Anti-Bacterial Use and Resistance Pattern in Urinary Tract Infections

Abstract

Despite warnings at the beginning of the industrial antibiotic era 70 years ago, antimicrobial resistance (AMR) has become an increasingly intractable health issue. For common bacterial infections, such as urinary tract infections (UTIs), sepsis, and sexually transmitted infections, high rates of antibiotic resistance have been observed globally for the commonly used antibiotics used to treat these infections. This observation indicates that we are facing a shortage of effective antibiotics. This global problem has a significant impact on pregnant women, necessitating urgent multi-sectoral action to achieve the Sustainable Development Goals, with a particular focus on perinatal health. The current chapter focuses on shedding light on the commonly prescribed antibiotics for treating UTI during pregnancy. This chapter also addresses the overview of UTI management and principles of antibiotic regimen selections (effectiveness). Furthermore, it also pointed to the safety concern for selected antibiotics or class of antibiotics primarily used for treatment of UTI. Finally, it provides the details of current tsunami of AR specifically among pregnant women diagnosed with UTI in different settings and countries. In general, without the effective and cautious use of antibiotics, the progress made by the United Nations in reducing maternal and child mortality and morbidity by treating infections during pregnancy, such as UTI, would be at a heightened risk.

1. Introduction

Despite the fact that both men and women are susceptible to urinary tract infections (UTIs), women are more prone to them due to various factors. These factors include having a shorter urethra compared to men, proximity to the anus which increases the risk of fecal contamination, hormonal changes, and pregnancy [1, 2]. UTIs frequently happen during pregnancy. It is the most typical bacterial illness that pregnant women get. It refers to the invasion of microorganisms and their subsequent growth in any part of the urinary tract system including the kidneys, ureters, bladder, and urethra (Figure 1). It can be asymptomatic (positive urine culture in an asymptomatic woman), as well as symptomatic, complicating the diagnostic and antibiotic use process. The three main manifestations of UTI during pregnancy are asymptomatic bacteriuria (ASB), acute cystitis, and pyelonephritis [2, 3]. Approximately, 30% of women with ASB will experience acute cystitis during their pregnancy, despite the fact that the general incidence of UTI in pregnancy is about 8% [2, 4]. It is of great importance to obstetricians due to its association with significant maternal and perinatal morbidity and mortality.

Figure 1.

Female urinary tract system. I declare that there are no copyrights and that the figure is quoted from any other published work for this figure and it is available from the following web link (https://www.drugs.com/cg/urinary-tract-infection-in-women.html).

Pregnancy-related significant bacteriuria is a frequent, serious factor that contributes to maternal and perinatal morbidity and mortality [2, 5]. Bacteriuria during pregnancy raises the mother’s risk of anemia, pre-eclampsia, chorioamnionitis, preterm delivery, and postpartum endometritis. Both the fetus and the newborn are at risk of various dangers due to UTI, including preterm birth, stillbirth, perinatal mortality, mental impairment, and developmental delay [1, 3]. The cause is hypothesized to be a combination of direct bacterial endotoxin damage and cerebral hypo-perfusion. All are amenable to investigation and treatment, which improves outcomes significantly. However, the rising trend of antimicrobial resistance (AMR) has had a negative impact on the overall outcome of UTI management, as well as neonatal and maternal outcomes [1, 3, 5].

2. Causative pathogens

A meta-analysis of 20 studies from Ethiopia found that 15% of pregnant women receiving prenatal care in various regions had significant bacteriuria [6]. Similar to this, another study from low-income nations found that 13.5% of bacterial uropathogens that cause UTIs were isolated from the urine sample [7]. The majority of the times, the bacteria that cause UTIs in pregnant women are also present in non-pregnant patients. Gram-negative aerobic bacilli that originate in the digestive system are the most frequent cause of UTI. Frequent pathogens responsible for UTI include Citrobacter, Enterobacter, Enterococcus, Escherichia, Klebsiella, Proteus, Pseudomonas, Serratia, and Staphylococcus, which colonize the genitourinary tract [6, 8, 9]. Escherichia coli accounts for 60–80% of all UTIs in pregnancy and is the most prevalent pathogenic bacterium linked to both asymptomatic and symptomatic bacteriuria [6, 7, 10]. Other bacteria identified in UTIs during pregnancy include Klebsiella pneumoniae (K. pneumoniae), Staphylococcus aureus, coagulase negative Staphylococci, Enterobacter spp., Pseudomonas aeruginosa, Enterococcus spp., Proteus mirabilis, and others [7]. Klebsiella, E. coli, Pseudomonas, and Proteus spp. are the most influential gram-negative organisms responsible for UTIs [8]. Among gram-positive bacterial pathogenic strains, Staphylococcus and Streptococcus spp. have been found to be the most common bacteria responsible for UTIs [6, 11].

