Multidrug-resistant uropathogens are becoming widespread both in community and hospital setting. Safe yet effective treatments are a priority. Fosfomycin is an antibacterial that displays good activity against most bacteria causing urinary tract infections (UTIs), including multidrug-resistant bacteria. The aim of this study was to evaluate fosfomycin susceptibility for uropathogens isolated from a microbiology laboratory at a tertiary academic hospital. In addition, this was compared to the susceptibility of other oral antimicrobials.
We conducted a retrospective analysis of laboratory reports for uropathogens isolated at Charlotte Maxeke Johannesburg Academic Hospital from September 2015 to August 2017. Antimicrobial susceptibility testing of the isolates was performed using the Kirby–Bauer disk diffusion method or the Vitek® 2 system according to the Clinical and Laboratory Standards Institute.
Overall susceptibility of fosfomycin for the 4700 Enterobacteriaceae isolates was 95.7%; 95% confidence interval (CI) 95.1–96.2. The overall susceptibility for fosfomycin against the gram-positives was 98.6%. There were 37.9% multidrug-resistant Enterobacteriaceae (MDRE) isolated during the study period. Fosfomycin displayed activity against 94.4% of extended-spectrum β-lactamase (ESBL) producers and 90.7% for carbapenem-resistant Enterobacteriaceae (CRE). None of the methicillin-resistant
This study confirmed the high susceptibility of fosfomycin against UTI pathogens isolated at our institution. In an era of increasing antimicrobial resistance, fosfomycin represents a potential option for the treatment of UTIs at Charlotte Maxeke Johannesburg Academic Hospital.
Urinary tract infections (UTIs) have become the most common bacterial infections, equally found in the community and in hospitals.
Fosfomycin is a broad-spectrum antimicrobial agent that inhibits the synthesis of the bacterial cell wall of both gram-negative and gram-positive bacteria.
The oral formulation of fosfomycin has only recently become available at our centre. Susceptibility testing for fosfomycin on urinary isolates has since been introduced at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) microbiology laboratory. Consequently, there was a lack of information regarding the susceptibility rates of fosfomycin amongst uropathogens isolated at our centre. In this study, we aimed to analyse retrospective data for fosfomycin susceptibility of gram-negative and gram-positive bacteria isolated from urine samples and to compare its activity with that of other oral antimicrobials usually used to treat lower UTIs. Furthermore, the burden of MDR uropathogens was also established. This information will assist in determining the role of oral fosfomycin at our centre. In addition, it will help with the formulation of guidelines for therapy of lower UTIs locally.
This is a retrospective laboratory-based study undertaken at CMJAH microbiology laboratory. Charlotte Maxeke Johannesburg Academic Hospital is a 1088-bed university hospital. Charlotte Maxeke Johannesburg Academic Hospital offers secondary, tertiary and quaternary services, as well as outpatient clinics. It also serves as a referral centre for several hospitals.
Antimicrobial susceptibility testing (AST) data for uropathogens isolated at CMJAH from September 2015 to August 2017 were used for analysis. Furthermore, the burden of MDR uropathogens for specific high-risk units for multidrug-resistant organisms (MDROs) was established. The data for this study were retrieved from the National Health Laboratory Service (NHLS) Corporate Data Warehouse (CDW).
In total 8906 bacterial isolates were included in the study. Repeat bacteria cultured from the same patient were considered to be duplicate organisms representing a single infection if isolated within 2 weeks and were removed from the analysis.
The microbiological diagnosis of a UTI requires ≥105 colony-forming units (CFU/mL) of a single microorganism in a midstream collected urine, or ≥104 CFU/mL of a single microorganism in catheter samples, or any bacterial growth in urine obtained by suprapubic route.
Routine AST of the isolates was performed using the disk diffusion method or the Vitek® 2 system (bioMérieux SA, France) according to the Clinical and Laboratory Standards Institute (CLSI).
