Comparative Study of Clinical Outcomes and Safety Between Colistin and Tigecycline for Multi-Drug Resistant Gram Negative Bacteria
Phase: PHASE4
Conditions: Infection in ICU
Sponsor: Beni-Suef University

 
 
 
 
 
 “Comparative Study of Clinical Outcomes and Safety between 
Colistin and Tigecycline for Multi-Drug Resistant Gram 
Negative Bacteria.’’ 
Protocol study 
Submitted for fulfillment Philosophy of Doctoral Degree in 
Pharmaceutical sciences (Clinical Pharmacy) 
Submitted by: 
Nada Abd El-Hamed Saad 
Clinical Pharmacist 
Under supervision of 
Dr. Raghda Roshdy Sayed Hussein 
Assistant Professor and Acting Head of Department of Clinical Pharmacy 
Faculty of Pharmacy, Beni-Suef University 
 
Dr. Shaymaa Nafady Abdelfattah 
Lecturer of Gastroenterology, Hepatology and Infectious diseases 
Faculty of Medicine, Beni-Suef University 
 
Dr. Yasmin Mohamed Madany 
Lecturer of Clinical Pharmacy 
Faculty of Pharmacy, Beni-Suef University 
 
Dr. Marwa Mohsen Mahmoud 
Lecturer of Clinical Pharmacy 
Faculty of Pharmacy, Beni-Suef University 
 
Faculty of Pharmacy 
Beni-suef University 
2024 
 

 
Comparative Study of Clinical Outcomes and Safety between 
Colistin and Tigecycline for Multi-Drug Resistant Gram Negative 
Bacteria.  
 
I. 
Introduction: 
 
The Centers for Disease Control and Prevention (CDC) and the European Center 
for Disease Prevention and Control have defined Multi-drug resistant (MDR) 
Gram-negative bacteria as acquired non-susceptibility to at least one drug in three 
or more antimicrobial categories. Extensively drug-resistant (XDR) Gram-negative 
bacteria was defined as non-susceptibility to at least one agent in all but two or 
fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one 
or two categories). Pan drug-resistant (PDR) was defined as non-susceptibility to 
all agents in all antimicrobial categories (1).  
 
MDR, XDR and PDR of Escherichia coli, Klebsiella pneumoniae, Enterobacter 
spp., Acinetobacterbaumannii, and Pseudomonas aeruginosa have been known by 
difficult-to-treat (DTT) infections that not respond to treat with as β-lactams, 
including carbapenems, extended-spectrum cephalosporins such as ceftazidime, 
ceftriaxone, and cefepime and β-lactam/ β-lactamase inhibitor combinations, and 
fluoroquinolones(2). 
In the past few decades, bacteria developed various mechanisms of resistance to 
almost available antibiotics as tetracycline, beta-lactams, fluoroquinolones and 
aminoglycosides. Colistin and tigecycline have become the last treatment for MDR 
gram negative bacteria(3)(2). 
 
Colisin is polymyxin E antibiotic. Colistin has a unique mechanism of action 
against MDR and XDR bacteria regardless of the resistance. Colistin has an 
antimicrobial activity against aerobic Gram-negative bacteria(4). Colistin is the last 
choice treatment for life-threatening infections, such as carbapenem-resistant P. 
aeruginosa, E. coli, A. baumannii, K. pneumoniae, and other 
Enterobacteriaceae(3). 
Although, colistin has a good antimicrobial activity against MDR and XDR, some 
old literatures reported that colistin associated with high side effects as 
neuorotoxicity, neuromuscular blockade, hematoxicity and nephrotoxicity and 
mortality risk (5)(6).In 1970, the use of colistin was limited for treatment patients 
with cystic fibrosis only. Latterly, some new studies reported that colistin’s side 

effects are less common than old studies and they resolved after discontinuation of 
colistin in severe cases (7). 
 
Tigecycline belongs to a tetracycline class that used for the treatment of MDR 
infections (gram negative and gram positive bacteria). In 2005, the Food and Drugs 
Administration (FDA) approved tigecycline that administrated in a parenteral 
form. The FDA reported in 2010 that the treatment with tigecycline was associated 
with high risk for mortality (8). Recently, tigecycline has been used for treatment 
complicated intra-abdominal infections (CIAI), complicated skin and skin 
structures infections (CSSTI) with the exclusion of diabetes foot infection, and 
community-acquired bacterial pneumonia (CAP) as monotherapy in adult(9). 
 
