Le Infezioni in Medicina, n. 4, 516-524, 2022

doi: 10.53854/liim-3004-5

REVIEWS

Role of tigecycline in the treatment of urinary tract infections: a systematic review of published case reports

Reema Charles1, Shreya Das Adhikari2, Ankit Mittal3, Souvik Chaudhuri4, Mukund Gupta5, Wasim Khot6, Marco Schito1, Nitin Gupta7

1CURE Drug Repurposing Collaboratory (CDRC), Critical Path Institute, Tucson, AZ, USA;

2Department of Anaesthesiology, Kasturba Medical College and Hospital, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India;

3Department of Medicine, All India Institute of Medical Sciences, New Delhi, Delhi, India;

4Department of Critical Care, Kasturba Medical College and Hospital, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India;

5Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences, Jodhpur, India;

6Infectious Disease, Global Hospitals, Mumbai, India;

7Department of Infectious Diseases, Kasturba Medical College and Hospital, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India

Article received 29 May 2022, accepted 21 September 2022

Corresponding author

Nitin Gupta

E-mail: nityanitingupta@gmail.com

SummaRY

Introduction: The emergence of multi-drug resistance has forced clinicians to occasionally use drugs that are not approved to treat urinary tract infections (UTIs). This systematic review aimed to evaluate the utility of tigecycline in patients with UTIs.

Methodology: A systematic review of case studies was used to retrieve articles between 1.1.1999 to 1.1.2021 from two databases, PubMed and Embase. The title-abstract screening was done for 198 articles, out of which 69 articles were included for full-text screening. A total of 18 articles with 27 cases were included for final analysis.

Results: Of the 27 cases, there were 13 cases with complicated UTI and five had catheter-associated UTI. The most common organisms were Klebsiella pneumoniae (n=11), Acinetobacter baumannii (n=9), and Escherichia coli (n=6). Tigecycline was used as monotherapy in 19 patients and as a combination therapy in 8 patients. The median duration of tigecycline was 13 (10-15) days. A favourable clinical or microbiological response at varying intervals was seen in 24/27 (88.9%). Within three months of a favourable response, recurrence of symptoms was seen in four patients.

Conclusion: In a small analysis of published case reports, tigecycline appeared to be a relatively effective treatment in patients with UTIs, caused by multidrug-resistant organisms. Where tigecycline is the only susceptible drug, it can be used for treatment. Further research, such as randomized controlled trials, is needed to fully assess the drug’s efficacy in this context.

Keywords: UTI, prostatitis, catheter-associated UTI, AMR.

INTRODUCTION

The emergence of multi-drug resistance in urinary tract infections (UTIs) poses a significant therapeutic challenge. This is especially true for developing countries where indiscriminate usage of antibiotics is common [1]. The choice of antimicrobials for UTIs is dependent not only on the organisms and their minimum inhibitory concentrations (MICs), but also on the ability of antimicrobials to achieve adequate concentration in the urine [2]. Drugs such as beta-lactams, aminoglycosides, nitrofurantoin and fluoroquinolones have traditionally been the mainstay of treatment [3]. However, with increasing rates of drug resistance, clinicians have been forced to look for alternatives such as newer beta-lactam/beta-lactam inhibitors (BL-BLI) combinations, as well as other antibiotics, such as fosfomycin and colistin [1]. In cases where clinical conditions, adverse effect profile, cost and availability preclude using these second-line drugs, rescue drugs such as tigecycline are the only available option. Tigecycline is approved for routine use in intra-abdominal infections and skin-soft tissue infections. Since tigecycline was thought to have poor urinary concentration, its use in UTIs has never been encouraged [4]. Therefore, in this systematic review, we aimed to summarize the available literature on the use of tigecycline for UTIs.

MATERIALS AND METHODS

A systematic review of case studies was conducted to ascertain the anecdotal efficacy of intravenous tigecycline in patients with urinary tract infections to achieve clinical and microbiological cure. All study types where the authors deemed the individual cases in question to be having a UTI were considered for the review. For the purpose of this review, UTI was defined broadly as infectious involvement of the urinary tract as evidenced by clinical or radiological evaluation and culture positivity [1]. In vitro or animal studies were excluded. The studies where individual details of the patients, details of identified organisms or evidence of clinical or microbiological cure were not present were also excluded.

