Which Antibiotic for Urinary Tract Infections in Pregnancy? A Literature Review of International Guidelines

Urinary tract infection (UTI) is considered to be a major problem in pregnant women. It is also one of the most prevalent infections during pregnancy, being diagnosed in as many as 50–60% of all gestations. Therefore, UTI treatment during pregnancy is extremely important and management guidelines have been published worldwide to assist physicians in selecting the right antibiotic for each patient, taking into account the maternal and fetal safety profile. A review of the literature was carried out and all international guidelines giving recommendations about antibiotic treatments for pregnancy-related UTI were selected. The search came back with 13 guidelines from 4 different continents (8 from Europe, 3 from South America, 1 from North America and 1 from Oceania). Our review demonstrated concordance between guidelines with regard to several aspects in the antibiotic treatment of UTI during pregnancy and in the follow-up after treatment. Nonetheless, there are some areas of discordance, as in the case of antenatal screening for bacteriuria and the use of fluoroquinolones in lower or upper UTI. Given the current evidence that we have from international guidelines, they all agree on several key points about antibiotic use.


Introduction
Urinary tract infection (UTI) is considered to be a major problem in pregnant women [1][2][3]. It is also one of the most prevalent infections during pregnancy, being diagnosed in as many as 50-60% of all gestations [4].
UTIs can be classified as lower urinary tract infections, including both asymptomatic bacteriuria (ASB) or acute cystitis (AC), and upper urinary tract infections or acute pyelonephritis (APN) [5]. Most infections are caused by Enterobacteriaceae, commonly found in the gastrointestinal tract, with Escherichia coli (E. coli) being responsible for 80-90% of cases. However, we can find other bacteria such as Group-B Streptococcus saprophyticus (GBSS), Klebsiella pneumoniae, coagulase-negative Staphylococcus, Staphylococcus aureus and Proteus mirabilis in a lower percentage [2,6].
In pregnant women, ASB occurs in an estimated 2-10% [7], and if left untreated, it can turn into symptomatic AC in 30% of patients and may progress to APN in up to 50% of those patients [6], which have been associated with several complications for both the mother and the unborn child [2,8].
Therefore, UTI treatment during pregnancy is extremely important and management guidelines have been published worldwide to assist physicians in selecting the right antibiotic for each patient, taking into account the maternal and fetal safety profile [5,6,9].
The aim of this study is to review the concordance in recommendations between evidence-based guidelines for antibiotic treatment of pregnancy-related UTI developed by different authorities around the world. Additionally, we will review their concordance in terms of ASB screening and follow-up after treatment.

Methods
A literature review was carried out in August 2021 using the PubMed and Scopus databases for clinical guidelines covering the topic of pregnancy-related UTI. An additional search was performed in the Guidelines International Network (G-I-N) for any relevant guidelines not identified by our PubMed and Scopus database search. Exclusion criteria included guidelines that did not include recommendations about antibiotic treatments for pregnancy-related UTI. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [10].
Different searches were carried out with the following medical subject heading (MeSH) terms and keywords: "urinary tract infection", "UTI", "pregnancy", "woman", "guideline", "asymptomatic", "bacteriuria", "cystitis" and "pyelonephritis". Boolean operators (AND, OR) were used to refine the search. The references of each included guideline were also reviewed. No time period nor language restrictions were applied.

Results
The PubMed and Scopus search returned 386 results and 20 additional guidelines were added after the G-I-N search. After duplicate removal and review of results, a total of 20 guidelines were selected of which 7 were excluded leaving 13 guidelines that fulfilled our inclusion criteria. The summary of the selection process is represented in Figure 1. different authorities around the world. Additionally, we will review their concordance in terms of ASB screening and follow-up after treatment.

Methods
A literature review was carried out in August 2021 using the PubMed and Scopus databases for clinical guidelines covering the topic of pregnancy-related UTI. An additional search was performed in the Guidelines International Network (G-I-N) for any relevant guidelines not identified by our PubMed and Scopus database search. Exclusion criteria included guidelines that did not include recommendations about antibiotic treatments for pregnancy-related UTI. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [10].
Different searches were carried out with the following medical subject heading (MeSH) terms and keywords: "urinary tract infection", "UTI", "pregnancy", "woman", "guideline", "asymptomatic", "bacteriuria", "cystitis" and "pyelonephritis". Boolean operators (AND, OR) were used to refine the search. The references of each included guideline were also reviewed. No time period nor language restrictions were applied.

