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Nitrofurantoin

Classification: A

Drug products: Furadantin®, Nitrofurantoin Alternova

ATC code: J01XE01

Substances: nitrofurantoin

Summary

Several studies on adverse events have shown that women have a higher risk than men for adverse events of nitrofurantoin. A Dutch study from 1988 based on 25 years register data found nitrofurantoin-induced liver injury to be slightly more common in women than in men.
A large study showed that gentamicin and nitrofurantoin were the most suitable treatment options for urinary tract infections in men and women in any age group.

In our opinion, at present the described differences do not motivate differentiated dosing or treatment in men and women. However, it should be considered that adverse events are more common in women.

Additional information

Pharmacokinetics and dosing

No studies with a clinically relevant sex analysis regarding the pharmacokinetics or dosing of nitrofurantoin have been found.

Effects

In some settings urine cultures to identify pathogens and resistance pattern cannot always be obtained and therapy of urinary tract infections then has to be empirical. A Brazilian study analyzed urine isolates to identify suitable empirical therapy options for cystitis and urinary tract infections in relation to patient’s sex and age (1098 men, 8700 women). Drug classes analyzed was ampicillin, nitrofurantoin, fluoroquinolones (ciprofloxacin and levofloxacin), trimethoprim-sulfamethoxazole, gentamicin, and ceftriazone/cefotaxime, Women exhibited higher susceptibility values for all drug classes studied than men. For women in any age group, only nitrofurantoin and gentamicin provided adequate activity for empirical therapy (> 80% susceptibility). For men in any age group, only gentamicin was suitable for empirical therapy. In women aged over 60 years, few suitable empirical treatment options were identified [1].Another study of urinary E. coliisolates (2274 men, 32265 women) has described age- and sex-specific antibiotic susceptibility patterns for ampicillin, amoxicillin clavulanate, ciprofloxacin, nitrofurantoin and trimethoprim-sulfamethoxazole. Nitrofurantoin susceptibility was similar in men and women (96.4% vs. 97.6%). Age-specific susceptibilities differed between men and women for all antibiotics studies except trimethoprim-sulfamethoxazole. However, the magnitude of the observed differences was generally less than 5% and the authors suggest that they may not represent clinically meaningful differences [2]. Resistance patterns for pathogens often differ between populations. A Dutch study comparing resistance in urinary samples from 560 men with historic data from urinary samples from 917 women [3] found no difference between men and women in E.colisusceptibility to nitrofurantoin [4]. In contrast to this a Portuguese retrospective analysis of urinary samples (120,691 (78%) from women and 34,898 (22%) from men) nitrofurantoin resistance was more common in male urinary samples positive forE. coli, P vulgaris, Klebsiella spp, Enterobacter spp[5].

Adverse effects

Allergic reactions to nitrofurantoin treatment have been reported to be almost identical in men and women (3.9% vs. 4.9%), while toxic reactions were more common in women (2.1% vs. 6.4%). The study found that the toxic reaction to nitrofurantoin was dependent on patient weight in both men and women [6]. Since women generally have a lower body weight, they are more vulnerable to toxic reactions.

Adverse reactions to nitrofurantoin in Sweden during the period 1966-1976 have been studied. Women accounted for 86% of the patient reports and had most of the following types of reactions: pulmonary (acute and chronic), allergic, liver damage, and neuropathy. Among the blood dyscrasias reports, there were more men. The risk of having an adverse reaction to nitrofurantoin was approximately twice as high in women as in men [7].

Clinical studies have reported a higher incidence of drug-induced liver injury in women with certain drugs such as nitrofurantoin, flucloxacillin, erythromycin and isoniazid [8]. A review reports female sex to be a risk factor for developing nitrofurantoin-induced liver injury [9]. A Dutch study of reported cases of liver injury as an adverse event to nitrofurantoin between 1963-1987, found that 89% of the chronic liver failure cases occurred in women compared to 74% of all nitrofurantoin prescriptions [10]. A possible explanation to this could be a hypersensitivity reaction among women [11].

Other adverse events from nitrofurantoin associated with women are diarrhea, abdominal pain, and gastrointestinal bleeding [12].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Updated: 2019-02-26

Date of litterature search: 2016-01-14

References

  1. Rocha JL, Tuon FF, Johnson JR. Sex, drugs, bugs, and age: rational selection of empirical therapy for outpatient urinary tract infection in an era of extensive antimicrobial resistance. Braz J Infect Dis. 2012;16:115-21. PubMed
  2. McGregor JC, Elman MR, Bearden DT, Smith DH. Sex- and age-specific trends in antibiotic resistance patterns of Escherichia coli urinary isolates from outpatients. BMC Fam Pract. 2013;14:25. PubMed
  3. den Heijer CD, Donker GA, Maes J, Stobberingh EE. Antibiotic susceptibility of unselected uropathogenic Escherichia coli from female Dutch general practice patients: a comparison of two surveys with a 5 year interval. J Antimicrob Chemother. 2010;65:2128-33. PubMed
  4. den Heijer CD, Penders J, Donker GA, Bruggeman CA, Stobberingh EE. The importance of gender-stratified antibiotic resistance surveillance of unselected uropathogens: a Dutch Nationwide Extramural Surveillance study. PLoS One. 2013;8:e60497. PubMed
  5. Linhares I, Raposo T, Rodrigues A, Almeida A. Frequency and antimicrobial resistance patterns of bacteria implicated in community urinary tract infections: a ten-year surveillance study (2000-2009). BMC Infect Dis. 2013;13:19. PubMed
  6. Koch-Weser J, Sidel VW, Dexter M, Parish C, Finer DC, Kanarek P. Adverse reactions to sulfisoxazole, sulfamethoxazole, and nitrofurantoin Manifestations and specific reaction rates during 2,118 courses of therapy. Arch Intern Med. 1971;128:399-404. PubMed
  7. Holmberg L, Boman G, Böttiger LE, Eriksson B, Spross R, Wessling A. Adverse reactions to nitrofurantoin Analysis of 921 reports. Am J Med. 1980;69:733-8. PubMed
  8. Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J. 2014;107:107-13. PubMed
  9. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95-106. PubMed
  10. Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology. 1988;8:599-606. PubMed
  11. Martindale: The Complete Drug Reference. Pharmaceutical Press.
  12. Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999
  13. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-06-30.] Socialstyrelsens statistikdatabas

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson