Nitrofurantoin

What it is

Nitrofurantoin is a synthetic nitrofuran antibacterial, in clinical use since 1953, that concentrates in urine rather than in body tissues. It is taken by mouth as capsules or suspension; the Macrobid form combines 25 mg of slow-dissolving macrocrystals with 75 mg of monohydrate that gels in the gut and releases the drug gradually. Blood levels stay low, usually under 1 mcg/mL, and about 20 to 25 percent of a dose appears unchanged in the urine within 24 hours, which is why it works for bladder infection and not for kidney or bloodstream infection.

What the research says

For simple bladder infection in women the evidence is good. A placebo-controlled trial found a number needed to treat of about 3 for symptom improvement at one week, and a 2015 systematic review of 27 controlled trials in 4,807 patients found clinical cure rates of 79 to 92 percent and equivalence with trimethoprim-sulfamethoxazole, ciprofloxacin and amoxicillin when given for 5 to 7 days, though it was slightly worse than comparators on bacteriological cure and clearly worse if given for only 3 days. For prevention of recurrent infection, continuous antibiotic prophylaxis works while it is being taken but the benefit disappears after stopping and adverse events increase. The harms that matter are rare but serious and cluster in long-term users: lung injury (acute allergic reactions and insidious chronic interstitial pneumonitis or fibrosis), liver injury that can progress to cirrhosis, peripheral nerve damage that may not reverse, and haemolysis in people with G6PD deficiency.

Evidence grade: Well established.

How it works

Drug class: Nitrofuran antibacterial (urinary antiseptic)

Bacteria in the urine convert nitrofurantoin into reactive chemical fragments using their own enzymes. Those fragments damage several different bacterial targets at once, including the ribosomal proteins that build proteins, and the systems for energy metabolism, DNA, RNA and cell-wall production. Because it attacks many targets rather than one, bacteria have found it hard to become resistant: a bug would need several simultaneous mutations, which would probably kill it. It is bactericidal in urine at the doses used. (Source 1)

What it is used for

• This is the approved use and the best-evidenced one. Against placebo, 3 days of nitrofurantoin gave a number needed to treat of 1.6 for bacteriological cure in women with proven infection. A systematic review of 27 controlled trials put clinical cure at 79 to 92 percent and found it equivalent to trimethoprim-sulfamethoxazole, ciprofloxacin and amoxicillin over 5 to 7 days, with a small disadvantage in microbiological cure. Evidence: established. (Source 2)
• Explicitly not an indication. Nitrofurantoin does not reach useful concentrations in tissue outside the urine, so it cannot treat infection of the kidney itself. Evidence: not-supported. (Source 3)
• Widely used this way and supported by trial data for antibiotic prophylaxis as a class, but the benefit lasts only while the drug is taken and the serious lung, liver and nerve harms are concentrated in long-term users. A Cochrane review of 19 trials in 1,120 women found a number needed to treat of 1.85 during prophylaxis, no difference after stopping, and more side effects than placebo. Evidence: limited. (Source 4)
• The label contraindicates it below 60 mL per minute, but two large observational studies disagree about whether mild to moderate reduction matters. A Canadian study of older women found nitrofurantoin failed more often than comparators at both low and high filtration rates, concluding that mild or moderate reduction did not justify avoiding it; a Dutch cohort found no excess ineffectiveness but a fourfold higher risk of pulmonary adverse events needing hospital admission below 50 mL per minute. Evidence: disputed. (Source 5)

Interactions

• Food (any meal) (pharmacokinetic study): Taking nitrofurantoin with food raises the amount absorbed by about 40 percent and improves tolerance, which is why the label tells people to take it with meals. This is one of the few interactions where more absorption is wanted, not avoided. (Source 6)
• Magnesium trisilicate antacids (pharmacokinetic study): Magnesium trisilicate antacids soak nitrofurantoin onto their surface in the gut, so both the speed and the total amount absorbed drop. The label tells people not to use these antacids while on nitrofurantoin. Note this is specifically magnesium trisilicate, not magnesium supplements in general. (Source 7)
• Probenecid and sulfinpyrazone (uricosuric gout drugs) (pharmacokinetic study): These drugs block the kidney's secretion of nitrofurantoin, so blood levels rise (more toxicity) while urine levels fall (less benefit in the bladder, where the drug needs to be). (Source 7)
• Quinolone antibiotics (for example ciprofloxacin) (theoretical): In laboratory dishes nitrofurantoin and quinolones work against each other. The label itself says the clinical meaning of this is unknown. (Source 8)
• Urine glucose tests using Benedict's or Fehling's solution (label): Nitrofurantoin can make an old-style copper-reduction urine sugar test read falsely positive. Modern enzyme-based glucose test strips are not affected. (Source 9)