The FARES and the clinical trial studies suggested that tigecycline administration 
associated with gastrointestinal symptoms (nausea, vomiting and diarrhea), 
pancreatitis, increased hepatic function, jaundice, cholestatic, bleeding risk, 
thrombocytopenia and Steven-Johnson syndrome(8)(10). 
 
The objective of this study to prospectively compare between the clinical outcomes 
and safety of colistin and tigecycline in patients with MDR gram negative bacteria 
in Intensive Care Unit. 
 
II. 
Aim and objectives: 
 
Objective from this study to compare the clinical outcomes and safety between 
colistin and tigecycline for multi-drug resistant gram negative bacteria. 
 
III. 
Method and material: 
Study site: 
 
Study will be in Beni-Suef university hospital. 
 
Study design: 
 
Prospective randomized controlled study. The method of randomization was a 
sealed envelope technique. 
Study duration: 
The study will be conducted from December 2024 to May 2025. 

 
Study population: 
 Group I: 66 patients received intravenous colistin 300 mg colistin base activity 
(CBA) as loading dose, followed by 2.5–5mg/kg/day of CBA in 2 divided 
doses as a maintenance dose in intensive care unit to treat their MDR 
infection.(11) 
 Group II: 66 patients received intravenous tigecycline100 mg single dose as 
loading dose, followed by 25-50 mg every 12 hours maintenance dose in 
intensive care unit to treat their MDR infection(12). 
 
Sample size technique: 
Sample size was calculated using G*Power (3.1.9.4) software for windows using 
Fisher analysis test. A total sample size of 132 participants was estimated for 95% 
power, α- error probability 0.05. Analysis of data was performed using IBM SPSS 
v. 25 (Statistical Package for Social science) for Windows. 
 Sample size calculation:  
Exact - Proportions: Inequality, two independent groups (Fisher's exact test)  
Options: Exact distribution 
Analysis: A priori: Compute required sample size  
Input: 
Tail(s) 
= Two 
 
Proportion p1 
= 0.58 
 
Proportion p2 
= 0.261 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.95 
 
Allocation ratio N2/N1 = 1 
Output: Sample size group 1 
= 66 
 
Sample size group 2 
= 66 
 
Total sample size 
= 132 
 
Actual power 
= 0.9501125 
                Actual α 
= 0.0316077 
 
 
 
 
 
 

 
 
 Inclusion criteria: 
 
Study will include adult patient (male, female), (age from 18 to 70 years) admitted 
to intensive care unit in study period (six months) who received intravenous 
colistin or tigecycline as antimicrobial drug for treatment their MDR gram negative 
infection (13). 
Exclusion criteria:  
 Patient admitted to intensive care unit younger than 18 years or older than 70 
years (14). 
 Liver transplantation patients. 
 Patients are chronic kidney disease (CKD on hemodialysis or baseline 
creatinine clearance (crcl) < 10 ml/min (estimated by Cockcroft Gault 
equation). 
 Patients received renal replacement therapy before or during admission. 
 Patient is on any other nephrotoxic drug (vancomycin, aminoglycosides, 
NSAIDs, cyclosporine, amphotericin B, etc.) (Aggarwal & Dewan, 2018). 
 Pregnant and lactating women (16). 
 Patients refused the consent of the study. 
Study procedure: 
 Demographic and medical history for all patients included in this study will be 
recorded. 
 Complete physical examination for all patients included in this study will be 
taken. 
 Basic routine investigation for all patients included in this study will be 
measured as Complete blood Count test (CBC), blood pressure and 
temperature. 
 Improvement of signs and symptoms after the end of antibiotic course as 
temperature. 
 Renal function tests will be measured before patients received colistin or 
tigecycline and after 72 hours from first dose: 

 Serum creatinine level (scr). 
 Hepatic function tests will be measured before patients received colistin or 
tigecycline and after 72 hours from first dose: 
 Alanine transaminase (ALT) 
 Aspartate transaminase (AST) 
 Serum total bilirubin (TBIL)  
 14 days Survival rate after starting colistin or tigecycline will be recorded. 
 The severity of the illness will be assessed by using the Acute Physiology and 
Chronic Health Evaluation II (APACHE II) scoring system will be 
calculated.(Wu et al., 2022). 
 