The following search string was used to retrieve articles between 1.1.1999 to 1.1.2021 from two databases, PubMed and Embase: Tigecycline AND (Urinary Tract Infections OR bacteriuria OR pyuria OR prostatitis OR pyelonephritis OR cystitis OR UTI). For Embase, the search was restricted to title and abstract only. A total of 93 articles were retrieved from PubMed, and 157 articles were retrieved from Embase. A total of 6 papers were added from additional sources (references of included articles). After removing 58 duplicates, the title-abstract screening (done by two independent authors) was done for 198 articles. A total of 69 articles were included for full-text screening. Fifty-one articles were excluded either because they did not meet the inclusion/exclusion criteria (n=50), or because full text was unavailable (n=1). A total of 18 articles with 27 cases were included in the final analysis (4-21) (Figure 1).

Figure 1 - PRISMA chart showing the inclusion process of articles where tigecycline was used for treating patients with urinary tract infections.

The included articles were analyzed using the JBI checklist to critically appraise case reports (Table 1) (22). Of the eight questions on the checklist, only one article had all eight positive responses. Six articles had a total of seven positive responses to the checklist question. All of these six articles had a negative response to the identifying adverse event question. It should, however, be noted that adverse event identification was not an objective of the study. The rest of the articles had four or more positive responses.

Table 1 - JBI checklist for critical appraisal of case reports where tigecycline was used for urinary tract infections.

The following demographic and clinical data were collected from each case: age, gender, country of origin, year of presentation, co-morbidities, presenting features, treatment details and outcome. Those patients with urinary symptoms accompanied by fever, kidney or prostate involvement on radiology or blood culture positivity with the same organism were classified as complicated UTI. Those patients with a history of at least three UTIs in the last year were classified as recurrent UTIs. Those patients with a significant improvement in clinical symptoms after initiating tigecycline were said to have a positive clinical outcome. Those patients where culture negativity was established any time after initial culture positivity and initiation of tigecycline therapy were said to have a positive microbiological outcome. Those patients with either positive clinical or positive microbiological outcomes were classified as an overall positive outcome. All three outcomes were evaluated separately.

The data were entered into an excel workbook, and the analysis was done using SPSS v26. For categorical variables, the frequencies were expressed as a percentage. Mean (+ Standard deviation) or Median (with interquartile range) were calculated for quantitative variables.

RESULTS

The majority of the cases were from Europe (n=12) and the United States of America (n=13) and were reported between 2005 and 2018. The mean age of the included cases was 58.4+14.9 years. Of the 24 cases where gender was specified, there were 13 females (Table 2).

Table 2 - Clinical features, and microbiological details in cases with urinary tract infections treated with tigecycline.

There were 13 cases with complicated UTI (including two with prostatitis) and five with catheter-associated UTI (CAUTI). A total of five patients had a history of recurrent UTIs (Table 2). The most common co-morbidities were diabetes (DM) (n=5), chronic kidney disease (CKD) (n=6), history of surgery (n=6) and transplants (n=4). The most common organisms were Klebsiella pneumoniae (n=11), Acinetobacter baumannii (n=9), and Escherichia coli (n=6) (Table 2). Of the cases where susceptibility results were available, the organism was resistant to carbapenems in 86% (18/21) patients and resistant to colistin in 47% (8/17) patients. The organism was sensitive to tigecycline in all the 17 tested patients. Barring one patient, E-test was used to determine the susceptibility of tigecycline in all the patients (Table 2).

Tigecycline was used as monotherapy in 19 patients, as a combination therapy with two drugs in 5 patients and as a combination of three drugs in 3 patients (Table 3). Carbapenems (n=3) and colistin (n=2) were most frequently used as combination therapy. Tigecycline was used in the following maintenance dosages: 50 mg BD (n=13), 100 mg BD (n=6), 200 mg OD (n=1) and 100 mg OD (n=1) (Table 2). The median duration of tigecycline use was 13 (10.25-14.75) days. The outcomes were assessed at varying time points: while on treatment (n=10), at treatment completion (n=9), and after a variable period of follow-up was completed (n=8). A microbiological response was seen in 15/19 patients (78.9%), and a clinical response was seen in 21/24 (87.5%) patients. Overall positive response was seen in 24/27 (88.9%) patients (Table 3). Within three months of a favourable response, recurrence of symptoms was seen in four (15%) patients.