Stopping it

• Nitrofurantoin is not habit-forming and has no withdrawal syndrome; the stopping advice in the literature runs the other way, towards stopping it promptly when toxicity appears. For lung reactions the label says to discontinue immediately and take appropriate measures, noting that pulmonary reactions have been reported as a contributing cause of death. (Source 10)
• For liver injury the label says to withdraw the drug immediately if hepatitis occurs, and to monitor liver blood tests periodically because chronic active hepatitis can start insidiously. (Source 11)
• Stopping is what the lung injury responds to in most people with the chronic form. In the Mayo Clinic series of 18 patients, nitrofurantoin was discontinued in all and most improved afterwards, with corticosteroids used in 9 of the more severely affected. (Source 12)
• Blood abnormalities also tend to resolve on stopping: the label records that in most cases the haematological changes resolved following cessation of therapy, and that haemolysis in G6PD deficiency ceases when the drug is withdrawn. (Source 13)
• For prophylaxis, stopping removes the benefit. The Cochrane review found no significant difference in recurrence between antibiotic and placebo groups once prophylaxis ended, though one case review reported improvement maintained for at least 6 months afterwards in most patients where prophylaxis had worked. (Source 14)

What goes wrong

Of 921 Swedish adverse-reaction reports for nitrofurantoin, acute pulmonary reactions made up 43 percent and allergic reactions 42 percent; 71 percent of all reactions were severe enough to need hospital admission and 1 percent were fatal. (Source 15)

• Case series, Low certainty.
• Size: 921 adverse reaction reports.
• Who: Swedish patients reported to the Swedish Adverse Drug Reaction Committee, 1966-1976.
• How long: 11 years of spontaneous reporting.
• Result: Acute pulmonary reactions 43%, allergic reactions 42%; the remainder chronic pulmonary reactions, liver damage, blood dyscrasias or neuropathy; 71% of reactions led to hospitalization; 1% were fatal; risk rose with age and was higher in women.
• Funding: not stated.

Seventy-one percent of all reactions were severe enough to cause the patient's hospitalization; only 1 percent was fatal. The risk of an adverse reaction varies with sex and age, increases with age and is higher in women than in men.

In the same Swedish reporting system, 447 pulmonary reactions were recorded (398 acute, 49 chronic), three-quarters needed hospital admission and six were fatal. (Source 16)

• Case series, Low certainty.
• Size: 447 pulmonary reaction cases.
• Who: Swedish patients reported 1966-1976; about 85% women; median age 59 years for acute and 68 years for chronic reactions.
• How long: 11 years of reporting.
• Result: 398 acute and 49 chronic pulmonary reactions; three-quarters hospitalized; six fatal.
• Funding: not stated.

Pulmonary reactions constituted about half of these reports: 398 cases with acute and 49 with chronic reactions. Three-quarters of the patients were hospitalized in connection with the reaction. Six reactions were fatal.

In 18 patients with chronic nitrofurantoin lung disease at the Mayo Clinic, 94 percent were women and symptoms began a median of 23 months after starting the drug for urinary-infection prevention. (Source 12)

• Case series, Low certainty.
• Size: 18 patients.
• Who: patients seen at the Mayo Clinic, Rochester, 1997-2002, with chronic nitrofurantoin-induced lung disease; median age 72 years (range 47-90)
• How long: median 23 months of nitrofurantoin (range 10-144 months) before symptom onset.
• Result: 17/18 (94%) women; all had persistent dyspnoea and cough with lung infiltrates; all 10 available CT scans showed bilateral ground-glass opacities; most improved after stopping the drug; 9 received corticosteroids.
• Funding: not stated.

Onset of symptoms occurred after a median interval of 23 months (range, 10-144 months) following the initiation of nitrofurantoin therapy for the prevention of recurrent urinary tract infections.

