What are safe antibiotics to use for a pregnant patient to treat UTI?

Comment by InpharmD Researcher

In large, the risk of untreated urinary tract infections (UTI) significantly outweighs the risk of any antibiotic. Nitrofurantoin, trimethoprim-sulfamethoxazole, and fluoroquinolones are generally avoided in pregnant patients with UTIs unless culture sensitivities or refractory infections suggest benefit. Cephalosporins have a particularly positive pregnancy safety profile and may be useful for some UTIs. Most importantly, clinicians should be sensitive to the timing of pregnancy as medications have the most impact early in fetal development (first trimester) or on infant safety around delivery (3rd trimester). See Table 1 for pregnancy recommendations for commonly used antibiotics in UTIs.

Background

Urinary tract infections (UTIs) are generally caused by the same pathogens in both pregnant and non-pregnant patients. Escherichia coli remains the most common pathogen but other bacteria such as Klebsiella pneumoniae, Staphylococcus, Streptococcus, Proteus, and Enterococcus may be present. Pyelonephritis is a serious consequence of UTIs, especially for pregnant patients, so it is necessary to ensure prompt evaluation and treatment. Antibiotic selection is ideally tailored to culture sensitivities. Commonly used antibiotics include amoxicillin, ampicillin, cephalosporins, nitrofurantoin, and trimethoprim-sulfamethoxazole. [1] However, some data suggest sulfa derivatives and nitrofurantoin causes congenital disabilities that have led to decreased use in the first trimester. [2] In the late third trimester, trimethoprim-sulfamethoxazole should be avoided due to the potential risk for the development of kernicterus in the infant following delivery. Fluoroquinolones are not recommended as a first-line treatment in pregnancy due to conflicting studies regarding teratogenicity. Short courses are unlikely to be harmful to the fetus, so they are utilized for resistant or recurrent infections. [1]

The 2021 European Association of Urology has the most recently updated guidelines regarding antimicrobial selection for urinary tract infections (UTI) during pregnancy. They recommend short courses of antimicrobial therapy for treatment of cystitis in pregnancy with the following agents: penicillins, cephalosporins, fosfomycin, nitrofurantoin (not in case of glucose-6-phosphate dehydrogenase deficiency and during the end of pregnancy), trimethoprim (not in the first trimester) and sulfonamide (not in the last trimester). [3]

American College of Obstetricians and Gynecologists (ACOG) has withdrawn several committee opinions regarding UTIs in pregnant and non-pregnant women as well as the risk of birth defects for sulfonamides and nitrofurantoin. They provided no rationale for the withdrawal and currently offer no clinical guidance for UTIs. [4], [5], [6] Other guidance such as from the American Academy of Family Physicians (AAFP) or Infectious Diseases Society of America (IDSA) have not been consistently updated or do not apply to pregnancy. [7], [8]

A 2015 Cochrane review assessed the duration of treatment for asymptomatic bacteriuria during pregnancy. Their findings suggest single-dose regimens may be less effective than short (4-7 day) courses, but this recommendation is limited by small sample size, heterogeneous population, and inconsistencies in reported outcomes and trial design. There was no assessment of efficacy or safety for specific antibiotic regimens. [9]

A 2019 meta-analysis assessed the safety of macrolides during pregnancy (N= 21 studies). The analysis showed the increase in the odds of birth defects among women who consumed macrolides during their pregnancy is very low (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.01 to 1.10). A subgroup analysis revealed the association is strongest during the first trimester (OR 1.06, 95% CI 1.01–1.11). Like many teratogen studies, this analysis is limited due to small occurrences and lack of complete information in registries. [10]

A 2020 meta-analysis assessed the association of sulfonamide use during pregnancy and adverse outcomes (N= 10 studies; N= 1,096,350 participants). Maternal exposure to sulfonamides was found to be possibly associated with increased risk of congenital malformations (OR = 1.21, 95% CI 1.07–1.37). The researchers concluded use of sulfonamides in the first trimester of pregnancy and during the entire pregnancy might be associated with congenital malformations. As with many studies examining drug exposure and pregnancy outcomes, it is difficult to assess duration of exposure and prescribing rationale using registry data. [11]

References:

[1] Habak PJ, Griggs, Jr RP. Urinary Tract Infection In Pregnancy. [Updated 2021 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537047/
[2] Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163(11):978-985. doi:10.1001/archpediatrics.2009.188
[3] European Association of Urology. Urological infections. Updated 2021. Available from: https://uroweb.org/guideline/urological-infections/#3 Accessed 14 December 2021
[4] American College of Obstetricians and Gynecologists.Committee Opinion No. 717: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects. Obstet Gynecol. 2017;130(3):e150-e152. doi:10.1097/AOG.0000000000002300
[5] American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 494: Sulfonamides, nitrofurantoin, and risk of birth defects. Obstet Gynecol. 2011;117(6):1484-1485. doi:10.1097/AOG.0b013e3182238c57
[6] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 91: Treatment of urinary tract infections in nonpregnant women. Obstet Gynecol. 2008;111(3):785-794. doi:10.1097/AOG.0b013e318169f6ef
[7] Delzell JE Jr, Lefevre ML. Urinary tract infections during pregnancy [published correction appears in Am Fam Physician 2000 Jun 15;61(12):3567]. Am Fam Physician. 2000;61(3):713-721.
[8] Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the infectious diseases society of america. Clinical Infectious Diseases. 2010;50(5):625-663.
[9] Widmer, M., et al. Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev, 2015: CD000491.
[10 ] Mallah N, Tohidinik HR, Etminan M, Figueiras A, Takkouche B. Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis. Drug Saf. 2020;43(3):211-221. doi:10.1007/s40264-019-00884-5

[11] Li P, Qin X, Tao F, Huang K. Maternal exposure to sulfonamides and adverse pregnancy outcomes: A systematic review and meta-analysis. PLoS One. 2020;15(12):e0242523. Published 2020 Dec 2. doi:10.1371/journal.pone.0242523

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What are safe antibiotics to use for a pregnant patient to treat UTI?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→



Please see Table 1 for your response.