Table 3 - Treatment details and response in cases with urinary tract infections treated with tigecycline.

DISCUSSION

Tigecycline is a glycylcycline antibiotic derived from minocycline that inhibits bacterial protein synthesis and is effective against a wide range of organisms, including multi-drug resistant Gram-­negative bacilli (MDR GNB), Vancomycin-Resistant Enterococcus (VRE) and Methicillin-Resistant Staphylococcus aureus (MRSA). It should be noted that Morganella morganii, Proteus mirabilis and Pseudomonas aeruginosa are intrinsically resistant to tigecycline. Acquired resistance is rare with tigecycline and is most likely due to over-expression of the efflux pumps. Tigecycline exhibits complicated linear and non-linear pharmacokinetics at different dosing schedules with highly variable elimination half-lives. Moreover, the protein binding of the drug is also pH-dependent. Most of the drug (59%) is excreted unchanged in faeces, whereas only 10-15% of the drug is excreted unchanged in the urine.

Since Enterobacteriaceae like Klebsiella pneumoniae and Escherichia coli are most commonly associated with urinary tract infections, it is understandable that most included cases in the review were from the Enterobacteriaceae family. However, this review also had nine cases of Acinetobacter spp., which is not a common cause of UTI. Since Acinetobacter spp. is multi-drug resistant with limited therapeutic options, there are more reported cases where tigecycline was used as salvage therapy. In the cases where details of UTI associated with Acinetobacter spp. were reported, it was commonly seen that UTI was descending and a part of multi-system disease [7, 8, 14]. A total of 86% of the isolates were carbapenem-resistant and 47% were resistant to colistin in this review. In some cases, especially for colistin, susceptibility was done by unsuitable methods [23]. All of the tested isolates were sensitive to tigecycline in the included studies. Tigecycline susceptibility was determined by E-test in most cases. Data on the susceptibility of newer BL-BLI were not available in the included studies.

Based on the available PK-PD data, standard tigecycline dosing may not be ideal for UTIs [24, 25]. Higher doses of tigecycline have been successfully utilized in patients with ventilator-associated pneumonia. Given the urgent need for an effective drug against MDR/XDR organisms and a favourable susceptibility profile, there has been some interest in high-dose tigecycline as a treatment for UTIs caused by highly resistant organisms. Although recent studies have discussed the pharmacokinetics of high-dose tigecycline in nosocomial pneumonia, soft tissue infections and intra-abdominal infections, literature on UTIs is still scarce [26-28]. Recent systematic reviews have concluded that high dose tigecycline is associated with lower all-cause mortalities, higher clinical cure and microbiological eradication [29, 30]. In our review, 7 cases were treated with high doses. While 100 mg twice daily was the most common dosing schedule, Cunha et al. used 200 mg once daily for their patient. When compared to monotherapy, the role of combination therapy needs special mention with tigecycline. Since tigecycline is not approved for the treatment of UTIs, many patients inevitably receive combination therapy with other drugs. In our review, eight patients were on variable combination therapy with either one or two drugs. Although the majority of patients on combination therapy responded in our review, it is difficult to ascertain whether the addition of the partner drug had any impact on the outcome. In practice, use of tigecycline as a monotherapy may be ill-advised in the context of high drug resistance. Strategic combination therapies should be studied more robustly to reduce the likelihood of development of further resistance.

