The problem of resistance
The invaders
Resistance to common drugs
Current options
References
Further reading
Urinary tract infections (UTIs) are among the most common infections worldwide. Though generally minor, they can escalate to cause pyelonephritis, chronic infection, or septicemia in the elderly or high-risk population. Moreover, they may trigger the formation or growth of urinary calculi.
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The problem of resistance
Antibiotic resistance is a significant complicating factor, making it much harder to treat such infections. With the marked rise in antibiotic prescriptions globally, for infections in which they play no role or for infections that do not require them, more and more resistant organisms are emerging.
The reasons for the very high prevalence of resistance to some antibiotics are, doubtless, the tendency to stop taking antibiotics early, the inappropriate use of antibiotics by prescription or by self-medication, taking inadequate doses of medication, gross variations in the quality of the drugs used, and the failure to use culture results in treating UTIs.
Antibiotic resistance leads to the survival of some bacterial strains after antibiotic use, which increases the difficulty of their eradication.
To avoid this, antibiotics should be used in accordance with current guidelines and continued for the full duration, irrespective of symptomatic improvement.
The invaders
UTIs include bladder infection or cystitis, urethritis, and infection of the ureters and/or kidneys (pyelonephritis). Enterobacteriaceae are implicated in most UTIs, and the most common cause of UTI is uropathogenic Escherichia coli (UPEC), found in over 60-80% of cases.
Other important UTI pathogens include Klebsiella, Enterobacter, Proteus, and Enterococci, as well as some species of Staphylococcus.
Diagnosing and treating UTI as early as possible is essential to prevent the prolongation of illness and avert the risk of ascending infection and renal involvement. As a result, UTI treatment with antibiotics is primarily empirical until the culture results are obtained.
The potential pathogen and its susceptibility pattern must be known in each region to ensure that the treatment is appropriate in most cases. This justifies regular studies of UTIs and causative organisms with their antibiotic sensitivity reports.
Resistance to common drugs
Fosfomycin and nitrofurantoin are the first line of treatment for uncomplicated cystitis. Nitrofurantoin also retains efficacy against UPEC in 77% to ~90% of cases but not against Staphylococcus and Klebsiella, which showed resistance in ~58%. Cotrimoxazole is another widely used first-line antimicrobial, but increasing resistance is being reported worldwide, up to 60%, according to several European studies.
Ampicillin and amoxicillin were widely used, but above 85% of UPEC and Enterobacteriaceae and Staphylococci are resistant to the common antibiotic ampicillin, while more than 75% are resistant to amoxicillin.
Over 70% are resistant to the broad-spectrum antibiotic tetracycline, while at least 60% are resistant to common cephalosporins.
While first-generation cephalosporins have mainly become ineffective against UTI pathogens, second and third-generation drugs such as cefixime have also been widely overused, resulting in the rapid emergence of resistance in as much as two of three cases in developing countries.
However, other studies indicate that in more developed societies, these antibiotics continue to be effective, with <10% to 20% resistance being observed.
The quinolone antibiotic nalidixic acid showed high resistance rates, probably because it has been extensively used to treat UTIs.
Similarly, ciprofloxacin resistance is significant and increasing (55% to 85%) in developing countries, and it is not a suitable empirical choice for UTIs in people with a history of recent use of these drugs.
In contrast, most of these pathogens remain susceptible to ciprofloxacin and other fluoroquinolones in developed countries.
Chloramphenicol also retains significant sensitivity at less than 30% resistance. While UPEC and Klebsiella remain sensitive to amikacin, at above 80-90%% in most cases, gentamicin has fallen out of favor because of high levels of resistance at 30% to 50%. The frequency of resistance varies between regions.
However, most are sensitive to imipenem, which continues to be highly effective against these pathogens. It shows close to 85% to 100% sensitivity in many countries. This may be primarily due to the limited use, higher cost, and requirement for intravenous injection of this drug.
Multidrug-resistant (MDR) Gram-negative bacteria (GNB) have rapidly acquired extended-spectrum β-lactamases (ESBLs), as well as carbapenemases via plasmids. Over half of UPEC and a third of Klebsiella strains are currently MDR to all beta-lactams and carbapenems.