Among 78 people with nitrofurantoin-induced liver injury in the US Drug Induced Liver Injury Network, 38 percent of those on long-term treatment had bridging fibrosis, nodularity or cirrhosis, and 7 patients across the longer-exposure groups died or needed a transplant. (Source 17)

• Cohort study, Moderate certainty.
• Size: 78 individuals with definite, highly likely or probable nitrofurantoin liver injury, enrolled 2004-2020; HLA comparison against 14,001 population controls, 231 idiopathic autoimmune hepatitis and 661 non-nitrofurantoin DILI controls.
• Who: US patients enrolled in the Drug Induced Liver Injury Network; 44 long-exposure (1 year or more), 18 short (7 days or less), 16 intermediate.
• How long: exposure from 7 days to over a year; enrolment 2004-2020.
• Result: Hepatocellular injury 69%, icteric 55%. In long-term cases, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence of cirrhosis, in 38%, with massive or sub-massive necrosis in 20%. Nobody in the short-exposure group died or was transplanted, whereas 7 (12%) patients from the other groups died or underwent transplantation. HLA-DRB1*11:04 odds ratio 4.29 versus population controls (p = 1.15 x 10^-4)
• Funding: not stated in the abstract (DILIN is funded by the US National Institutes of Health)

Limit of this finding: Two of this paper's p-values are printed with superscripts that the abstract record flattens: 'p = 1.15 x 10-4' and 'p = 7.76 x 10-5' mean 10 to the power minus 4 and minus 5, in other words about 0.0001 and 0.00008. They are not '10 minus 4'. The quotation is left as the record prints it.

No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation.

The DILIN investigators reported that nitrofurantoin liver injury can result in parenchymal necrosis, bridging fibrosis, cirrhosis and death or liver transplantation, especially with long-term exposure, and asked regulators to revise the prescribing information. (Source 18)

• Cohort study, Moderate certainty.
• Size: 78 individuals.
• Who: US DILIN enrollees with nitrofurantoin liver injury.
• How long: 2004-2020.
• Result: Association with HLA-DRB1*11:04; two distinct injury patterns by exposure length.
• Funding: not stated in the abstract.

NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04.

In a Dutch cohort of 21,317 women treated with nitrofurantoin, renal impairment below 50 mL/min/1.73 m2 was associated with a fourfold higher risk of pulmonary adverse events leading to hospital admission, although overall adverse-event rates were very low. (Source 19)

• Cohort study, Low certainty.
• Size: 21,317 women on nitrofurantoin and 7,926 on trimethoprim as a comparator cohort.
• Who: women treated in Dutch primary care for urinary tract infection, from the Pharmo Record Linkage System.
• How long: ineffectiveness assessed within 1 month; serious adverse events within 90 days.
• Result: Overall incidence density for adverse events 0.02 per 1,000 person-days. With renal impairment under 50 ml/min/1.73 m2, hazard ratio for pulmonary adverse events leading to hospitalization 4.1 (95% CI 1.31-13.09). Moderate renal impairment was not associated with ineffective treatment (HR 1.1, 95% CI 0.74-1.51)
• Funding: not stated.

Limit of this finding: The publisher never tagged this paper's conclusions, so the word CONCLUSIONS and the whole conclusions paragraph sit inside the results field of the PubMed and Europe PMC records. We have split them into two separate quotations. Note also how small the absolute numbers are: adverse events ran at 0.02 per 1,000 person-days overall, and the confidence interval on the fourfold pulmonary hazard runs from 1.31 to 13.09, so the size of that risk is very uncertain even though it reached significance.

In patients with renal impairment (<50 ml/min/1.73 m²) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09)

Two reported cases of nitrofurantoin small-fibre neuropathy were neither dose-dependent nor linked to impaired kidney function, and recovery was slow or incomplete. (Source 20)

• Case series, Very low certainty.
• Size: 2 patients (a 59-year-old woman and a 53-year-old woman)
• Who: patients at a tertiary teaching hospital in Baltimore with non-length-dependent small-fibre neuropathy attributed to nitrofurantoin.
• How long: not stated.
• Result: Normal nerve conduction studies; skin biopsies showed clustered terminal nerve swellings; slow or incomplete recovery and possibly irreversible damage.
• Funding: not stated.

The neuropathy was neither dose dependent nor associated with impaired renal function. Results from nerve conduction studies were normal.

The label records in capitals that pulmonary reactions have been cited as a contributing cause of death and that chronic pulmonary reactions develop insidiously, generally in people treated for six months or longer. (Source 10)

• Official position, Low certainty.
• Size: not quantified.
• Who: patients treated with nitrofurantoin.
• How long: chronic reactions generally after six months or more of therapy.
• Result: No rates given; described as occurring rarely but able to be fatal and to leave permanently impaired lung function.
• Funding: industry-funded (manufacturer label)

CHRONIC PULMONARY REACTIONS (DIFFUSE INTERSTITIAL PNEUMONITIS OR PULMONARY FIBROSIS, OR BOTH) CAN DEVELOP INSIDIOUSLY. THESE REACTIONS OCCUR RARELY AND GENERALLY IN PATIENTS RECEIVING THERAPY FOR SIX MONTHS OR LONGER.