3. Anti-bacterial use in UTI management

Antibiotics are used to treat ASB and acute cystitis. Because ASB is a known risk factor for developing pyelonephritis and having a premature delivery, pregnant women should be screened for it using urine culture and treated with appropriate antimicrobials. Active UTI should be treated as soon as possible after diagnosis; waiting for culture and sensitivity results in the pregnant population is not recommended due to the risk of developing ascending infection [3, 5]. A microbiologic sample must be obtained prior to treatment in order to tailor antibiotic treatment as per the “Start Smart Then Focus principles” of antibiotic stewardship. Any treatment decision should be reconsidered once culture and sensitivity reports are available. All women should be checked to ensure that their urine is sterile after treatment for both ASB and active infections [1, 5].

3.1 General principles of anti-bacterial selection

Antibacterial are among the most often prescribed drugs for UTI treatment worldwide, and they are vital to global health. Despite their importance, the development of resistance threatens antibiotics’ long-term effectiveness. The overuse and misuse of antibiotics has been the primary cause of antibiotic resistance. The misuse of antibiotics by the general population is a significant risk factor for antibiotic resistance [12], while some studies have also reported that some pregnant women are ignorant of the management of common infections which results in AMR [13].

When the actual cause of the infection and the pattern of resistance are uncertain, empirical antibiotics are chosen [2]. The antibiotics used to treat UTIs are chosen based on a variety of factors, including the relative frequency of uropathogenic organisms, local resistance patterns, levels of observed resistance, the clinical syndrome presented by the patient, and the source of the infection, whether nosocomial or acquired in the community. Therefore, an empirical antibiotic for the treatment of UTIs should be active against gram-positive organisms like Staphylococcus saprophyticus and, ideally, Enterococcus spp. as well as gram-negative Enterobacteriaceae like E. coli (E. coli) and Klebsiella spp.

Pregnant women should be treated when bacteriuria is identified (Table 1). The choice of antibiotic should address the most common infecting organisms (i.e., gram-negative gastrointestinal organisms). The risk of resistance mutations in the population as well as the specific patient has a significant impact on the selection of empirical antibiotics. Therefore, it is crucial to obtain a comprehensive clinical history since certain patient groups may require early treatment with broad-spectrum antibiotics. Patients who have recently been admitted as inpatients, those who have taken repeated antibiotic courses, and those who live in nursing homes are particularly at risk of contracting infections with multidrug resistant (MDR) organisms. Experts recommend that the choice of antibiotic for empirical treatment should take into account local rates of resistance in uropathogens. Choosing the right antibiotics for pregnant patients with UTIs is critical. It is not only important to choose the right drug, but also consideration should be given to selecting the right dose and treatment duration. When urine culture results are available, antibiotic selection can be tailored based on organism sensitivities. In pregnancy, 1-day antibiotic treatments are not recommended. Instead, 3-day courses are recommended and have been proven to be effective [16, 17]. It is hoped that by effectively treating UTIs, the risk of maternal sepsis, pyelonephritis, preterm labor, and adverse fetal outcomes will be reduced. When selecting antibiotics, potential teratogenicity should be taken into account. The antibiotic should be safe for both the mother and the fetus.

Antibiotic	Dosage	Pregnancy category
1. Cephalexin	50 mg two or four times daily	B
2. Erythromycin	250–500 mg four times daily	B
3. Nitrofurantoin	50–100 mg four times daily	B
4. Sulfisoxazole	1 g four times daily	C*
5. Amoxicillin clavulanic acid	250 mg four times daily	B
6. Fosfomycin	One 3g sachet	B
7. Trimethoprimsulfamethoxazole	160/180 mg twice daily	C**

Table 1.

Antibiotic selection for treatment of UTIs during pregnancy [14, 15].

