Effect of resistance to third-generation cephalosporins on morbidity and mortality from bloodstream infections in Blantyre, Malawi: a prospective cohort study

Abstract

Background: The burden of antimicrobial resistance is a major threat to global health; however, prospective clinical outcome data from Africa are scarce. In Malawi, third-generation cephalosporins are the antibiotics of choice in patients admitted to hospital despite a rapid proliferation of resistance to these drugs. We aimed to quantify the effect of resistance to third-generation cephalosporins on mortality and length of hospital stay among patients with bloodstream infections.

Methods: We did a prospective cohort study of patients admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Patients of all ages who had positive blood cultures for Enterobacterales were included, with the exception of those from the genus Salmonella, and were followed up for 180 days. We characterised blood culture isolates using whole-genome sequencing and used Cox regression models to estimate the effect of resistance to third-generation cephalosporins on length of hospital stay, in-hospital mortality, and survival.

Findings: Between Jan 31, 2018, and Jan 13, 2020, we recruited 326 patients, from whom 220 (68%) of 326 isolates were resistant to third-generation cephalosporins. The case fatality proportion was 45% (99 of 220) in patients with bloodstream infections that were resistant to third-generation cephalosporins, and 34% (36 of 106) in patients with bloodstream infections that were sensitive to third-generation cephalosporins. Resistance to third-generation cephalosporins was associated with an increased probability of in-hospital mortality (hazard ratio [HR] 1·44, 95% CI 1·02-2·04), longer hospital stays (1·5 days, 1·0-2·0) and decreased probability of discharge alive (HR 0·31, 0·22-0·45). Whole-genome sequencing showed a high diversity of sequence types of both Escherichia coli and Klebsiella pneumoniae. Although isolates associated with death were distributed across clades, we identified three E coli clades (ST410, ST617, and ST648) that were isolated from 14 patients who all died.

Interpretation: Resistance to third-generation cephalosporins is associated with increased mortality and longer hospital stays in patients with bloodstream infections in Malawi. These data show the urgent need for allocation of resources towards antimicrobial resistance mitigation strategies in Africa.

Funding: Wellcome Trust and Wellcome Asia and Africa Programme.

Figure 1

Kaplan-Meier curves for survival and time to discharge Kaplan-Meier survival curves of all participants (A) and participants stratified by third-generation cephalosporin resistance status (B). Crosses indicate censoring. The p value is derived from a log-rank test comparing the survival of participants with infections that were resistant and those with infections that were sensitive to third-generation cephalosporins. Outcome data were missing for three participants. Kaplan-Meier curves showing time to discharge for all participants (C) and participants stratified by third-generation cephalosporin resistance status (D). Crosses indicate censoring. The p value is derived from a log-rank test comparing length of hospital stay in participants with infections that were resistant and those with infections that were sensitive to third-generation cephalosporins. The date of discharge was missing for one participant.

Figure 2

Midpoint-rooted maximum likelihood core-gene phylogenetic trees (A) Phylogenetic tree for Escherichia coli. Tree clades are coloured by sequence type; rings around the tree, from the inside out, show patient outcomes at discharge, extended-spectrum β-lactamase (ESBL) phenotype, and presence of ESBL genes. (B) Phylogenetic tree for Klebsiella pneumoniae. Tree clades are coloured by sequence type; rings around the tree, from the inside out, show O-antigen types (O-type), patient outcome at discharge, ESBL phenotype, and presence of ESBL genes.