The label states that nitrofurantoin can trigger haemolysis in people with glucose-6-phosphate dehydrogenase deficiency, which it says is found in 10 percent of Black people and a small percentage of groups of Mediterranean and Near-Eastern origin. (Source 21)

• Official position, Low certainty.
• Size: not quantified.
• Who: people with G6PD deficiency taking nitrofurantoin.
• How long: not stated.
• Result: No incidence given; haemolysis stops when the drug is withdrawn.
• Funding: industry-funded (manufacturer label)

Cases of hemolytic anemia of the primaquine-sensitivity type have been induced by nitrofurantoin. Hemolysis appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the red blood cells of the affected patients.

In Macrobid's own clinical trials the most frequent drug-related adverse events were nausea in 8 percent, headache in 6 percent and flatulence in 1.5 percent, with no placebo arm reported. (Source 22)

• Official position, Low certainty.
• Size: not stated in the label.
• Who: patients in the Macrobid clinical trial programme.
• How long: not stated.
• Result: Nausea 8%, headache 6%, flatulence 1.5%; all other drug-related events under 1%. No placebo comparator rates are given in the label.
• Funding: industry-funded (manufacturer label)

the most frequent clinical adverse events that were reported as possibly or probably drug-related were nausea (8%), headache (6%), and flatulence (1.5%)

Nitrofurantoin showed carcinogenic activity in female B6C3F1 mice and in male F344/N rats, though the significance for human use is stated to be unknown. (Source 23)

• Animal study, Very low certainty.
• Size: multiple rodent bioassays.
• Who: B6C3F1 mice, F344/N rats, pregnant mice.
• How long: chronic feeding bioassays.
• Result: Increased tubular adenomas, benign mixed tumours and granulosa cell tumours of the ovary in female B6C3F1 mice; increased uncommon kidney tubular cell neoplasms, bone osteosarcomas and subcutaneous neoplasms in male F344/N rats; lung papillary adenomas in F1 mice after 75 mg/kg subcutaneous dosing of pregnant dams.
• Funding: industry-funded (manufacturer label)

Nitrofurantoin presented evidence of carcinogenic activity in female B6C3F 1mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

Spontaneous reports suggest a higher proportion of pulmonary reactions including deaths, and of severe hepatic reactions including deaths, in elderly patients, which the label attributes to longer-term use in that group. (Source 24)

• Official position, Very low certainty.
• Size: not quantified.
• Who: elderly patients taking nitrofurantoin.
• How long: long-term therapy.
• Result: No rates; a higher proportion of fatal pulmonary and severe hepatic reactions in spontaneous reports.
• Funding: industry-funded (manufacturer label)

Spontaneous reports suggest a higher proportion of pulmonary reactions, including fatalities, in elderly patients; these differences appear to be related to the higher proportion of elderly patients receiving long-term nitrofurantoin therapy.

What the evidence supports

Against placebo in women with bacteriologically proven urinary infection, 3 days of nitrofurantoin cleared the infection in 21 of 25 women against 5 of 25 on placebo, a highly significant difference, with a number needed to treat of about three; in the wider group with only suspected infection the three-day symptom benefit did not reach statistical significance. (Source 25)

• Randomized trial, Moderate certainty.
• Size: 78 women randomised in the clinically suspected group (40 nitrofurantoin, 38 placebo); 56 women with bacteriuria of at least 10(5) CFU/ml (29 nitrofurantoin, 27 placebo)
• Who: non-pregnant women aged 15 to 54 consulting a general practitioner with symptoms of uncomplicated lower urinary tract infection and a positive leucocyte esterase test.
• How long: nitrofurantoin 100 mg four times daily for 3 days, with follow-up at 3, 7 and 14 days.
• Result: Bacteriological cure at 3 days 21/25 vs 5/25 (P<0.001; the abstract gives 21/26 vs 5/25, NNT 1.6, 95% CI 1.2 to 2.6); at 7 days 17/23 vs 9/22 (P = 0.05, NNT 3, 95% CI 1.7 to 17). Combined symptomatic improvement and cure at 3 days 27/35 vs 19/35 (P = 0.08, NNT 4.4, 95% CI 2.3 to 79, not statistically significant); at 7 days 30/34 vs 17/33 (P = 0.003, NNT 2.7, 95% CI 1.8 to 6.0)
• Funding: independent (Flemish Fund for Scientific Research and the Ghent University Research Fund; Boehringer Mannheim Belgium supplied the urine test sticks)