*

Contraindicated in pregnant women at term.

**

Avoid during first trimester and at term.

Amoxicillin, ampicillin, ceftriaxone, nitrofurantoin, and trimethoprim-sulfamethoxazole are common antibiotics. Due to conflicting studies on teratogenicity, fluoroquinolones are not recommended as first-line treatment in pregnancy [18]. However, it is reasonable to take this class of medication with resistant or recurrent infections because short courses are unlikely to be detrimental to the fetus. Historically, ampicillin was the drug of choice, but E. coli has become increasingly resistant to ampicillin in recent years. Around 20–30% of E. coli isolated from urine in an outpatient environment have ampicillin resistance [17]. The high urine concentration of nitrofurantoin makes it a good choice. Cephalosporins, on the other hand, are well tolerated and effectively treat the key microorganisms. Fosfomycin is a novel antibiotic that is administered in a single dose. Sulfonamides are safe to use during the first and second trimesters, but they increase the risk of kernicterus in the third trimester, especially in preterm infants. Other common antibiotics (for example, fluoroquinolones and tetracyclines) should not be used during pregnancy due to potential fetal toxicity [17, 18].

Usually, a 7- to 10-day course of antibiotics is enough to completely get rid of the infection(s). However, shorter treatment durations, including 1-day therapy, have been recommended by some experts. There is still debate over whether pregnant individuals should take shorter antibiotic rounds of treatment. In a clinical trial conducted by Masterton et al. [14], it was found that for isolates that were sensitive to ampicillin, the cure rate reached up to 88% with a single 3 g dosage of ampicillin. According to several other studies, cure rates for bacteriuria ranged from 50% to 78% when amoxicillin, cephalexin, or nitrofurantoin was given as a single dosage [15, 19]. Fosfomycin is effective when taken as a single, 3g sachet [20, 21]. Further research is necessary to evaluate whether a shorter course of other antibiotics would be as successful as the standard treatment duration for UTIs because other antibiotics have not been well studied for use in UTIs [15]. Following the completion of the treatment regimen, a repeat culture should be obtained to document successful bacteriuria eradication [19].

3.2 Anti-bacterial safety concern in pregnancy

Due to the excretion of several drugs through the kidneys, they may prove beneficial in treating UTI due to their potential to concentrate in the renal system. However, where the safety of the fetus or newborn is a concern, the pregnancy state prohibits the use of certain antibiotics. When the benefits outweigh the risks, the antibiotic can be used if no other option is available. As a result, the choice of antibiotics during pregnancy may be limited in comparison to the general population due to the risk of teratogenicity, or harm to the developing fetus. For example, trimethoprim is avoided in the first trimester due to a risk of neural tube abnormalities, and the danger of hemolysis prevents the use of nitrofurantoin at term [22].

3.2.1 Sulfa derivatives and nitrofurantoin

Recent research suggests that using nitrofurantoin and sulfa derivatives during the first trimester of pregnancy increases the risk of congenital disabilities. While acknowledging the severe limitations of these trials, current guidelines advise against using these drugs during the first trimester of pregnancy when alternatives are available [23]. However, due to the potential serious implications of untreated UTIs during pregnancy, it is considered reasonable to use these drugs when necessary, as the benefits significantly outweigh the associated risks. There are additional warnings regarding these two types of antibiotics. Patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency should not be prescribed sulfa derivatives or nitrofurantoin as these medications can precipitate hemolysis. Trimethoprim sulfamethoxazole (TMP-SMX) should be avoided in the late third trimester due to the potential risk for the development of kernicterus in the newborn after birth. If sufficient serum levels are present at the time of delivery, sulfonamides pose a risk of neonatal jaundice. The addition of trimethoprim increases activity but trimethoprim inhibits folate synthesis, which is crucial for preventing neural tube deformities. Trimethoprim alone or TMP-SMX combinations should be avoided in the first trimester as well as after 32 weeks gestation [23].