Results
The PubMed and Scopus search returned 386 results and 20 additional guidelines were added after the G-I-N search. After duplicate removal and review of results, a total of 20 guidelines were selected of which 7 were excluded leaving 13 guidelines that fulfilled our inclusion criteria. The summary of the selection process is represented in Figure  1. Of the 13 guidelines coming from 4 different continents (Table 1), 8 came from Europe, produced on behalf of the European Association of Urology (EAU) [7], German Society of Urology (German acronym: DGU) [11], Swiss Society of Gynaecology and Obstetrics (SSGO) [12], Spanish Society of Clinical Microbiology and Infectious Diseases Full-text articles excluded after full text evaluation (n = 7) Guidelines that did not specify antibiotic therapy during pregnancy Studies included in qualitative synthesis (n = 13) Of the 13 guidelines coming from 4 different continents (Table 1), 8 came from Europe, produced on behalf of the European Association of Urology (EAU) [7], German Society of Urology (German acronym: DGU) [11], Swiss Society of Gynaecology and Obstetrics (SSGO) [12], Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) [13], joint report of French Infectious Diseases Society/Urological French Association (French acronym: SPILF/AFU) [14], joint report of the Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland/Clinical Strategy and Programs Division, Health Service Executive (IOGRCPI/ CSPDHSE) [15] and 2 guidelines coming from the National Institute for Health and Care Excellence (NICE) [16,17]; 1 from North America, produced on behalf of the Infectious Diseases Society of America (IDSA) [18]; 3 from South America, produced on behalf of the joint report of the Brazilian Society of Infectious Diseases/Brazilian Federation of Gynecology and Obstetrics Associations/Brazilian Society of Urology/Brazilian Society of Clinical Pathology/Laboratory Medicine (SBI/FEBRASGO/SBU/SBPC/ML) [19], joint report of the Argentinean Society of Infectious Disease (SADI) [20] and Colombian Association of Infectious Disease (Spanish acronym: ACIN) [21]; and 1 from Oceania, produced on behalf of South Australian Health (SAH) [22]. For better understanding of the main purpose of the present report, the obtained results have been divided into different sections. Those sections are organized as follows: screening for ABU, antibiotics in ABU, antibiotics in cystitis, antibiotics in APN, urine culture follow-up and prophylaxis follow-up.
Key points of antibiotic use in pregnancy according to international guidelines (for ASB, cystitis, APN and prophylaxis) are summarized in Table 2. Table 2. Key points of frequently used antibiotics during pregnancy.
Colombia and Brazil recommended to repeat this screening in the third trimester of pregnancy [19,21], especially in patients with chronic kidney disease (CKD), diabetes mellitus (DM) and history of UTI [21]. Argentina recommended to repeat this screening every 3 months with the presence of risk factors [22].
When referring to lines of treatment, as first line, nitrofurantoin [16,21], fosfomycin [21] and amoxicillin [14] were proposed. Second-line treatments were pivmecillinam [14], cephalexin [16] and amoxicillin (if sensible) [16]. France was the only country that gives up to five-line treatments [14], with fosfomycin being the third-line treatment; trimethoprim, the fourth-line one; and nitrofurantoin, amoxicillin/clavulanate, cefixime and TMP/SMX, the fifth-line treatment. TMP/SMX was also suggested as the last antibiotic choice in Germany [11].
Results are summarized in Table 3, including the dosage recommended by each guideline.
Results are summarized in Table 3, including the dosage recommended by each guideline.
As a third-line option, France proposed ciprofloxacin in case of beta-lactamase allergy [14]. The AFU also specified a 10 day-treatment for UTI caused by extended-spectrum beta-lactamase producing E. coli (ESBLE). Ciprofloxacin, levofloxacin or TMP-SMX was the first-line choice, amoxicillin-clavulanate was the second-line choice and cefoxitin, piperacillin-tazobactam or temocillin was the third-line choice.
A couple of European guidelines proposed oral antibiotics for uncomplicated AP: cephalexin (1stGC) [17] or amoxicillin/clavulanate [12] as a first-line treatment and TMP/ SMX [12] as third-line treatment. Table 4, including the dosage recommended by each guideline.
After one episode of APN, prophylaxis with nitrofurantoin was recommended by Irish guidelines [15]