Limit of this finding: Two versions of this trial disagree and we have followed the published paper. The abstract record held by the US National Library of Medicine, which Europe PMC and the journal's own web abstract both mirror, prints the three-day symptomatic result as P = 0.008. The paper itself prints P = 0.08 three times - in its summary, in Table 1, and in the sentence 'the effect of the treatment, although evident, was not statistically significant (P = 0.08)' - so the three-day symptom result was a trend, not a significant finding, and the number needed to treat of 4.4 with a confidence interval running to 79 fits that. Note also that the paper's body reports bacteriological cure in 21/25 women where its own abstract says 21/26.

Significant bacteriuria had disappeared in 21/25 women after three days of nitrofurantoin, versus only 5/25 in the placebo group. This difference is statistically highly significant (P<0.001)

A systematic review and meta-analysis of 27 controlled trials in 4,807 patients found clinical cure rates of 79 to 92 percent for short-course nitrofurantoin and equivalence with comparator antibiotics on clinical cure, but a small disadvantage on microbiological cure. (Source 26)

• Meta-analysis, Low certainty.
• Size: 27 controlled trials including 4,807 patients.
• Who: patients treated for lower urinary tract infection with nitrofurantoin for 14 days or less.
• How long: trials published 1946 to 2014; most conducted between the 1970s and 1990s.
• Result: Clinical cure 79% to 92%; equivalence with trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin at 5 or 7 days; microbiological efficacy slightly favoured comparators (risk ratio 0.93, 95% CI 0.89-0.97); 3-day courses gave reduced clinical efficacy of 61% to 70%; toxicity 5% to 16% in the 17 reporting studies, with no difference versus comparators.
• Funding: not stated; the review itself notes most trials were at increased risk of various biases.

Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%.

In a 513-woman randomised trial, 5 days of nitrofurantoin achieved clinical resolution in 70 percent versus 58 percent for single-dose fosfomycin, an absolute difference of 12 percentage points. (Source 27)

• Randomized trial, Moderate certainty.
• Size: 513 randomised; 475 (93%) completed; 377 (73%) with confirmed positive baseline culture.
• Who: non-pregnant women aged 18 and over with symptoms of lower urinary tract infection and a positive dipstick, in Geneva, Lodz and Petah-Tiqva.
• How long: nitrofurantoin 100 mg three times daily for 5 days; outcome assessed over 28 days after therapy.
• Result: Clinical resolution through day 28: 171/244 (70%) nitrofurantoin vs 139/241 (58%) fosfomycin, difference 12% (95% CI 4%-21%), P = .004. Microbiologic resolution 129/175 (74%) vs 103/163 (63%), difference 11% (95% CI 1%-20%), P = .04. Nausea 7/248 (3%) and diarrhea 3/248 (1%) on nitrofurantoin vs 5/247 (2%) and 5/247 (1%) on fosfomycin.
• Funding: not stated in the abstract.

Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004).

What the evidence does not support

In the same trial, among all the women with symptoms and pyuria but no culture confirmation, the three-day symptomatic benefit of nitrofurantoin over placebo did not reach statistical significance. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 78 women randomised (40 nitrofurantoin, 38 placebo); 70 assessable at day 3.
• Who: non-pregnant women aged 15 to 54 consulting a general practitioner with symptoms of uncomplicated lower urinary tract infection and a positive leucocyte esterase test, irrespective of culture result.
• How long: nitrofurantoin 100 mg four times daily for 3 days, assessed at 3, 7 and 14 days.
• Result: Symptom cure at day 3 13/35 (37%) on nitrofurantoin vs 7/35 (20%) on placebo; combined cure plus improvement 27/35 (77%) vs 19/35 (54%); P = 0.08 for the complete-case analysis and P = 0.2 on intention to treat. By day 7 the combined result was 30/34 (88%) vs 17/33 (51%), P = 0.003.
• Funding: independent (Flemish Fund for Scientific Research and the Ghent University Research Fund; Boehringer Mannheim Belgium supplied the urine test sticks)

Limit of this finding: Two versions of this trial disagree and we have followed the published paper. The abstract record held by the US National Library of Medicine, which Europe PMC and the journal's own web abstract both mirror, prints the three-day symptomatic result as P = 0.008. The paper itself prints P = 0.08 three times - in its summary, in Table 1, and in the sentence 'the effect of the treatment, although evident, was not statistically significant (P = 0.08)' - so the three-day symptom result was a trend, not a significant finding, and the number needed to treat of 4.4 with a confidence interval running to 79 fits that. Note also that the paper's body reports bacteriological cure in 21/25 women where its own abstract says 21/26.

