicated gram-negative bloodstream infections. Infection. 2017;45(5):613-20.32 Introduction Objective Determine optimal treatment duration for uncomplicated GNB Methods Study Design Retrospective cohort study

• Palmetto Health Richland and Baptist hospitals in Columbia, South Carolina • January 1st, 2010 to December 31st, 2013 • SC (7-10 days) vs. LC (> 10 days) appropriate therapy • Infection site acquisition: community-acquired, healthcare-associated, and

hospital-acquired • Uncomplicated bacteremia defined as absence of in-hospital mortality,

hospitalization > 14 days, or deep-seated infections • Inadequate source control defined as > 72-hour delay in source of infection

removal (i.e. abscess drainage, central venous catheter removal, or biliary stone removal)

• Recurrent infection defined as subsequent BSI or primary site infection with same genus and species

Population Inclusion: • Aerobic, GN bacillus

positive blood culture

Exclusion:

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• Hospitalization • Adults

• Treatment duration dictated by outcome (in-hospital mortality) and clinical response to therapy (prolonged hospitalization)

• Complicated GN BSI • Treatment < 7 days or undetermined

duration of therapy Outcome(s) Primary: Compare rates of treatment failure (mortality or recurrent infection within

90 days of index bacteremia) between SC and LC antimicrobial therapy • Subgroup analysis including only patients who received either IV or highly

bioavailable oral agents Statistical Methods

• Adjusted for propensity to receive SC antimicrobial therapy using multivariate logistic regression by identifying associations between baseline variables and treatment group o χ2 or Fisher’s exact test used for categorical variables o Wilcoxon rank-sum test used for continuous variables o Variables considered in multivariate logistic regression if P value of

univariate association < 0.10 o Propensity analysis baseline variables included demographics, chronic

comorbidities, site of infection, and indwelling central venous catheter or urologic disorders prior to bacteremia

o Odds ratio (OR) with 95% CI reported • Cox proportional hazards regression model to compare treatment failure rates

o Univariate analysis included demographics, clinical characteristics, antibiotic route, and bioavailability of definitive antimicrobial agents

o Multivariate Cox model included univariate variables associated with treatment failure with P value < 0.10 and therapy duration group Model incorporated covariate of adjusted propensity to receive SC

therapy o Kaplan-Meier analysis used to evaluate model and provide treatment

failure rates o Hazard ratio (HR) and 95% CI reported

• Subgroup analysis employed multivariate Cox proportional hazards regression • 2-sided P value < 0.05 considered statistically significant unless otherwise

specified Results Baseline Characteristics

• 411 patients out of 832 met eligibility criteria Table 7: Clinical Characteristics of Patients

Variable SC Therapy (n = 117)

LC Therapy (n = 294) P Value

Age, y, median (IQR) 69 (58-79) 65 (52-78) 0.03 Female, n (%) 78 (67) 180 (61) 0.30 Ethnicity, n (%)

Caucasian African American Other

67 (57) 47 (40)

3 (3)

140 (48) 137 (47)

17 (6)

0.13

Preexisting conditions, n (%) Diabetes

43 (37)

110 (37)

0.90

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ESRD Liver cirrhosis Cancer Immune compromised host Central venous catheter Urologic disorder

1 (1) 2 (2)

16 (14) 15 (13) 14 (12)

7 (6)

15 (5) 10 (3)

35 (12) 30 (10) 32 (11) 27 (9)

0.04 0.52 0.62 0.44 0.75 0.29

Site of acquisition, n (%) Community-acquired Healthcare-associated Hospital-acquired

63 (54) 43 (37) 11 (9)

159 (54) 104 (35) 31 (11)

0.93

Pitt bacteremia score ≥ 4, n (%) 8 (7) 35 (12) 0.13 Urinary source of infection, n (%) 81 (69) 201 (68) 0.86 Inadequate source control, n (%) 2 (2) 12 (4) 0.37 Definitive therapy with IV/high bioavailable oral agents, n (%)

