Monika Kumaraswamy

Urinary tract infections (UTIs) are common in children and are predominantly caused by uropathogenic Escherichia coli (UPEC). An increasing proportion of these strains produce extended-spectrum β-lactamases (ESBLs), which render β-lactam antibiotics ineffective. Interestingly, some patients with ESBL-producing UTIs improve clinically following treatment with antibiotics like cephalexin, despite demonstrated in vitro resistance. Working alongside and at times synergistically with antibiotics, host immune factors, such as the antimicrobial peptide cathelicidin (LL-37), contribute to bacterial clearance through direct killing and inhibition of biofilm formation. In this review, we summarize the current understanding of pediatric ESBL-producing UPEC infections and present selected in vitro and in vivo experimental data evaluating the combined effects of LL-37 and cephalexin on clinical isolates. Although no synergy was observed, ESBL-producing isolates demonstrated reduced bacterial burden in vivo compared to a non-ESBL UPEC strain. These findings suggest that host immune factors and environmental conditions may influence the fitness and virulence of drug-resistant UTI pathogens, warranting further investigation.

Colistin (COL) is a cationic cyclic peptide that disrupts the membranes of Gram-negative bacteria and is often used as a last resort antibiotic against multidrug-resistant strains. The emergence of plasmid-borne mcr genes, which confer transferable COL resistance, has raised serious concerns, particularly in strains also carrying extended-spectrum β-lactamase and carbapenemase genes. Standard antimicrobial susceptibility testing (AST), performed in enriched bacteriological media, indicates no activity of COL against mcr ⁺ strains, leading to its exclusion from treatment regimens. However, these media poorly reflect in vivo physiology and lack host immune components. Here we show that COL retained bactericidal activity against mcr-1 ⁺ Escherichia coli , Klebsiella pneumoniae , and Salmonella enterica when tested in tissue culture medium containing physiological bicarbonate. COL enhanced serum complement deposition on bacterial surfaces and synergized with human serum to kill pathogens. At clinically achievable concentrations, COL killed mcr-1 ⁺ strains in freshly isolated human blood and was effective as monotherapy in a murine E . coli bacteremia model. These findings suggest that COL, currently dismissed based on conventional AST, may offer clinical benefit against mcr-1 ⁺ infections when evaluated under more physiological conditions — warranting reconsideration in clinical microbiology practices and future trials for high-risk patients.