3.2.2 Beta lactam antibiotics

Usually, data on pregnancy safety is very limited, which raises serious concerns during prescription. Furthermore, many studies on the safe use of antibiotics during pregnancy are inconclusive or require more evidence. Nevertheless, beta-lactam antibiotics, known for their extensive use without causing significant adverse effects on fetuses, continue to be the safest choice during pregnancy. Due to their mechanism of action, which involves targeting the bacterial cell wall—a structure exclusive to bacteria—beta-lactam antibiotics exhibit higher selective toxicity. As a result, all penicillin antibiotics are classified as “category B” in terms of safety during pregnancy. Furthermore, with over 80 years of clinical experience, these antimicrobial agents are among the oldest known antibiotics [24, 25]. For example, ampicillin is semi-synthetic safest penicillin and particularly active against enterococcus. Ampicillin shows high levels of concentration in the urinary tract, which explains its continued use despite the emergence of resistance. Furthermore, the addition of clavulanic acid, a B-lactamase inhibitor, enhances its efficacy against B-lactamase producing E. coli [24, 25, 26].

The beta-lactam ring and comparable mechanism of action, which interfere with the formation of the bacterial cell wall, make cephalosporins and penicillin very similar antibiotics. They are the most commonly administered antibiotics during pregnancy after penicillin, although they also have significant selective toxicity. The Hungarian study [27] observed that 458 (1.2%) women used some kind of cephalosporin. Food and Drug Authority (FDA) considers these antibiotics as “category B”. Cephalosporins are generally thought to be safe to use during pregnancy, however if administered a day before delivery, ceftriaxone’s strong protein binding capacity may displace bilirubin, increasing the risk of neonatal jaundice, especially in preterm infants. Other cephalosporins have also specific recommendation based on their pharmacokinetics profiles. There is little information on the use of cefadroxil during pregnancy and lactation. It is unknown whether cefadroxil passes through the placenta. Teratogenicity studies in rodents are reassuring. Cefadroxil, like most cephalosporins, is safe to use during pregnancy and lactation [28]. Cephalexin crosses the placenta in a carrier mediated fashion. As a result, fetal concentrations are greater than the Minimum inhibitory concentration (MIC) for most sensitive pathogens. Cephalexin is the most often prescribed cephalosporin during pregnancy. Women using this antibiotic have not yet been linked to any teratogenic concerns. Cephalexin excretes very little into breast milk and is usually thought to be safe for nursing [29, 30]. Cefixime can be found in amniotic fluid after maternal treatment, indicating that it crosses the placenta. Rodent teratogenicity studies are reassuring. Most cephalosporins are excreted in breast milk, and cefixime appears to be no exception. Cefixime, like all cephalosporins, is generally thought to be safe to use while breastfeeding [31].

Postpartum infections have been successfully treated with other beta-lactams (carbapenem antibiotics), such as imipenem and meropenem [32]. However, there is little or no substantiated clinical experience with imipenem in pregnancy, and there have been no reports of teratogenicity. It is classified as “Category C” by FDA [33]. Aztreonam is a monocyclic beta-lactam antibiotic that is highly effective against gram-negative aerobic bacilli. The spectrum of activity is similar to that of the aminoglycoside agents, but without side effects such as ototoxicity and nephrotoxicity [34]. Although the drug crosses the placenta, it is only found in trace amounts in fetal serum and breast milk [35]. The great majority of studies on aztreonam use in pregnant women were conducted during the perinatal period, and all of them concluded that the drug is safe. During the first trimester of pregnancy, very few inconclusive investigations were conducted [36]. Thus, the teratogenic potential of aztreonam has not been well established.

3.2.3 Fosfomycin

Neither clinical investigations nor animal models have shown any evidence linking the usage of fosfomycin to teratogenic side effects [37]. Fosfomycin crosses the rat placental barrier and has no teratogenic effects in pregnant rats at extremely high doses such as 1000 mg/kg/day, which is approximately nine times the human dose based on body weight. Perhaps, lack of teratogenic effects of fosfomycin may be explained by its mechanism of action. By inactivating the enzyme enolpyruvyl transferase, this synthetic antibiotic prevents bacterial cell wall synthesis. It is well absorbed orally and effective against a variety of common UTIs. A single dose results in high serum concentrations, exceeding the MIC for common urinary pathogens for up to 3.5 days [38]. According to comparative clinical trials, a single dose of fosfomycin is as effective as 7–10 day treatment regimen of nitrofurantoin, norfloxacin, or cotrimoxazole. However, it is important to note that due to the lack of adequate and well-controlled human studies, the FDA classifies fosfomycin as “category B” [37].