71 (61) 110 (37) < 0.001

Inadequate empirical therapy, n (%) 6 (5) 9 (3) 0.38 Duration of adequate IV therapy, days, median (IQR)

4.9 (3-7) 4.8 (3-8) 0.17

Total duration of adequate therapy, days, median (IQR)

8.5 (7-10) 13.3 (12-15) < 0.001

IQR = interquartile range; ESRD = end-stage renal disease Table 8: Microbiology by Duration of Therapy

Bacteria SC (n = 117) LC (n = 294) E. coli, n (%) 79 (68) 192 (65) Klebsiella spp., n (%) 15 (13) 46 (16) P. mirabilis, n (%) 8 (7) 17 (6) P. aeruginosa, n (%) 6 (5) 12 (4) Enterobacter spp., n (%) 3 (3) 9 (3) Other, n (%) 6 (5) 18 (6)

spp. = species Endpoints Primary:

• 32 of 290 (11.0%) patients experienced treatment failure within 90 days o 11 deaths, 21 recurrences (9 recurrent BSIs, 12 recurrent UTIs) o 36 days (range: 10-69 days) was median time to treatment failure

• Univariate analysis: o No difference in unadjusted treatment failure rates: 13.2% SC vs. 8.5% LC,

P = 0.14 Unadjusted 90-day mortality: 8.2% SC vs. 3.3% LC, P = 0.04 Unadjusted 90-day recurrence rates: 6.7% SC vs. 6.5% LC, P = 0.93

o Treatment failure associated risk factors: end-stage renal disease, liver cirrhosis, immune compromised host, central venous catheter, and route/bioavailability of definitive antimicrobial agents

o Subgroup analysis: Unadjusted treatment failure rates in patient’s receiving definitive

therapy with IV/highly bioavailable oral agents: 11.4% SC vs. 2.5% LC, P = 0.02

• Multivariate analysis:

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Table 9: Risk Factors for Treatment Failure Variable HR 95% CI P Value

Duration of adequate therapy > 10 days 7-10 days

1

2.60

Referent 1.20-5.53

0.02 Liver cirrhosis 5.53 1.89-15.02 0.004 Immune compromised host 4.30 1.57-10.80 0.006 Central venous catheter 1.50 0.52-3.93 0.44 Definitive therapy with IV/high bioavailability oral agents

0.33 0.14-0.73 0.006

• Additional analysis (n = 181): o Each additional day of antimicrobial therapy > 7 days resulted in significant

decline in risk of treatment failure (HR, 0.59; 95% CI, 0.39-0.82; P < 0.001) o 7-day treatment failure rate 18.6% declined to 0% at ≥ 12 days of therapy

Author’s Conclusion

In patients with uncomplicated GNB, > 10 days of IV or highly bioavailable oral agents recommended

Discussion Critique Strengths:

• More stringent definition of SC therapy

• Minimum treatment duration of 7 days

• Included immune compromised patients

• 90-day recurrence • Adjusted for propensity to

receive SC antimicrobial therapy

• Subgroup analysis included only IV/highly bioavailable oral agents

Limitations: • Retrospective – selection bias • 121 patients lost to follow-up • Inclusion of in-hospital mortality and

hospitalization > 14 days in complicated bacteremia definition

• 129 sources of infection not documented • No mention of power • Timeframe allows for more death due to

other causes • No maximum treatment duration, with 118

(29%) of patients receiving > 14 days of therapy in LC group

Take Home Point(s)

In patients receiving IV or highly bioavailable oral agents, no patients experienced treatment failure at day 12 or beyond

Chotiprasitsakul D, Han JH, Cosgrove SE, et al. Comparing the outcomes of adults with

Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis. 2018;66(2):172-177.33

Introduction Objective Determine optimal duration of antimicrobial therapy for GNB by comparing clinical

outcomes of adult patients with Enterobacteriaceae bacteremia receiving SC vs. prolonged-course (PC) antibiotic therapy

Methods Study Design Retrospective, multicenter, propensity score-matched cohort study

• 3 medical centers: Johns Hopkins Hospital, University of Maryland Medical Center, and Hospital of the University of Pennsylvania