However, the effect of the treatment, although evident, was not statistically significant (P = 0.08).

The Cochrane reviewers concluded that the reduction in infections applies only while the antibiotic is being taken and that two studies showed no difference once it stopped. (Source 28)

• Systematic review, Low certainty.
• Size: 19 studies, 1,120 women.
• Who: non-pregnant women with recurrent urinary tract infection.
• How long: 6 to 12 months of prophylaxis with post-prophylaxis follow-up.
• Result: RR of one microbiological recurrence after prophylaxis 0.82 (95% CI 0.44 to 1.53), not statistically significant.
• Funding: not stated.

Limit of this finding: Two problems with this review's abstract as published. It labels its first comparison 'Antibiotic versus antibiotic' and then immediately compares against placebo ('against 0.8 to 3.6 with placebo', 'favouring placebo'): that first set of ten trials is antibiotic versus placebo, and the same label is reused further down for the genuine head-to-head trials. So the relative risk of 0.21 is antibiotic against placebo, not one antibiotic against another. The abstract also contains the typographical slips 'nodifference', 'woman who have UTI' and a missing '95%' before one confidence interval, all of which we have left as printed. Finally, this review is about preventive antibiotics as a class in non-pregnant women; it does not single out nitrofurantoin, so it is not nitrofurantoin-specific evidence.

Continuous antibiotic prophylaxis for 6-12 months reduced the rate of UTI during prophylaxis when compared to placebo. After prophylaxis two studies showed nodifference between groups. There were more adverse events in the antibiotic group.

In a population study of older Canadian women, nitrofurantoin failed more often than ciprofloxacin regardless of kidney function, with 13.8 percent needing a second antibiotic versus 6.5 percent on ciprofloxacin. (Source 29)

• Cohort study, Low certainty.
• Size: 3,739 nitrofurantoin and 1,989 ciprofloxacin recipients in the low-eGFR analysis.
• Who: older women in Ontario, mean age 79, median eGFR 38 mL/min per 1.73 m2, prescribed an antibiotic for urinary tract infection.
• How long: treatment failure assessed over 14 days.
• Result: Second antibiotic prescription 130/1989 (6.5%) ciprofloxacin vs 516/3739 (13.8%) nitrofurantoin, OR 0.44 (95% CI 0.36-0.53); hospital encounter 21/1989 (1.1%) vs 95/3739 (2.5%), OR 0.41 (95% CI 0.25-0.66). A similar excess failure rate with nitrofurantoin was also seen in women with relatively high eGFR.
• Funding: not stated.

Limit of this finding: Read the odds ratios the right way round. They are reported as 'ciprofloxacin v. nitrofurantoin', so a figure below 1, such as 0.44, means fewer failures on ciprofloxacin, that is to say more failures on nitrofurantoin. The passage is correct as written but is easy to read backwards.

Relative to nitrofurantoin, the other antibiotics (including ciprofloxacin) were associated with a lower rate of treatment failure among women with relatively low estimated glomerular filtration rate

Where the evidence is mixed

The same review flagged that most of the underlying trials were old and at increased risk of bias, and that a 3-day course is not enough. (Source 26)

• Meta-analysis, Low certainty.
• Size: 27 controlled trials, 4,807 patients.
• Who: lower urinary tract infection.
• How long: trials from 1946 to 2014.
• Result: Microbiological efficacy risk ratio 0.93 (95% CI 0.89-0.97) favouring comparators; 3-day clinical efficacy 61% to 70% versus 79% to 92% for 5 to 7 days.
• Funding: not stated.

Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases.

In two phase 3 trials, 5 days of nitrofurantoin achieved therapeutic success in only 47.0 percent and 43.6 percent of women, and was beaten by the new antibiotic gepotidacin in one of the two. (Source 30)

• Randomized trial, Moderate certainty.
• Size: EAGLE-2: 764 randomised to nitrofurantoin; EAGLE-3: 800 randomised to nitrofurantoin (primary analysis populations 287 and 264)
• Who: non-pregnant patients assigned female at birth, aged 12 or older, weighing 40 kg or more, with at least two urinary symptoms and nitrofurantoin-susceptible uropathogens.
• How long: nitrofurantoin 100 mg twice daily for 5 days; test of cure at day 10-13.
• Result: EAGLE-2 therapeutic success 135/287 (47.0%) nitrofurantoin vs 162/320 (50.6%) gepotidacin, adjusted difference 4.3% (95% CI -3.6 to 12.1). EAGLE-3 115/264 (43.6%) vs 162/277 (58.5%), adjusted difference 14.6% (95% CI 6.4 to 22.8). Most common nitrofurantoin adverse event nausea, 29/760 (4%) and 35/798 (4%)
• Funding: industry-funded (GSK, with the US Biomedical Advanced Research and Development Authority)

In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8).