How can we solve the antibiotic resistance crisis? - Gerry Wright
Current options
UPEC continues to show high sensitivity to Fosfomycin and nitrofurantoin. Second-line antibiotics include cephalosporins, fluoroquinolones, and beta-lactams, such as the amoxicillin-clavulanate combination.
The combination of amoxicillin and clavulanic acid is a first-line treatment for pyelonephritis and other complicated UTIs. With beta-lactamase-producing Enterobacteriaceae, nitrofurantoin, piperacillin-tazobactam, carbapenems, cefepime, and pivmecillinam are among the options.
For extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, cotrimoxazole and ciprofloxacin are unlikely to be useful. These are treated with nitrofurantoin for ESBL-E. Coli. While pivmecillinam, fosfomycin, and finafloxacin are orally administered options for both this and ESBL-Klebsiella pneumoniae (K. pneumoniae).
Parenteral drugs for ESBL-Enterobacteriaceae, as well as for carbopenem resistance, include combinations like piperacillin-tazobactam, beta-lactam-beta-lactamase inhibitor combinations such as meropenem/vaborbactam, ceftazidime-avibactam, and nd aztreonam/avibactam; aminoglycosides including plazomicin; Fosfomycin; and sitafloxacin, besides the siderophore cephalosporin cefiderocol.
MDR-GNB is a huge challenge to health care universally, causing higher mortality and adverse outcomes among infected patients. MDR increases with age; thus, geriatric patients are more likely to have severe infections.
These combinations are also used to treat multi-drug-resistant (MDR)-Pseudomonas. These must be used with great selectivity to avoid a situation in which microbes also develop resistance to them.
References
- Mortazavi-Tabatabaei, S. A. R. et al. (2019). Pattern of Antibacterial Resistance in Urinary Tract Infections: A Systematic Review and Meta-analysis. International Journal of Preventive Medicine. https://doi.org/10.4103%2Fijpvm.IJPVM_419_17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826787/
- Zhao, F. et al. (2020). A Systematic Review and Meta-Analysis of Antibiotic Resistance Patterns, And the Correlation Between Biofilm Formation with Virulence Factors in Uropathogenic E. Coli Isolated from Urinary Tract Infections. Microbial Pathogenesis. doi: 10.1016/j.micpath.2020.104196. https://pubmed.ncbi.nlm.nih.gov/32283258/
- Kot, B. et al. (2019). Antibiotic Resistance Among Uropathogenic Escherichia coli. Polish Journal of Microbiology. doi: 10.33073/pjm-2019-048. https://pubmed.ncbi.nlm.nih.gov/31880885/
- Bader, M. S. et al. (2020). Treatment of Urinary Tract Infections in The Era of Antimicrobial Resistance and New Antimicrobial Agents. https://doi.org/10.1080/00325481.2019.1680052. https://pubmed.ncbi.nlm.nih.gov/31608743/
- Wright, H. et al. (2017). New Agents for The Treatment of Infections with Gram-Negative Bacteria: Restoring the Miracle or False Dawn? Clinical Microbiology and Infection. https://doi.org/10.1016/j.cmi.2017.09.001. https://pubmed.ncbi.nlm.nih.gov/28893690/
- Kanj, S. S. et al. (2022). Clinical Data From Studies Involving Novel Antibiotics To Treat Multidrug-Resistant Gram-Negative Bacterial Infections. International Journal of Antimicrobial Agents.https://doi.org/10.1016/j.ijantimicag.2022.106633. https://pubmed.ncbi.nlm.nih.gov/35787918/
- Huang, L. et al. (2022). Urinary Tract Infection Etiological Profiles and Antibiotic Resistance Patterns Varied Among Different Age Categories: A Retrospective Study from a Tertiary General Hospital During a 12-Year Period. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2021.813145. https://www.frontiersin.org/articles/10.3389/fmicb.2021.813145/full
- Matuszkiewicz-Rowińska, J. et al. (2015). Urinary Tract Infections in Pregnancy: Old and New Unresolved Diagnostic and Therapeutic Problems. Archives of Medical Science. https://doi.org/10.5114%2Faoms.2013.39202. https://www.ncbi.nlm.nih.gov/
- Smaill, F. Et Al. (2008). Asymptomatic Bacteriuria and Symptomatic Urinary Tract Infections In Pregnancy. European Journal of Clinical Investigation. https://doi.org/10.1111/j.1365-2362.2008.02009.x. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2362.2008.02009.x
Further reading