• 2008 to 2014 • SC (6-10 days) vs. PC (11-16 days) appropriate therapy

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• Infectious diseases-trained physicians determined source of infection and appropriateness of control measures o Bacteremia considered uncomplicated if source control achieved within 7

days o Source control defined as infected hardware removal, fluid collection

drainage, or resolution of urinary or biliary obstruction during therapy Population Inclusion:

• Initial episode of Enterobacteriaceae bacteremia

• Admission to 1 of 3 study hospitals

• ≥ 18 years old

Exclusion: • Polymicrobial bacteremia • Treatment duration < 6 days or > 16 days • Antibiotic discontinuation due to hospice transfer • Death while receiving therapy • Lacking ≥ 1 agent with in vitro activity from time of

culture to completion of therapy • Aminoglycoside monotherapy • Hematopoietic stem cell or solid organ transplant

recipients Outcome(s) Primary: 30-day posttreatment, all-cause mortality

Secondary: • 30-day posttreatment:

o Recurrent bacteremia with same organism o C. difficile infection o Multidrug-resistant gram-negative (MDRGN) colonization or infection not

present in previous year prior to index blood culture date Additional: 30-day mortality post positive blood culture day 1

Statistical Methods

• 1:1 nearest neighbor propensity score matching via a multivariable logistic regression model without replacement to account for confounding by indication o Propensity score covariates included calendar year of bacteremia, hospital,

age, preexisting conditions, Pitt bacteremia score, ICU stay on day 1 of bacteremia, source of bacteremia, and source control measures

• Baseline categorical variables compared via χ2 or Fisher’s exact test between matched pairs

• Baseline medians of continuous variables compared via Wilcoxon rank-sum test • Unadjusted HR and 95% CI for potential risk factors associated with time to

mortality estimated using Cox proportional hazards model • Multivariable models included immunocompromised status and variables

yielding P values < 0.10 on univariable analysis • OR and 95% CIs for secondary outcomes estimated using logistic regression • 2-sided P value < 0.05 considered statistically significant

Results Baseline Characteristics

• 1,769 patients out of 4,967 met eligibility criteria and were well-matched into 385 matched pairs

Table 10: Propensity Score-Matched Cohort Baseline Characteristics

Characteristic SC

(n = 385) PC

(n = 385)

P Value Age, y, median (IQR) 60 (49-69) 60 (49-70) 0.73 Female, n (%) 191 (49.6) 174 (45.2) 0.22 Race/ethnicity, n (%) 0.15

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White Black or African American Asian Latino Unknown/multiracial

196 (50.9) 154 (40.0)

11 (2.9) 8 (2.1)

16 (4.2)

177 (46.0) 161 (41.8)

17 (4.4) 18 (4.7) 12 (3.1)

0.17 0.61 0.25 0.05 0.44

Source of bacteremia, n (%) Pneumonia Skin and soft tissue Urinary tract Biliary Gastrointestinal Catheter-associated

36 (9.4) 14 (3.6)

134 (34.8) 60 (15.6) 87 (22.6) 54 (14.0)

33 (8.6) 17 (4.4)

144 (37.4) 65 (16.9) 66 (17.1) 52 (13.5)

0.71 0.58 0.45 0.63 0.12 0.83

Inadequate source control, n (%) 3 (0.8) 4 (1.0) 0.45 Pitt bacteremia score on day 1, median (IQR)

2 (1-3) 2 (1-3) 0.59

ICU day 1, n (%) 113 (29.4) 122 (31.7) 0.48 Preexisting conditions, n (%)

End-stage liver disease ESRD requiring dialysis Structural lung disease Heart failure Diabetes

35 (9.1) 18 (4.7) 34 (8.8)

46 (11.9) 96 (24.9)

31 (8.1) 21 (5.5) 24 (6.2)

51 (13.2) 96 (24.9)

0.61 0.62 0.17 0.59 1.00

Immunocompromised, n (%) 127 (33.0) 134 (34.8) 0.59 IQR = interquartile range; ICU = intensive care unit; ESRD = end-stage renal disease