Discussion
When choosing antimicrobials during pregnancy, safety considerations for both mother and fetus must be considered. Most of the antibiotics recommended by international guidelines are category B according to the United States Food and Drug Administration (FDA), meaning that there are no adverse effects in well-controlled studies of human pregnancies. However, some of the antibiotics used for UTI in pregnancy such as trimethoprim, TMP/SMX, gentamicin and ciprofloxacin are FDA category C, and must be used with caution [23].
Our review demonstrated concordance between guidelines with regard to several aspects in the antibiotic treatment of UTI during pregnancy and in the follow-up after treatment. Nonetheless, there are some areas of discordance, as in the case of antenatal screening for bacteriuria. There is adequate evidence showing that ASB is associated with an increased risk of APN, preterm labor and an increased risk of delivering a low-birthweight infant, among other adverse fetal outcomes [8,[24][25][26]. Moreover, studies have also shown a reduction of these complications by treating ASB in this population [27][28][29][30]. Based on this evidence we can describe a first scenario, screening for asymptomatic bacteriuria. All guidelines coming from North America, South America, the only one from Oceania and most European guidelines agreed on recommending systematic screening for ABU, even if most of the published studies have low-quality evidence. In summary, if we choose to carry out a screening for bacteriuria in pregnancy and we end up with a positive urine culture, then we can treat it tailoring the antibiotic treatment according to the weeks of pregnancy and urine culture sensitivity.
The only two European guidelines that do not recommend this screening anymore are the ones from Germany and Switzerland [11,12], with the exception of women at high risk for developing UTI (women with diabetes mellitus, immunosuppression, functional or structural abnormalities of the urinary tract, previous episodes of pyelonephritis, previous premature births or late pregnancy loss). This recommendation is mainly due to a recent high-quality study that demonstrated that in women with an uncomplicated singleton pregnancy, untreated ASB is related to a low risk of developing APN but it is not associated with an increased risk of premature birth or other neonatal or maternal complications [31].
Concerning antibiotic therapy for lower UTI, it was similar around the world. Few guidelines gave specific lines of treatments for ASB and cystitis. This may be related to variable patterns of antimicrobial resistance worldwide, meaning that treatment should be based on UC and sensitivities recommended by the laboratory report, taking into account the antibiotics allowed during the trimester of pregnancy. We remarked that only two European guidelines [12,16] and one from South America [21] highlighted the need for considering the local antimicrobial resistance profile (AMR) data when prescribing antibiotic treatment for UTI. Furthermore, German, Swiss and UK guidelines [11,12,16] were the only ones that made a statement about the AMR of each antibiotic according to their local population. A recent meta-analysis that investigated the AMR of different antibiotics used in pregnancy-related UTI, which also included studies from Europe and South America, showed that the most prevalent uropathogen was E. coli, followed by Klebsiella sp., two bacterial agents that were highly susceptible to nitrofurantoin [32]. This may be the reason why nitrofurantoin is still highly recommended by most international guidelines, being the first line of treatment in the UK and Colombia. Moreover, E. coli is also sensitive to 1stGC but extremely resistant to ampicillin and to other aminopenicillins worldwide [32,33]. Due to antimicrobial resistance, amoxicillin is not preferred as a first-line option, as specified by NICE and South Australian guidelines [16,22]. Instead, it can be recommended as a second-line treatment if there is no improvement of symptoms after using first-line antibiotics for at least 48 h, or when first-line treatment is not suitable [16].