Our review supplements the systematic review conducted by Brust et al. on the role of tigecycline in the treatment of MDR GNB related UTIs. Similar to our findings, their review of 14 cases of UTIs noted favourable clinical (78.6%) and microbiological (85.7%) outcomes with a similar mean duration of antibiotic therapy [32]. In the study by Van Duin et al. on UTIs due to carbapenem-resistant Klebsiella pneumoniae, 30 patients were treated with tigecycline monotherapy, and 36 were treated with tigecycline-based combination therapy [31]. The microbiological cure rate in those with a definitive outcome was 3/17 (17.6%) for monotherapy patients and 5/18 (27.8%) for combination therapy patients. Tigecycline therapy was independently associated with poor microbiological outcomes. However, this study considered a microbiological failure as any culture positivity after seven days from the index culture positivity. This duration of therapy was possibly inadequate as the median duration of therapy in our analysis was 13 days. Also, most of the patients were labelled with indeterminate outcomes in their study, making the analysis difficult. The drug dosage used and the final duration of therapy was also not mentioned, thereby severely limiting the conclusions of that study. In another study by Satlin et al. (2011), of 21 patients with carbapenem-resistant Klebsiella pneumoniae treated with tigecycline, microbiological cure rates were achieved in 9/21 (43%) patients [33]. Compared to aminoglycosides and colistin, the microbiological clearance rates were significantly worse with tigecycline. However, it should be noted that the standard dosing of tigecycline was used in this series (50 mg twice daily). Also, the median duration of tigecycline before a follow-up culture was taken was only six days. Similar to the study by Van Duin et al., this study also included patients who could have had asymptomatic colonization, leading to persistently positive cultures [31].

Our review is mainly plagued by publication bias, where positive outcomes are more likely to be reported than negative outcomes. Also, the method of susceptibility testing, reporting of outcome and follow-up for recurrence was non-uniform. Hence, it would be premature to draw conclusions about the efficacy of tigecycline in UTIs without an adequately conducted randomized controlled trial. However, it can be reasonably concluded that in UTI cases, due to multidrug-resistant organisms, where tigecycline is the only susceptible drug, it can be used as a rescue drug, preferably at a higher dose and longer duration of treatment.

Conflict of interest

None

Funding

None

REFERENCES

[1] Bader MS, Loeb M, Brooks AA. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2017; 129 (2), 242-258.

[2] Nicolle LE. Urinary tract infection. Crit Care Clin. 2013; 29 (3), 699-715.

[3] Zare M, Vehreschild MJGT, Wagenlehner F. Management of uncomplicated recurrent urinary tract infections. BJU Int. 2022; 129 (6), 668-678. doi: 10.1111/bju.15630. Epub 2021 Nov 17.

[4] Bhatt M, Gupta N, Kodan P, Soneja M. Tigecycline: A rescue drug for multi-drug resistant organisms causing urinary tract infection. J Clin Urol. 2020; 2051415820930625.

[5] Tsai H-Y, Liao C-H, Cheng A, et al. Emergence of tigecycline-resistant Klebsiella pneumoniae after tigecycline therapy for complicated urinary tract infection caused by carbapenem-resistant Escherichia coli. J Infect. 2012; 65 (6), 584-586.

[6] Geerlings SE, van Donselaar-van der Pant KAMI, Keur I. Successful treatment with tigecycline of two patients with complicated urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. J Antimicrob Chemother. 2010; 65 (9), 2048-2049.

[7] Reid GE, Grim SA, Aldeza CA, Janda WM, Clark NM. Rapid development of Acinetobacter baumannii resistance to tigecycline. Pharmacotherapy. 2007; 27 (8), 1198-1201.

[8] Aykota MR, Sari T, Yilmaz S. Successful treatment of extreme drug resistant Acinetobacter baumannii infection following a liver transplant. J Infect Dev Ctries. 2020; 14 (4), 408-410.

[9] Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrug-resistant Gram-negative organisms treated with tigecycline. Clin Infect Dis. 2008; 46 (4), 567-570.

[10] Drekonja DM, Johnson JR. Tigecycline treatment for urinary tract infections: case report and literature review. J Chemother. 2011; 23 (3), 168-170.

[11] Gallagher JC, Rouse HM. Tigecycline for the treatment of Acinetobacter infections: a case series. Ann Pharmacother. 2008; 42 (9), 1188-1194.

[12] Cunha BA, McDermott B, Nausheen S. Single daily high-dose tigecycline therapy of a multidrug-resistant (MDR) Klebsiella pneumoniae and Enterobacter aerogenes nosocomial urinary tract infection. J Chemother. 2007; 19 (6), 753-754.

[13] Krueger WA, Kempf VAJ, Peiffer M, Nagele U, Unertl KE, Schroeder TH. Treatment with tigecycline of recurrent urosepsis caused by extended-spectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol. 2008; 46 (2), 817-820.

[14] Kuo S-C, Wang F-D, Fung C-P, et al. Clinical experience with tigecycline as treatment for serious infections in elderly and critically ill patients. J Microbiol Immunol Infect. 201; 44 (1), 45-51.