Pregnancy Recommendations for Commonly Prescribed Antibiotics for Urinary Tract Infections
Agent Briggs' Rating  Briggs' Pregnancy Summary  Package Insert
Amoxicillin-clavulanate Human Data Suggest Risk in 1st and 3rd Trimesters

Penicillins are generally considered low risk at any stage of pregnancy. This assessment may have to be modified for the aminopenicillins (ampicillin and amoxicillin) because there is some evidence that exposure to these two antibiotics during organogenesis is associated with oral clefts. However, even if the association is causal, the absolute risk is very low.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Cefpodoxime Compatible No detectable teratogenic risk with cephalosporin antibiotics has been found

There are no adequate and well-controlled studies of cefpodoxime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ceftriaxone Compatible No detectable teratogenic risk with cephalosporin antibiotics has been found

There are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cephalexin Compatible Although some data suggest an association with congenital malformations, most studies have found that cephalosporin antibiotics, in general, are safe to use in pregnancy

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ciprofloxacin Contraindicated (use only if no other alternatives)

The use of ciprofloxacin during human gestation does not appear to be associated with an increased risk of major congenital malformations. Although a number of birth defects have occurred in the offspring of women who had taken this drug during pregnancy, the lack of a pattern among the anomalies is reassuring. However, a causal relationship with some of the birth defects cannot be excluded. Because of this and the available animal data, the use of ciprofloxacin during pregnancy, especially during the 1st trimester, should be used with caution, but the overall risk appears to be low. Fluoroquinolones should be reserved for those who do not have alternative treatment options.

There are no adequate and well-controlled studies in pregnant women. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
Fosfomycin Compatible

 The lack of teratogenicity in animals and the apparently safe use of fosfomycin during human pregnancy appear to indicate that the drug presents a low risk, if any, to the fetus.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Levofloxacin Contraindicated (use only if no other alternatives)

Although only a few reports describing the use of levofloxacin during human gestation have been located, the available evidence for other members of this class suggests that the risk of major malformations is low. However, a causal relationship with birth defects cannot be excluded. Because of these concerns and the available animal data, levofloxacin should be used cautiously during pregnancy, especially during the 1st trimester. Fluoroquinolones should be reserved for those who do not have alternative treatment options.

Published information from case reports, case control studies and observational studies on levofloxacin administered during pregnancy have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
Nitrofurantoin Human Data Suggest Risk in 3rd Trimester

Nitrofurantoin is not an animal teratogen with doses close to those used in humans, and although two retrospective studies reported associations with congenital anomalies, there are no confirmed data suggesting that it is a human teratogen. The two studies require confirmation. However, there appears to be risk of hemolytic anemia in newborns, including those who are not glucose-6-phosphate dehydrogenase (G6PD) deficient, who are exposed in utero to nitrofurantoin close to delivery. Although the incidence is unknown, the rare reports of this toxicity combined with the popularity of the drug for urinary tract infections in pregnant women suggest that the risk is rare. The safest course, however, is to avoid nitrofurantoin close to delivery.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Trimethoprim/

sulfamethoxazole

Human and Animal Data Suggest Risk/

Human Data Suggest Risk in 3rd Trimester

Trimethoprim is a dihydrofolate reductase inhibitor that is teratogenic in animals and humans. Defects that have been associated with trimethoprim include cardiovascular defects and neural tube defects (NTDs), and possibly oral clefts. Folic acid supplementation, at least 0.4 mg/day, started before conception or concurrently with trimethoprim may reduce the risk of these congenital defects.

Taken in sum, sulfonamides, as single agents, do not appear to pose a significant teratogenic risk. One study has found associations with birth defects, but a causative association cannot be determined with this type of study, and they may have been due to other factors, particularly if trimethoprim was combined with the sulfonamide. Confirmation is required. Because of the potential toxicity to the newborn, these agents should be avoided near term.

Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole and trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.
References:

[1] European Association of Urology. Urological infections. Updated 2021. Available from: https://uroweb.org/guideline/urological-infections/#3. Accessed 14 December 2021.
[2] Drugs in Pregnancy and Lactation (Briggs) [Database]. Lexicomp. Available from: https://online.lexi.com/. Accessed 14 December 2021.
[3] AMOXICILLIN AND CLAVULANATE POTASSIUM. [prescribing information]. Micro Labs Limited; 2021
[4] CEFPODOXIME PROXETIL. [prescribing information]. Aurobindo Pharma Limited; 2019
[5] CEFTRIAXONE [prescribing information]. Sagent Pharmaceuticals; 2020
[6] CEPHALEXIN [prescribing information]. AvKARE, Inc.; 2020
[7] CIPROFLOXACIN [prescribing information]. Carlsbad Technology, Inc.; 2017
[8] FOSFOMYCIN [prescribing information]. Ascend Laboratories, LLC; 2021
[9] LEVOFLOXACIN [prescribing information].Cipla USA Inc.; 2020
[10] NITROFURANTOIN [prescribing information]. Actavis Pharma, Inc.; 2018
[11] SULFAMETHOXAZOLE AND TRIMETHOPRIM [prescribing information]. Amneal Pharmaceuticals LLC; 2021