3.2.4 Quinolones

Quinolones are broad-spectrum bactericidal antibiotics that inhibit bacterial DNA-gyrase. Ciprofloxacin, norfloxacin, gatifloxacin, levofloxacin, and ofloxacin are examples of this class [39]. Due to the significant similarity between mammalian gyrase and bacterial gyrase, there is great concern regarding the use of these agents during pregnancy. The quinolones are found in high concentration in the umbilical cord blood and amniotic fluid [40]. Due to their ability to attain high concentrations in the urinary tract, they are used to treat urinary infections that are unresponsive to conventional treatment methods [41]. However, the use of these drugs during pregnancy is still highly debated. Several studies have found no evidence of an increased risk of major malformations, fetal musculoskeletal defects, spontaneous abortions, prematurity, intrauterine growth retardation, or postnatal disorders. For example, Ciprofloxacin crosses the placenta. While short-term therapy seems safe, the impact of ongoing exposure (for example, in inflammatory bowel disease) is still unknown. Ciprofloxacin is found to enter breast milk at varying concentrations. One breastfed infant has been diagnosed with Clostridium difficile pseudomembranous colitis, and discolored teeth have been reported in neonates treated with ciprofloxacin [42, 43]. Although ciprofloxacin is generally regarded as safe for breastfeeding mothers, some experts advise against use or caution when using it. In many circumstances, there are better options that have been proven to work during pregnancy and lactation.

3.2.5 Macrolides

Macrolides have become the group of choice for the “allergic-to-penicillin” patients. These agents are bacteriostatic and they act in the bacterial ribosome, linking to the 50S sub-unit inhibiting protein synthesis [44], which is different from the human ribosome. The spectrum of activity favors gram-positive cocci and has little effect on S. aureus. Macrolides are only permitted to be used during pregnancy to treat upper respiratory illnesses and syphilis in patients who have a history of penicillin allergies. Moreover, it has been used to treat urethritis brought on by Chlamydia trachomatis and toxoplasmosis [45]. Erythromycin is the oldest known macrolide and it is usually presented as estolate or stearate formulation. Pregnant women should avoid the estolate formulation because it causes hepatoxicity in 2–10% of the users; FDA classifies erythromycin as a “category B” agent. There are no reports about the teratogenic effects of this antimicrobial agent [46].

4. Anti-bacterial resistance pattern in pregnant women diagnosed with UTI

While antibiotics are highly effective at treating UTIs, they are also associated with AMR, which is a global health threat. AMR refers to the evolution of microorganisms to develop resistance to antimicrobial treatment. AMR kept rising as a result of the worldwide rapid growth of resistant microorganisms [47]. Recent World Health Organization (WHO) surveillance data from 22 high- and low-income countries show a high level of AMR to numerous bacterial infections, with E. coli and K. pneumoniae being the most common resistant pathogens [48]. Additionally, a meta-analysis of 23 studies from various parts of the world revealed that pregnant women with substantial bacteriuria had a high incidence of Enterobacteriaceae that produce extended-spectrum beta-lactamases (ESBLs) [49]. Uropathogenic resistance to third-generation cephalosporin, amoxicillin, and other antibiotics in pregnant women, particularly in Africa, poses a significant barrier to the treatment of UTI during pregnancy [49, 50]. Increases in bacterial resistance and the emergence of antibiotic-resistant diseases are closely correlated with the prescription and use of antibiotics.

Resistant infections are difficult to treat and have a high morbidity and mortality rate. There is evidence to suggest that antibiotics to treat UTIs are overused in pregnant women [51], potentially leading to an increase in resistant UTIs. Resistant UTIs can be particularly concerning during pregnancy [2]. Treating such infections can already be challenging, but the additional complexity of ensuring the safety of both the woman and the fetus adds further difficulty in the context of pregnancy. In the majority of low-income nations, routine antibiotic susceptibility testing is a significant problem [52]. As a result, most pregnant women are treated with an unnecessary antibiotic, which contributes to the emergence of resistant pathogens [53]. Considering this, it is necessary to monitor the use of antibiotics in pregnancy to optimize prescribing and consumption of these valuable medicines and facilitate antimicrobial stewardship in antenatal care.