Table 11: Enterobacteriaceae Bloodstream Isolates in Matched Cohort Enterobacteriaceae SC (n = 385) PC (n = 385)

E. coli, n (%) 177 (46.0) 184 (47.8) Klebsiella spp., n (%) 137 (35.6) 114 (29.6) Enterobacter spp., n (%) 36 (9.4) 54 (14.0) Serratia spp., n (%) 13 (3.4) 9 (2.3) Proteus spp., n (%) 13 (3.4) 14 (3.6) Citrobacter spp., n (%) 9 (2.3) 10 (2.6)

spp. = species *Note, all patients initiated on β-lactam antibiotic at time of blood cultures

Endpoints Primary: • 37 (9.6%) deaths SC group (median treatment duration 8 days, IQR = 7-9 days) • 39 (10.1%) death PC group (median treatment duration 15 days, IQR = 13-15

days) • No difference in mortality reduction with each additional day of therapy

Table 12: 30-Day Posttreatment, All-Cause Mortality

Variable Unadjusted HR

(95% CI) P Value Adjusted HR

(95% CI) P Value SC therapy 1.12 (0.70-1.80) 0.64 1.00 (0.62-1.63) 0.97 Urinary source 0.36 (0.19-0.67) 0.001 0.49 (0.26-0.94) 0.03 Pneumonia 3.06 (1.73-5.42) < 0.001 1.60 (0.85-3.02) 0.15 Pitt bacteremia score 1.31 (1.21-1.42) < 0.001 1.29 (1.17-1.43) < 0.001

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ICU on day 1 of bacteremia

2.38 (1.48-3.81) < 0.001 0.99 (0.56-1.76) 0.98

End-stage liver disease 3.58 (2.05-6.06) < 0.001 4.12 (2.30-7.39) < 0.001 Immunocompromised status

1.03 (0.63-1.70) 0.89 1.40 (0.83-2.36) 0.21

ICU = intensive care unit Secondary: • Recurrent bacteremia with same organism: 5 (1.3%) SC vs. 9 (2.3%) PC

o OR, 1.32; 95% CI, 0.48-3.41 • C. difficile infection: 7 (1.8%) SC vs. 6 (1.6%) PC

o OR, 1.16; 95% CI, 0.39-3.51 • MDRGN colonization/infection: 17 (4.4%) SC vs. 28 (7.3%) PC

o OR, 0.59; 95% CI, 0.32-1.09; P = 0.09 Additional: No difference in 30-day mortality between groups when first positive blood culture represented day 1 (adjusted HR, 0.92; 95% CI, 0.59-1.45)

Author’s Conclusion

SC antibiotic therapy for uncomplicated Enterobacteriaceae bacteremia yielded no difference in mortality and potentially protected against development of MDRGN bacteria 30 days posttreatment

Discussion Critique Strengths:

• Appropriate therapy from day of initial blood culture

• 385 propensity score-matched pairs

• Examined detrimental effects of PC therapy

• Mortality 30 days posttreatment reduced likelihood of death due to other causes

• Included immunocompromised patients

Limitations: • Retrospective – selection bias • Enterobacteriaceae exclusive • Potentially unaccounted-for recurrence

with 30-day posttreatment window • Post-hoc power of 40% to detect

MDRGN colonization/infection • Technically not limited to

uncomplicated GNB (< 1% inadequate source control within 7 days)

• No breakdown of IV/oral therapy

Take Home Point(s)

In patients with Enterobacteriaceae bacteremia, may consider treating for 6-10 days provided adequate source control

Future Studies

Table 13: Randomized Controlled Trials Trial Overview

Phase 4, randomized, controlled multicentric, open-label clinical trial to prove that the 7-day course of treatment for Enterobacteriaceae bacteremia is more efficient and equally safe than 14-day scheme34

Design: open label randomized, multicentric clinical trial with a superiority design comparing 7-day vs. 14-day antibiotic therapy Location: Spain Population: 238 adult patients with Enterobacteriaceae BSI Outcomes: clinical and microbiological cure at 28 days, adverse reactions related to antimicrobial therapy

