Complicated Urinary Tract Infections: Current Management Challenges & Need to Look Beyond

Key Messages:

• Antimicrobial resistance is one of the top global public health threats.
• Complicated urinary tract infections (cUTIs) are the most common bacterial infections in the community and healthcare settings. Escherichia coli and Klebsiella pneumoniae are the common causative uropathogens.
• The mortality associated with Carbapenem-resistant Enterobacterales (CRE) infections is high (20% to 54.3%), which further underscores the need for newer treatment options.
• Currently, aminoglycosides, beta-lactams, beta-lactamase inhibitors, or carbapenems are recommended for the treatment of urinary tract infection (UTI) caused by extended-spectrum beta-lactamase (ESBL)-producing gram-negative organisms.

Antibiotic Resistance - Global and Indian Brunt:

Antimicrobial resistance (AMR) is a significant global health concern in the twenty-first century. The spread of drug-resistant pathogens substantially threatens human health, and growing evidence shows that AMR is also a major health problem in India. (1) Bacterial AMR is estimated to have caused or contributed to 49.5 lakh deaths worldwide and is directly responsible for 12.7 lakh deaths, according to the World Health Organization (WHO) data. (2) In 2019, of the 10.7 lakh deaths linked to AMR in India, approximately 3 lakh deaths are directly caused by AMR. (3) The projections by the Organization for Economic Cooperation and Development (OECD) indicate an anticipated twofold surge in resistance to last-resort antibiotics by 2035, underscoring the urgent need for robust antimicrobial stewardship practices and enhanced surveillance coverage worldwide. (2) In India, Escherichia coli, Klebsiella pneumoniae, are common uropathogens responsible for complicated urinary tract infections (cUTIs) and pyelonephritis and are associated with a higher number of AMR deaths. (3)

Complicated Urinary Tract Infections (cUTIs):

cUTIs are common bacterial infections in the community and healthcare settings (4). They are usually associated with a higher risk of recurrence, progression, or more unfavorable outcomes than uncomplicated UTIs. (5)  The mean duration of hospital stay among cUTI is 9.1 ± 2.7 days among Indians, with frequent need for intensive care. Diabetes is one of the common risk factors for cUTI, which is highly pervasive in India (6) Most cUTI is caused by Enterobacteriaceae (commonly Escherichia coli, which accounted for 49.6%) (5,7), followed by Klebsiella pneumoniae and Enterococcus spp.). (8)

Current Management of Urinary Tract Infections (UTIs)

The Indian Society of Critical Care Medicine (ISCCM) Guideline for Antibiotic Prescription in Intensive Care Unit recommended antibiotics that cover ESBL (extended-spectrum beta-lactamase) producing gram-negative organisms, include aminoglycosides, beta-lactam and beta-lactamase inhibitors or carbapenems (Level of Recommendation 2A), as the initial choice of antibiotics to treat UTIs in the ICU settings. (9)

The ICMR (Indian Council of Medical Research) Treatment Guidelines for Antimicrobials Use in Common Syndromes 2022 suggested Piperacillin–tazobactam, Ertapenem, Imipenem, Meropenem and Amikacin as an empirical treatment in treating infective urinary syndromes such as acute pyelonephritis.  The guideline further noted that local antimicrobial resistance patterns should be the basis for empiric treatment. Antibiotics should be changed based on susceptibility results as soon as they are available. (10)

High Resistance to Current Anti-infectives Agents

Resistance to anti-infective drugs is an urgent public health problem threatening the treatment and control of infectious diseases. (11) The ICMR 2022 Annual Report for AMR Surveillance Network, emphasised that among hospital-acquired infections, Gram-negative bacteria (GNB) accounted for 74.4% of all Blood Stream Infection (BSI) cases. Among cUTIs, GNB accounted for 57.7% of cases, and Klebsiella spp. (30.4%) was the most common GNB involved. A high rate of resistance was seen against third-generation cephalosporins, carbapenems, fluoroquinolones, colistin, and aminoglycosides in   Klebsiella pneumoniae, E.  coli and Acinetobacter baumannii and Pseudomonas aeruginosa causing UTIs; nearly 60% isolates of Enterococcus faecium were vancomycin-resistant.  (12) The mortality associated with Carbapenem-resistant Enterobacterales (CREs) infections, including bacteremia, may be as high as 20% to 54.3%, further underscoring the need for newer antimicrobial treatment options. (13)

Need for Novel Treatment Options for cUTIs

AMR among gram-negative pathogens, specifically MDR Enterobacterales, is a major public health concern. There is rising CRE prevalence, especially among Enterobacterales which limits antibiotic options available in India for treating cUTI. The higher prevalence of PBP3 insert amongst E. coli and rising colistin resistance further limit the treatment options. Thus, there is an urgent need for an antibiotic that has activity against MDR, carbapenem and colistin-resistant pathogens causing cUTI. (14)

Plazomicin a US-FDA approved (2018) molecule for treatment of cUTI and acute pyelonephritis in adult patients by susceptible microorganism(s): E. coli, K. pneumoniae, P. mirabilis, and E. cloacae. By virtue of its distinct structure, Plazomicin retains its activity against CRE [MBL, Oxa-48, KPC] (17), ESBL-producing, colistin-resistant (18), aminoglycoside-resistant Enterobacteriaceae and against most AME (aminoglycoside modifying enzymes) producing Enterobacteriaceae (19). Plazomicin will provide a new option for the treatment of cUTI and pyelonephritis in Indian patients and could meet an unmet demand in the era of AMR for managing cUTI patients in Indian clinical settings. (20)

References:

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