Statistical analysis: 
All statistical analysis will be performed by using SPSS version 23. The 
demographic and clinical characteristics of patients will be expressed as 
mean ± standard deviation (SD). Student's t-tests or Mann-Whitney tests will 
be used to compare between groups. Chi-square tests or exact tests (Fisher’s 
exact test or likelihood ratio test) will be used to detect the existence of 
association between variables. 
Ethical consideration: 
 
An ethical approval will be obtained from ethical committee of Faculty of 
medicine Beni-Suef University. 
All patients in study agree to participate of their own free will and that they have 
been fully informed regarding the procedures of the research project and any 
potential risks. 
If any patient included in study want to withdraw, stop study in this patient 
immediately. 
The study will start after approval of the research ethical committee and according 
to guideline of the Declaration of Helsinki. 
 
 
 
 
 
 

 
IV. 
References: 
1. 
Kadri SS, Adjemian J, Lai YL, Spaulding AB, Ricotta E, Rebecca Prevots D, et al. Difficult-to-treat 
resistance in gram-negative bacteremia at 173 US hospitals: Retrospective cohort analysis of 
prevalence, predictors, and outcome of resistance to all first-line agents. Clinical Infectious 
Diseases. 2018;67(12):1803–14.  
2. 
Abushanab D, Nasr ZG, Al-Badriyeh D. Efficacy and Safety of Colistin versus Tigecycline for Multi-
Drug-Resistant and Extensively Drug-Resistant Gram-Negative Pathogens—A Meta-Analysis. 
Antibiotics. 2022 Nov 1;11(11).  
3. 
El-Sayed Ahmed MAEG, Zhong LL, Shen C, Yang Y, Doi Y, Tian GB. Colistin and its role in the Era of 
antibiotic resistance: an extended review (2000–2019). Vol. 9, Emerging Microbes and Infections. 
Taylor and Francis Ltd.; 2020. p. 868–85.  
4. 
Falagas ME, Kyriakidou M, Voulgaris GL, Vokos F, Politi S, Kechagias KS. Clinical use of intravenous 
polymyxin B for the treatment of patients with multidrug-resistant Gram-negative bacterial 
infections: An evaluation of the current evidence. Vol. 24, Journal of Global Antimicrobial 
Resistance. Elsevier Ltd; 2021. p. 342–59.  
5. 
Yahav D, Farbman L, Leibovici L, Paul M. Colistin: New lessons on an old antibiotic. Vol. 18, Clinical 
Microbiology and Infection. Blackwell Publishing Ltd; 2012. p. 18–29.  
6. 
Shatri G, Tadi P. Polymyxin. 2024.  
7. 
Andrade FF, Silva D, Rodrigues A, Pina-Vaz C. Colistin update on its mechanism of action and 
resistance, present and future challenges. Vol. 8, Microorganisms. MDPI AG; 2020. p. 1–12.  
8. 
Kaewpoowat Q, Ostrosky-Zeichner L. Tigecycline: A critical safety review. Vol. 14, Expert Opinion 
on Drug Safety. Informa Healthcare; 2015. p. 335–42.  
9. 
Yaghoubi S, Zekiy AO, Krutova M, Gholami M, Kouhsari E, Sholeh M, et al. Tigecycline antibacterial 
activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. 
Available from: https://doi.org/10.1007/s10096-020-04121-1 
10. 
Huang YT, Yu CI, Chen PY, Wang CC, Wu CC. Comparison of bleeding risk between colistin– 
tigecycline and colistin–carbapenem treatment regimens: A retrospective cohort study. Infect 
Drug Resist. 2021;14:4949–55.  
11. 
Lee YJ, Wi YM, Kwon YJ, Kim SR, Chang SH, Cho S. Association between Colistin Dose and 
Development of Nephrotoxicity. Crit Care Med. 2015 Jun 20;43(6):1187–93.  
12. 
Yaghoubi S, Zekiy AO, Krutova M, Gholami M, Kouhsari E, Sholeh M, et al. Tigecycline antibacterial 
activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. 
Available from: https://doi.org/10.1007/s10096-020-04121-1 
13. 
Wu S, Wu G, Wang X, Jiang H, Wu H. A study of clinical characteristics and risk factors of mortality 
associated with tigecycline. 2022; Available from: https://doi.org/10.21203/rs.3.rs-1603424/v1 

14. 
Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH, et al. 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 20;43(6):1194–204.  
15. 
Aggarwal R, Dewan A. Comparison of nephrotoxicity of Colistin with Polymyxin B administered in 
currently recommended doses: A prospective study. Ann Clin Microbiol Antimicrob. 2018 Mar 
23;17(1).  
16. 
Fan G, Jin L, Bai H, Jiang K, Xie J, Dong Y. Safety and Efficacy of Tigecycline in Intensive Care Unit 
Patients Based on Therapeutic Drug Monitoring [Internet]. 2020. Available from: 
http://journals.lww.com/drug-monitoring