1. Multi-Drug Resistance Journal Club – Diana Nicole Nowicki – 06/24/2016
1
BACKGROUND AND OVERVIEW
Article Title/Citation “Comparable efficacy of Tigecycline versus Colistin Therapy for Multidrug-Resistant and Extensively Drug-
Resistant Acinetobactor baumannii Pneumonia in Critically Ill Patients”
Kim WY, Moon JY, Huh JW, Choi SH, Lim CM, Koh Y, Chong YP, Hong SB. Comparable Efficacy of
Tigecycline versus Colistin Therapy for Multidrug-Resistant and Extensively Drug-Resistant Acinetobacter
baumannii Pneumonia in Critically Ill Patients. PLoS One. 2016 Mar 2;11(3):e0150642
Study objectives/purpose
(and research hypothesis, if
applicable)
1. Compare the clinical outcomes of patients with multi-drug resistance/extensively drug-resistant
Acinetobactor baumannii (MDR/XDRAB) pneumonia treated with either a tigecycline-based therapy or
colistin-based therapy.
2. Evaluate the efficacy of combination therapy versus monotherapy.
Brief background (why
issue is important, summary
of previous literature)
With the growth of multi-drug resistance organisms (MDROs), we have seen an increase in antimicrobial
stewardship programs, government-funded research, and ‘superbug’ occurrences worldwide (with the first
reported in U.S. in May 2016)1. Acinetobactor baumannii, an aerobic gram-negative bacillus that is ubiquitous in
nature, causes a range of infections. In the intensive care unit (ICU), especially mechanically ventilated (MV)
patients, MDR/XDRAB is associated with high mortality.2 Agents commonly used are meropenem, colistin,
polymyxins b, amikacin, rifampin, minocycline, sulbactam, zosyn and tigecycline.3
Agents Tigecycline Colistin
[aka polymyxins E; Colistimethate Sodium (CMS)]
Brand Tygacil® Coly-Mycin M
Class glycylcycline polymyxin
Hx 1st glycylcycline; Approved 2005 c. 1949; abandoned in 1980s d/t nephrotoxicity
Indications SSTI, IAIs, CAP, HAPa MDR Gram-negative bacilli infections, CF ppx a
Black Box Increase all-cause mortality -
MOA Binds to 30s ribosomal subunit
inhibiting protein synthesis
Inactive prodrug converts to CMS with multi-
targets that allows permeability of outer membrane
Dosing 100mg IV then 50mg IV Q12H IV 2.5-5 mg/kg/day (Consider loading dose)
Adjustments Sever hepatic impairment Renal impairment, RRT/HD
ADRs GI (N/V/D) Nephrotoxicity, neurotoxicity
MOR MDR efflux pump mechanism Gene amplification at high concentrations (mcr-1)
aoff-label use;
Definitions – CF ppx: Cystic fibrosis prophylaxis; RRT: renal replacement therapy; HD: hemodialysis
Funding sources Authors “received no specific funding for this work.”
METHODS
Study design and
methodology
Single-centered retrospective observational study at Asan Medical Center, a 2,680-bed university affiliated
hospital in Seoul, Korea. Reviewed medical records of patients admitted to the medical or cardiothoracic
ICU between January 2009 and December 2010. IRB approved study protocol. Patients records were
anonymized and de-identified prior to analysis.
Normal Renal Function Dosing Tigecycline Colistin
Loading Dose 100mg IV x 1 5mg/kg CBA IV x 1
Maintenance Dose 50 mg IV Q12h 150mg CBA IV Q12h
Definitions – CBA: Colistin Base Activity
Patient selection &
enrollment [inclusion/
exclusion criteria]
Inclusion Exclusion
≥ 20 yo who:
• Confirmed dx of HAP or VAP by
MDR/XDRAB
• Received tigecycline or colistin as
mono –or- combination therapy as
initial therapy for at least 3 days
• If multiple episodes in one patient,
only first episode was included
• Concomitant use of tigecycline and colistin
• “inadequate treatment” (< 3 days)
• Combination infection without
“appropriate Abx therapy” (empiric
therapy didn’t include “one effective Abx”)
Outcome measures/
endpoints
Primary Outcome: Clinical Success Rate = clinical cure (e.g. resolution of s/sx infection by end of therapy
or clinical improvement (e.g. partial resolution of s/sx of infection)

2. Multi-Drug Resistance Journal Club – Diana Nicole Nowicki – 06/24/2016
2
Outcome measures/
endpoints (ctd.)