Duration of antibiotics for the treatment of gram-negative bacilli

Design: open label randomized controlled trial comparing SC (≤ 7 days) vs. LC (> 7 days) Location: Israel and Italy

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bacteremia - a randomized controlled trial35

Population: approximately 600 hospitalized adults with GNB randomized on day 7 of appropriate IV or oral antibiotic treatment Primary Outcome: composite of 90-day all-cause mortality, treatment failure, hospital readmission or extended hospitalization Secondary Outcomes: 30-day C. difficile infection, antibiotic resistance, carriage of carbapenem resistant K. pneumoniae, and adverse events

The PIRATE project: point-of-care, informatics-based randomized controlled trial for decreasing overuse of antibiotic therapy in gram-negative bacteremia36

Design: multicenter randomized controlled non-inferiority trial comparing 7-day vs. 14-day vs. individualized duration Location: Switzerland Population: 500 adult patients with GNB randomized on day 5 of appropriate therapy 1:1:1 to treatment groups Primary Outcome: 30-day clinical failure Secondary Outcomes: 90-day clinical failure, all-cause mortality, and C. difficile infection

Recommendations

1. Microbiological (n = 1,359 isolates) and source breakdown of 3 preceding trials

Figure 5: Microorganisms

2. Treatment considerations a. Uncomplicated GNB b. Source c. Adequate source control d. Patient lacks the following

i. Liver cirrhosis ii. Immunocompromised status

e. Initiation of appropriate antimicrobial therapy

Table 14: Source Distribution Source Number

Urinary 655 Intra-abdominal/biliary 299 Other/indeterminate 162 Catheter 131 Respiratory tract 80 Skin and soft tissue 32

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i. Susceptible organism ii. IV β-lactam therapy until afebrile for ≥ 72 hours

1. Continue therapy OR 2. Deescalate to another IV or a highly bioavailable oral agent

3. Recommendation a. Organism

i. Non-lactose fermenting, non-Enterobacteriaceae: 14 days of antibiotic therapy ii. Enterobacteriaceae: 7-10 days of antibiotic therapy

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Appendices Appendix A: Pitt Bacteremia Score

Table 15: Pitt Bacteremia Score37 Criterion Points

Fever (oral temperature) ≤ 35°C or ≥ 40°C 35.1-36.0°C or 39.0-39.9°C 36.1-38.9°C

2 1 0

Hypotension Acute hypotensive event with drop in systolic blood pressure > 30 mmHg and diastolic blood pressure > 20 mmHg or Requirement for IV vasopressor agents or Systolic blood pressure < 90 mmHg

2

Mechanical ventilation 2 Cardiac arrest 4 Mental status

Alert Disoriented Stuporous Comatose

0 1 2 4

All criteria graded within 48 hours before or on the day of first positive blood culture. The highest point score during that time is recorded. Appendix B: Nelson et al.

Table 16: Unadjusted Treatment Failure Rates by Duration and Type of Definitive Antimicrobial Therapy32

Definitive antimicrobial therapy 7-10-day duration (N = 117) > 10-day duration (N = 294)

N (%) TFR (%) N (%) TFR (%) IV or highly bioavailable oral agents 71 (61) 11.4 110 (37) 2.5

IV agents 46 (39) 16.0 39 (13) 3.7 Oral levofloxacin 25 (21) 4.0 71 (24) 2.0

Other oral agents 46 (39) 18.7 184 (63) 11.3 Ciprofloxacin 28 (24) 13.6 107 (36) 11.2 Trimethoprim-sulfamethoxazole 4 (3) 25.0 21 (7) 10.1 Penicillins and cephalosporins 14 (12) 25.9 56 (19) 13.2

TFR = treatment failure rate from Kaplan-Meier analysis IV agents include ceftriaxone (27), piperacillin-tazobactam (12), cefepime (8), meropenem (7), ciprofloxacin (7), gentamicin (6), ertapenem (5), levofloxacin (5), and others (8)