Fosfomycin and other oral antibiotic susceptibility results were reported as percentage susceptible. The difference between the percentage of isolates susceptible to fosfomycin and other oral antibiotics was calculated using 95% confidence intervals (CIs) and
The 95% CI was calculated using the Poisson distribution. A
The study was accepted by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand, approval number M170935.
The distribution of isolated uropathogens from CMJAH is shown in
Distribution of uropathogens isolates from Charlotte Maxeke Johannesburg Academic Hospital.
Uropathogens | % | |
---|---|---|
4142 | 56.0 | |
1252 | 16.9 | |
98 | 1.3 | |
475 | 6.4 | |
314 | 4.2 | |
129 | 1.7 | |
364 | 4.9 | |
241 | 3.2 | |
Others | 380 | 5.1 |
143 | 9.5 | |
12 | 0.8 | |
792 | 52.4 | |
182 | 12.1 | |
227 | 15.0 | |
Others | 155 | 10.3 |
97 | 54.8 | |
Non- |
80 | 45.2 |
, Urine samples from September 2015 to August 2017 (study period).
Fosfomycin susceptibility testing results were available for 4700 Enterobacteriaceae. The overall susceptibility of fosfomycin for the Enterobacteriaceae was 95.7%; 95% CI: 95.1–96.2;
Antimicrobial susceptibility of urinary Enterobacteriaceae to fosfomycin.
A breakdown of the 76 gram-positive organisms tested for fosfomycin susceptibility demonstrated 47 (61.8%)
Antimicrobial susceptibility of urinary gram-positive cocci to fosfomycin.
There were 2520 (37.9%) multidrug-resistant Enterobacteriaceae (MDRE) isolated during the study period. Extended-spectrum β-lactamase production was identified in 23.2% (
Multidrug-resistant enterobacteriaceae urinary isolates at high risk units for MDRO.
Percentage of multidrug-resistant Enterobacteriaceae urinary isolates.
MDRE | % | |
---|---|---|
Total number of Enterobacteriaceae | 6652 | - |
Total number of MDRE | 2520 | 37.9 |
ESBL | 1545 | 23.2 |
AmpC | 815 | 12.3 |
CRE | 160 | 2.4 |
MDRE, multidrug-resistant Enterobacteriaceae; AMP C, AmpC β-lactamase producers; ESBL, extended spectrum β-lactamase producers; CRE, carbapenem-resistant Enterobacteriaceae.
For the subset of MDRE with fosfomycin results available, the fosfomycin susceptibility was: 94.4% for ESBL producers and 90.7% for CRE. All the MRSA and VRE isolates tested showed 100% susceptibility to fosfomycin (data not shown).
In the present study, fosfomycin showed the highest susceptibility (95.7%, 95% CI: 95.1–96.2) against the tested Enterobacteriaceae. There was a statistically significant difference between the susceptibility rates of fosfomycin (
Antimicrobial susceptibility of fosfomycin compared with other oral antibiotics used to treat Enterobacteriaceae causing urinary tract infections (including multidrug-resistant Enterobacteriaceae [MDRE]).
The key finding of this study is that fosfomycin shows outstanding in vitro activity against uropathogens, including MDR isolates. Overall, the susceptibility of fosfomycin against Enterobacteriaceae was 95.7%. Fosfomycin activity against
The overall susceptibility of fosfomycin for gram-positives in this study was 98.6%. The most frequent gram-positive uropathogens were
Fosfomycin also demonstrated good activity against UTIs caused by MDRO. In this current study, the susceptibility of fosfomycin for MDRE causing UTIs was 90.7% (CRE), 92.3% (AmpC) and 94.4% (ESBL). Comparable to this study, a systematic review of
Studies have demonstrated the clinical efficacy of fosfomycin as therapy for lower UTIs caused by both susceptible and MDR uropathogens. A report by Neuner confirmed microbiological cure rates in 71% of patients with UTIs caused by VRE and ESBL producers. The study population included patients with co-morbidities such as diabetes mellitus, solid-organ transplant recipients and chronic kidney disease.
