Hanna Montelin: Antibiotic-Induced Damage on the Intestinal Microbiota and Treatment of Urinary Tract Infections Caused by ESBL- and Non-ESBL-Producing Bacteria

Abstract

Therapeutic options for urinary tract infection (UTI) caused by Escherichia coli and Klebsiella pneumoniae are limited due to resistance against cephalosporins and carbapenems, which is typically mediated by the production of extended-spectrum β-lactamases (ESBLs) and carbapenemases. ESBL-producing bacteria are frequently co-resistant to other antibiotic classes, resulting in a shortage of treatment options. While all systemic antibiotic treatments are likely to disturb the microbiota and increase selection of resistance, evidence on the extent and persistence of such effects for different antibiotics is limited. The primary objective of this thesis was to investigate the therapeutic effect of carbapenem-sparing and narrow-spectrum oral antibiotics in the treatment of UTI, and to evaluate the impact of commonly used antibiotics on the intestinal microbiota. 

The first study investigated the efficacy of nitrofurantoin and pivmecillinam for lower UTI in men (n=171), with trimethoprim as a comparator. We concluded that nitrofurantoin and pivmecillinam are suitable for empirical treatment of lower UTIs in men, considering their high activity against Eschericha coli and limited impact on the microbiota. 

In a prospective multi-center study conducted at 15 infectious diseases hospital departments, patients (n=235) with UTI caused by ESBL-producing Enterobacterales were recruited. We aimed to evaluate clinical and microbiological treatment outcomes and relapse rates. The results indicate that carbapenem-sparing antibiotics were effective for UTI caused by ESBL-producing Enterobacterales and can be recommended for non-critically ill patients. Moreover, we noted that certain bacterial genetic features (e.g., ST131 in Eschericha coli and haemolysin) were associated with microbiological failure and relapse.

In a randomized, controlled trial with healthy adults (n=86), we investigated the impact on the microbiota of five antibiotics (ceftibuten, ciprofloxacin, nitrofurantoin, pivmecillinam, trimethoprim-sulfamethoxazole) that are commonly used for UTI. Fecal samples were collected before and up to one year after five days of antibiotic treatment. Ciprofloxacin demonstrated significant immediate and long-term disruption of the intestinal microbiota in terms of diversity and taxonomy and stands out in comparison with the other antibiotics included in the study.

In a prospective study, we investigated the intestinal microbiota in patients with hematological diseases undergoing hematopoietic stem cell transplantation (HSCT, n=88). Changes over time and during antibiotic treatment and potential associations between the intestinal microbiota at baseline and patient outcomes were explored. Oral ciprofloxacin demonstrated a significant impact on the intestinal microbiota, which was greater than the impact of intravenous broad-spectrum antibiotics. A low microbiome diversity at baseline was associated with neutropenic fever and antibiotic treatment following HSCT.