The use of ciprofloxacin was another area of discordance in this review. French guidelines were the only ones that recommended ciprofloxacin as a third-line treatment for cystitis in pregnancy and as a first-line choice for ESBLE, together with levofloxacin or TMP-SMX [14]. In spite the fact that fluoroquinolones and TMP-SMX are both FDA category C, fluroquinolones are the only ones not reaching a consensus in international guidelines. Brazilian, Swiss and Irish guidelines do not recommend the use of ciprofloxacin during pregnancy [12,15,19], the latter being restricted to postpartum women only because of teratogenicity concerns [15]. Although fluoroquinolones have not been associated with increased risk of major malformations such as adverse effects in the musculoskeletal system, premature labor or intrauterine growth retardation [34][35][36][37], almost all guidelines do not mention them as an alternative treatment for UTI. In summary, this second scenario, which is treating a symptomatic UTI, recommends starting with an empiric antibiotic treatment according to the country's guidelines.
In terms of therapy duration for lower UTI in pregnancy, all guidelines recommended the shortest possible duration, varying from 3 to 7 days for all antibiotics but fosfomycin. Recent publications show that there is no clear difference between a single dose vs. a 4-7 day short course of antibiotics for lower UTI treatment, in terms of progression to pyelonephritis (very low-quality evidence) and preterm birth (moderate-quality evidence) [23]. This would encourage the use of fosfomycin trometamol in patients with poor drug compliance, and also because this broad-spectrum bactericidal antibiotic has demonstrated excellent tolerability and safety in pregnancy [38]. However, Swiss guidelines still recommend a more prolonged therapy if there is increased risk of premature birth [12].
On the other hand, focusing on APN, it is well known that initial antimicrobial therapy is empiric and should be modified according to the UC results [5]. All guidelines agreed on giving lines of treatment for APN. Nonetheless, there was no consensus on the drug of choice for the first-line treatment. Empiric parenteral antibiotics included were 2ndGC or aminopenicillins (i.e., amoxicillin, ampicillin) associated with an aminoside (gentamicin) [7,[13][14][15][16]20,22]. These traditional regimes have been associated with high efficacity withing the first 72 h [39][40][41] due to their ability to reach therapeutic concentrations in the upper urinary tract, contrary to nitrofurantoin and fosfomycin. However, concerns are being raised due to the AMR of the aminopenicillins [33]. Among international guidelines, Swiss and UK guidelines recommended starting with oral therapy, either with a 1st GC or amoxicillin/clavulanate, and as a second-line treatment parenteral antibiotic, if the patient is unable to take oral antibiotics or severely unwell [12,17]. All guidelines recommended switching to oral therapy, if the first antibiotic choice was parenteral, after 48 h of apyrexy [7,[12][13][14][15]17,20,22]. These different schemes of treatment among guidelines suggest that all first lines of treatments proposed for ACP in pregnancy are similar in efficacity and should be used depending on the AMR. In fact, to date, there is no evidence that one treatment regimen for APN is better than another [39][40][41][42].
Guidelines from South America and Europe specified the need for a second UC 1-2 weeks after the antibiotic course has been completed. This is in line with previous recommendations [26,43]. Those same guidelines also suggest the need to follow a prophylactic treatment in certain cases, following the antibiotic cautions. Special management is needed for patients that have suffered from a UTI caused by GBSS, in whom prophylactic antibiotics are also needed during labor to prevent neonatal sepsis [44].

Limitations
The main strength of our review lies in the inclusion of guidelines from different continents, which can give us un idea about the worldwide management of pregnancyrelated UTI. However, this study is not devoid of limitations. First, we acknowledge that some guidelines might have not been included because they were not found in our database search or because they vaguely mentioned the antibiotic treatment. Nonetheless, the aim of our study was to specifically present the antibiotic recommendations for UTIs. Second, the lack of specifications of certain guidelines in terms of dosage and optimal duration of antibiotic courses in pregnancy made the results more general.

Conclusions
Antibiotics selected for UTI during pregnancy should be safe for both mother and unborn child. Guidelines from the four selected continents agree on several key points about antibiotic use. First lines of treatment are similar for lower and upper UTI around the world; however, before selecting the antibiotic of choice, it is mandatory to know the AMR in the local population.