Globally, the susceptibility rates of fosfomycin have continued to be quite stable since its introduction. Studies performed in three European countries, where parenteral and oral fosfomycin has been used since the 1970s, showed no significant decrease in fosfomycin susceptibility.
Enterobacteriaceae are the common aetiological agents of UTIs.
Rates of both nosocomial and community-acquired UTIs caused by MDR bacteria are escalating.
This study did not look at the risk factors associated with MDRE. Rather, we focused on establishing the burden of MDRE uropathogens in selected wards. Previous studies have acknowledged that prior fluoroquinolone use within 3 months, a hospital stay for at least 48 h, comorbidities, an indwelling urinary catheter, and urological procedures within the past 3 months are independent risk factors linked with MDRE UTIs.
The initiation of appropriate antimicrobial agents empirically is of utmost importance. However, in order to optimize empiric therapy, local patterns of antimicrobial resistance should be known. Antibiotic resistance rates and patterns differ by patient population type and change over time.
In our setting, when compared with other oral agents used for UTIs, isolates were more frequently susceptible to fosfomycin. Fosfomycin susceptibility rates for Enterobacteriaceae were the highest, followed by ciprofloxacin, nitrofurantoin and cefuroxime. Our data confirmed decreased ciprofloxacin susceptibility amongst the Enterobacteriaceae tested. Although fluoroquinolones are highly efficacious in a 3-day regimen, there has been a dramatic increase in resistance to these agents in gram-negative uropathogens in the past decade. A multicentre study conducted between 2007 and 2011 detected a significant decrease in ciprofloxacin susceptibility amongst
Nitrofurantoin susceptibility (70.1%) was lower compared to findings from previous studies in our region, where the reported susceptibility was above 90%.
Even though the first-generation cephalosporins reach high concentrations in the urine, they have high resistance rates when compared with other agents.
Although trimethoprim/sulfamethoxazole is still widely used and recommended for acute cystitis therapy, the limitation is that local resistance rates of uropathogens should not exceed 20%, or the infecting strain should be confirmed to be susceptible.
Fosfomycin has also been used off-label with success for complicated UTIs excluding pyelonephritis, perinephric abscess or bacteraemic UTIs.
Gardiner et al.
Research suggests that surgical antibiotic prophylaxis is beneficial for preventing UTIs post-urologic surgeries and procedures.
This study has several limitations. It was a retrospective single-centre study; therefore, the findings may not be generalised to other institutions with different susceptibility patterns and patient populations. A larger dataset, which includes data from other public and private hospitals, would offer further insight. As CMJAH is a referral hospital, antibiotic resistance rates may be higher than those found in local hospitals. Clinical and Laboratory Standards Institute breakpoints for
This study is important in that it represents the first local comprehensive evaluation of fosfomycin against gram-negative and gram-positive uropathogens. Fosfomycin has been shown to have good activity against both susceptible and MDR uropathogens. These findings together with its favourable side-effect profile, position it as a potential alternative oral agent for empiric and definitive treatment of UTIs for hospitalised and ambulatory patients at our centre.
The authors would like express their gratitude to the microbiology laboratory staff of the CMJAH for their assistance.
The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
All authors, L.M.M., N.N.B. and T.N., have made a significant contribution to the work and have seen and approved the content. L.M.M. was responsible for the following: conception and design of the project; acquisition, analysis and interpretation of data; L.M.M. drafted and wrote the manuscript. N.N.B. and T.N. assisted with design of the project and data interpretation. L.M.M., N.N.B. and T.N. revised the manuscript for intellectual content and approved the final version to be published.
This work was supported by the Department of Clinical Microbiology and Infectious Diseases, Witwatersrand University. Funding for this study was supported by research funds allocated by the University of Witwatersrand to the Department of Clinical Microbiology and Infectious Diseases.
Data sharing is not applicable to this article as no new data were created or analysed in this study.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.