A Cochrane review of antibiotic prophylaxis for recurrent urinary infection found a number needed to treat of 1.85 during prophylaxis, no retained benefit after stopping, and significantly more side effects than placebo. (Source 4)

• Systematic review, Low certainty.
• Size: 19 studies involving 1,120 women; antibiotic versus placebo comparison 10 trials, 430 women.
• Who: adult non-pregnant women with three or more urinary tract infections in 12 months.
• How long: continuous prophylaxis for 6 to 12 months.
• Result: Microbiological recurrence RR 0.21 (95% CI 0.13 to 0.34), NNT 1.85; clinical recurrence RR 0.15 (95% CI 0.08 to 0.28), NNT 1.85; after prophylaxis RR 0.82 (95% CI 0.44 to 1.53); severe side effects RR 1.58 (95% CI 0.47 to 5.28); other side effects RR 1.78 (95% CI 1.06 to 3.00) favouring placebo.
• Funding: not stated.

Limit of this finding: Two problems with this review's abstract as published. It labels its first comparison 'Antibiotic versus antibiotic' and then immediately compares against placebo ('against 0.8 to 3.6 with placebo', 'favouring placebo'): that first set of ten trials is antibiotic versus placebo, and the same label is reused further down for the genuine head-to-head trials. So the relative risk of 0.21 is antibiotic against placebo, not one antibiotic against another. The abstract also contains the typographical slips 'nodifference', 'woman who have UTI' and a missing '95%' before one confidence interval, all of which we have left as printed. Finally, this review is about preventive antibiotics as a class in non-pregnant women; it does not single out nitrofurantoin, so it is not nitrofurantoin-specific evidence.

The RR for severe side effects was 1.58 (95% CI 0.47 to 5.28) and for other side effects the RR was 1.78 (CI 1.06 to 3.00) favouring placebo.

A retrospective review of the case records of 219 female patients given a year of nitrofurantoin prophylaxis, with no randomisation and no untreated comparison group, found that prophylaxis failed to help 16 percent of them and that a quarter of those on the microcrystalline 50 mg twice-daily regimen stopped early because of side effects. (Source 14)

• Case series, Very low certainty.
• Size: 219 female patients, 173 assessable for efficacy.
• Who: female patients aged 9 to 89 given long-term (1 year) nitrofurantoin prophylaxis for recurrent urinary infection in one practice between 1975 and 1992; no men were included.
• How long: 12 months of prophylaxis.
• Result: Mean incidence of symptomatic episodes fell 5.4-fold; prophylaxis unhelpful in 16% of patients; 25.6% of group A (50 mg microcrystalline twice daily) stopped prematurely from an adverse event of any type versus 13% on Macrodantin (P < 0.01); no adverse event was life-threatening.
• Funding: not stated.

Limit of this finding: This is a look back through case notes, not a trial. The authors reviewed the records of 219 women treated in one practice between 1975 and 1992; nobody was randomised and there was no untreated comparison group, so the 'three regimens' and the p-values between them reflect which drug each woman happened to have been given rather than a planned comparison. Everyone in it was female. Efficacy rests on 173 of the 219, because 46 could not be assessed.

Case records from 219 female patients between 1975 and 1992 who were given long-term prophylaxis (1 year) with nitrofurantoin for the prevention of recurrent urinary infections have been reviewed.

The same authors concluded that mild or moderate reduction in kidney function did not justify avoiding nitrofurantoin, because the excess failure rate was present at high filtration rates too. (Source 31)

• Cohort study, Low certainty.
• Size: four antibiotic groups of older Ontario women.
• Who: older women with urinary tract infection.
• How long: 14-day outcome window.
• Result: Qualitative conclusion; the failure excess was not confined to the low-eGFR group.
• Funding: not stated.

In this study, the presence of mild or moderate reductions in estimated glomerular filtration rate did not justify avoidance of nitrofurantoin.