Antibiotic resistance has led to significant challenges in treating UTI [54]. Different studies from low-income countries showed high level of drug resistance. For example, the pooled analysis from Ethiopia showed gram-negative bacteria such as E. coli was highly resistant to amoxicillin (81%) and ampicillin (80%) [6]. Similarly, report from Ghana showed that 79.3% of E. coli were ampicillin resistant [55]. A multicenter investigation in Tanzania found higher resistance of E. coli to ampicillin (94.5%) and cotrimoxazole (88.8%) [56]. In contrast, a meta-analysis in Ethiopia revealed that relatively lower percentage (40%) of E. coli isolates were cotrimoxazole-resistant [6]. The results showed that E. coli was less resistant to the antibiotics nitrofurantoin (19%), ceftriaxone (20%), and ciprofloxacin (21%). Similarly, Emami et al. [50] reported that E. coli was 22% resistant to nitrofurantoin. The Ethiopian data report by [6] showed that 83% of the E. coli isolates were MDR and 19% were ESBL producers. This resistance burden is expected to be more prevalent in low resource settings like countries in Sub-Saharan Africa. For example, recent data from Ethiopia showed significantly high burden of anti-bacterial resistance among pregnant women diagnosed with UTI (Figures 2 and 3) [6]. Similar findings were reported in another meta-analysis by Mansouri et al. [49] and a study by Sekikubo et al. [53], where 17% and 18% of the E. coli strains identified from pregnant women with UTIs were ESBL producers, respectively.

Figure 2.

Pattern of antimicrobial resistance of gram-negative bacteria among pregnant women in Ethiopia [6], pp. 663–686.

Figure 3.

Pattern of antimicrobial resistance of gram-positive bacteria among pregnant women in Ethiopia [6], pp. 663–686.

Similarly, different studies showed significantly high burden of gram-positive resistance pathogen to common antibiotics. For instance, a meta-analysis from Ethiopia [6] revealed that 89% of the S. aureus isolates from urine samples of pregnant women with severe bacteriuria were MDR. Similarly, a study from Nigeria [57] which found that S. aureus isolated from urine samples of pregnant women was 90% resistant to cefoxitin, vancomycin, tetracycline, and cotrimoxazole. Another study by Asmat et al. [58] revealed that all S. aureus isolates were also MDR, with resistance to tetracycline, doxycycline, tobramycin, and pipemidic acid.

Unsurprisingly, multidrug-resistant bacteria such as extended spectrum beta-lactamases (ESBL), vancomycin-resistant Enterococci (VRE), and carbapenem-resistant Enterobacteriaceae (CRE) have increased and spread globally in recent years [59]. Understanding the local epidemiology of multidrug-resistant bacteria is critical for determining empirical antimicrobial therapy. Furthermore, in order to combat these multidrug-resistant bacteria, clinicians and scientists around the world are working against the clock to develop new antibiotics [59, 60].

5. Conclusion

In conclusion, significant bacteriuria is common among pregnant women. Resistance to commonly used antibiotics is widespread among common bacteria (E. coli, Klebsiella species, Staphylococcus species) causing UTIs in pregnant women. The high occurrence of bacteriuria in pregnant women should serve as a warning to health workers to screen for bacteriuria at least once using urine culture during antenatal care and treat if urine cultures are positive. Because of the high prevalence of drug resistance, it is imperative to create an effective infection control and stewardship program as well as routine epidemiological surveillance of antibiotic resistance. Failure to do so not only prolongs sickness and exposes patients to complications, but also contributes to the development of bacterial resistance as a result of injudicious antibiotic use. It is shown that a high number of antibiotics could be used with relatively great safety during pregnancy to treat UTI.

Conflict of interest

The author declares that there is no conflict of interest. The author declares that there are no copyrights and that the figure is quoted from any other published work in the figures.

Abbreviations

AMR	Antimicrobial resistance
ASB	Asymptomatic bacteriuria
CRE	Carbapenem-resistant Enterobacteriaceae
E. coli	Escherichia coli
ESBL	Extended spectrum beta lactamase
FDA	Food and drug authority
G6PD	Glucose 6 phosphate dehydrogenase
K. pneumoniae	Klebsiella pneumoniae
MDR	Multidrug resistance
MIC	Minimum inhibitory concentration
TMP-SMX	Trimethoprim sulfamethoxazole
UTI	Urinary tract infection
WHO	World Health Organization