Secondary Outcomes:
• Recurrence of infection (new episode of infection <72 h after preceding episode)
• Microbiological Success Rate (eradication of the pathogen (e.g., no growth of the pathogen in the
final culture of specimens during the entire hospitalization)
• Improvement in CPIS & radiologic score at day 7 compared with baseline
• Duration of MV, ICU and hospital stay
• Nephrotoxicity (In pts w/ normal renal function, nephrotoxicity was SCr >2 mg/dL, a 50%
reduction in the calculated CrCl compared w/ baseline, or initiation of RRT; In pts w/ preexisting
renal dysfunction, nephrotoxicity was increase of >50% baseline SCr or a 50% reduction in the
calculated CrCl compared with baseline)
• Mortality
• Clinical Failure
Statistical analyses Mann-Whitney U test [Continuous Variables], chi-square or Fisher’ s exact test [Categorical variables],
Hosmer-Leme show test [model calibration]. Two-tailed; P value < 0.05 was considered significant.
Univariate/multivariate analyses performed with SPSS version 22.0 for Windows (SPSS Inc., Chicago, IL)
RESULTS
Enrollment & baseline
characteristics
(Also see Table 1, page 5)
Of the 99 cases found, only 70 were used for this analysis. Tigecycline group was slightly older, colistin
group was larger (30 vs. 40 patients), while all other characteristics were similar. Concomitant use of
tigecycline and colistin was excluded, along with any patients that passed during 30-day period.
Summary of primary and
secondary outcomes
(Also see Table 2-3, page 6)
Appeared to be no statistical significance in any outcomes except for safety parameter, nephrotoxicity
occurred in colistin group and not tigecycline which was to be expected (0% and 20%, respectively;
p=0.009). More extensive hospital duration was apparent in colistin group but not significant per analysis
(19-58 days vs. 16-111 days, respectively; p = 0.44). Subgroup analysis on mono versus combination therapy
regimens based with tigecycline or colistin showed no significant difference in outcomes (ICU mortality 51%
vs. 31%, respectively; p=0.09).
AUTHORS’ DISCUSSION & CONCLUSIONS
Brief summary of authors’
main discussion points
and conclusions
• Assessed that the small population set and varying infection sites does not effectively project
tigecycline’s specific role in MDR/XDR treatment.
• They believe this study indicates comparable efficacy of tigecycline-based therapy to colistin-based
therapy in critically ill patients with MDR/XDRAB pneumonia.
• Study holds many limitations and further research must be conducted toward tigecycline.
STUDENT’S DISCUSSION & CONCLUSIONS
Study strengths Provided clear definitions.
Included causative pathogen of MDR/XDRAB pneumonia supported by microbiological data.
Routine susceptibility testing for tigecycline was performed for each isolate.
Universal healthcare system reporting.
Study limitations Poor study design (Non-randomized methods, size, not multi-center, no follow up, underpowered etc.)
Exclusions: Per-protocol – patients that died within 30 days were excluded (Monotherapy n=27 vs. Combo
n=21), combination therapy of tigecycline and colistin together (although mentioned in discussion), etc.
Did not provide dosing for renal adjustments, severity of CKD, or appear to analyze correlation to nephrotoxicity
and poor outcomes.
Applicability and impact
on
pharmacists/healthcare
providers
Need for further evaluation in appropriate therapy especially in high-risk mortality populations.
Supporting recommendation that colistin be used as adjunct therapy to prevent resistance, limit ADEs, and
provide synergistic antimicrobial effects with used in combination with other agents (mono-therapy does not
correlate to positive clinical outcomes).
Review proper dosing of colistin and CBA awareness.
Student Conclusions and
recommendations
Need quality RCTs/Prospective/Case Studies – although difficult with acute and severely ill patients
• Colistin Vs. Polymyxin b
• Further look into polymyxins b? (not available in Europe for human use, used in vet med)
• Best combinations with polymyxin.
Need to continue antimicrobial stewardship programs as resistance to these agents can happen quickly.
References
1. U.S. Department of Health and Human Services (HHS). Proactive Efforts by U.S. Federal Agencies Enable Early Detection of New Antibiotic Resistance.
HHS website. http://www.hhs.gov/blog/2016/05/26/early-detection-new-antibiotic-resistance.html. May 26, 2016. Accessed June 15, 2016.
2. Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH, Hsueh PR, Yang JL, Shen NJ, Wang JT, Hung CC, Chen YC, Chang SC. Excess Mortality
Associated With Colistin-Tigecycline Compared With Colistin-Carbapenem Combination Therapy for Extensively Drug-Resistant Acinetobacter
baumannii Bacteremia: A Multicenter Prospective Observational Study. Crit Care Med. 2015 Jun;43(6):1194-204.
3. Fan B, Guan J, Wang X, Cong Y. Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam
against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model. PLoS One. 2016 Jun 17;11(6):e0157757.