[15] Brust K, Evans A, Plemmons R. Favourable outcome in the treatment of carbapenem-resistant Enterobacteriaceae urinary tract infection with high-dose tigecycline. J Antimicrob Chemother. 2014; 69 (10), 2875-2876.

[16] Elemam A, Rahimian J, Mandell W. Infection with pan-resistant Klebsiella pneumoniae: a report of 2 cases and a brief review of the literature. Clin Infect Dis. 2009; 49 (2), 271274.

[17] Balfousias T, Apostolopoulos A, Angelis S, Filippou D, Maris S. Pandrug-resistant Acinetobacter baumannii infection identified in a non-intensive care unit patient: a case study. Cureus. 2019; 11 (12), e6321.

[18] Balandin Moreno B, Fernández Simón I, Pintado García V, et al. Tigecycline therapy for infections due to carbapenemase-producing Klebsiella pneumoniae in critically ill patients. Scand J Infect Dis. 2014; 46 (3), 175-180.

[19] Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne WM, Ritchie DJ. Treatment and clinical outcomes of urinary tract infections caused by KPC-producing Enterobacteriaceae in a retrospective cohort. Clin Ther. 2012; 34 (6), 1314-1323.

[20] Lo Priore E, Livermore DM, Buetti N, et al. Successful treatment of acute prostatitis caused by multidrug-resistant Escherichia coli with tigecycline monotherapy. Open Forum Infect Dis. 2020; 7 (1), ofz551.

[21] Licker M, Sorescu T, Rus M, et al. Extensively drug-resistant Myroides odoratimimus - a case series of urinary tract infections in immunocompromised patients. Infect Drug Resist. 2018; 11, 743-749.

[22] Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. CARE Group. The CARE guidelines: consensus-based clinical case report guideline development. J Diet Suppl. 2013; 10 (4), 381-390.

[23] Elias R, Duarte A, Perdigão J. A Molecular perspective on colistin and Klebsiella pneumoniae: mode of action, resistance genetics, and phenotypic susceptibility. Diagn Basel Switz. 2021; 11 (7), 1165.

[24] Du X, He F, Shi Q, et al. The rapid emergence of tigecycline resistance in blaKPC–2 harboring Klebsiella pneumoniae, as mediated in vivo by mutation in tetA during tigecycline treatment. Front Microbiol. 2018; 9, 648.

[25] Barbour A, Schmidt S, Ma B, et al. Clinical pharmacokinetics and pharmacodynamics of tigecycline. Clin Pharmacokinet. 2009; 48 (9): 575-584.

[26] De Pascale G, Lisi L, Ciotti GMP, et al. Pharmacokinetics of high-dose tigecycline in critically ill patients with severe infections. Ann Intensive Care. 2020; 10, 94.

[27] Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013; 57 (4), 1756-1762.

[28] Borsuk-De Moor A, Rypulak E, Potręć B, et al. Population pharmacokinetics of high-dose tigecycline in patients with sepsis or septic shock. Antimicrob Agents Chemother. 2018; 62 (4), e02273-17.

[29] Zha L, Pan L, Guo J, French N, Villanueva EV, Tefsen B. Effectiveness and safety of high dose tigecycline for the treatment of severe infections: a systematic review and meta-analysis. Adv Ther. 2020; 37 (3), 1049-1064.

[30] Gong J, Su D, Shang J, et al. Efficacy and safety of high-dose tigecycline for the treatment of infectious diseases. Medicine (Baltimore). 2019; 98 (38), e17091.

[31] Van Duin D, Cober E, Richter SS, et al. Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2015; 70 (4), 1203-1211.

[32] Brust K, Evans A, Plemmons R. Tigecycline in treatment of multidrug-resistant Gram-negative bacillus urinary tract infections: a systematic review. J Antimicrob Chemother. 2014; 69 (10), 2606-2610.

[33] Satlin MJ, Kubin CJ, Blumenthal JS, et al. Comparative effectiveness of aminoglycosides, polymyxin B, and tigecycline for clearance of carbapenem-resistant Klebsiella pneumoniae from urine. Antimicrob Agents Chemother. 2011; 55 (12), 5893-5899.