The same Dutch cohort found no higher rate of treatment failure in women with moderate renal impairment of 30 to 50 mL/min/1.73 m2, so the concern that nitrofurantoin would simply not work at that level of kidney function was not borne out. (Source 32)

• Cohort study, Low certainty.
• Size: 21,317 women on nitrofurantoin and 7,926 on trimethoprim as a comparator cohort.
• Who: women treated in Dutch primary care for urinary tract infection, from the Pharmo Record Linkage System.
• How long: ineffectiveness assessed within 1 month; serious adverse events within 90 days.
• Result: Hazard ratio for ineffectiveness with moderate renal impairment 1.1 (95% CI 0.74-1.51), an interval crossing 1. Pulmonary adverse events leading to hospitalization below 50 ml/min/1.73 m2 hazard ratio 4.1 (95% CI 1.31-13.09)
• Funding: not stated.

Limit of this finding: The publisher never tagged this paper's conclusions, so the word CONCLUSIONS and the whole conclusions paragraph sit inside the results field of the PubMed and Europe PMC records. We have split them into two separate quotations. Note also how small the absolute numbers are: adverse events ran at 0.02 per 1,000 person-days overall, and the confidence interval on the fourfold pulmonary hazard runs from 1.31 to 13.09, so the size of that risk is very uncertain even though it reached significance.

Nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m²).

Where the research disagrees

Whether nitrofurantoin should be avoided when kidney function is mildly or moderately reduced (creatinine clearance 30-60 mL per minute)

• Macrobid US prescribing information (SPL published 10 February 2026), position: Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) are contraindications. (Source 5)
• Singh and colleagues, CMAJ 2015 population study of older Ontario women, cohort: In this study, the presence of mild or moderate reductions in estimated glomerular filtration rate did not justify avoidance of nitrofurantoin. (Source 31)
• Geerts and colleagues, European Journal of Clinical Pharmacology 2013 Dutch cohort, cohort: In patients with renal impairment (<50 ml/min/1.73 m²) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09) (Source 19)

Whether serious hypersensitivity harms such as pulmonary fibrosis and hepatotoxicity should weigh on short-course prescribing

• Huttner and colleagues, Journal of Antimicrobial Chemotherapy 2015 systematic review of short-course use, meta-analysis: Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. (Source 26)
• Chalasani and colleagues, Journal of Hepatology 2023 DILIN cohort, cohort: To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. (Source 18)

How much

• Reference intake: There is no reference intake for an antibiotic. Dose is set by the prescriber. As a position, the Macrobid label states one 100 mg capsule every 12 hours for seven days in adults and patients over 12 years, taken with food (RemedyRepack/Almatica label, SPL effective 9 February 2026). (Source 33)
• Upper limit: No tolerable upper intake level exists for an antibiotic. The label sets no maximum dose but imposes limits by patient: it is contraindicated with anuria, oliguria or significant renal impairment (creatinine clearance under 60 mL per minute), in pregnancy at term, during labour and delivery, in neonates under one month, and after previous nitrofurantoin-associated cholestatic jaundice or hepatic dysfunction (SPL effective 9 February 2026). (Source 5)
• Studied: Nitrofurantoin 100 mg four times daily for 3 days versus placebo in a general-practice randomised trial in non-pregnant women aged 15 to 54. (Source 2)
• Studied: Nitrofurantoin 100 mg three times a day for 5 days versus a single 3 g dose of fosfomycin in 513 non-pregnant women aged 18 and over. (Source 27)
• Studied: Nitrofurantoin 100 mg twice daily for 5 days in the EAGLE-2 and EAGLE-3 phase 3 trials. (Source 30)
• Studied: For long-term prophylaxis, three regimens appear in a retrospective 18-year case-record review, assigned in ordinary practice rather than randomised: 50 mg microcrystalline nitrofurantoin twice daily, 100 mg macrocrystalline nitrofurantoin once daily, and 50 mg macrocrystalline nitrofurantoin once daily. (Source 14)

A common belief, and what the research shows

The belief: Nitrofurantoin is an old, gentle antibiotic, so a long course for repeated bladder infections is a low-risk way to keep them away.

What the research shows: Short courses really are well tolerated: the 2015 systematic review found "Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators." The serious harms are concentrated in long-term use, which is exactly how prophylaxis is given. In the Mayo Clinic series of chronic nitrofurantoin lung disease, "Onset of symptoms occurred after a median interval of 23 months (range, 10-144 months) following the initiation of nitrofurantoin therapy for the prevention of recurrent urinary tract infections." And in the DILIN liver-injury cohort, "No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation."

Questions and answers

What is it?

Nitrofurantoin is a synthetic antibiotic of the nitrofuran family, in use since 1953, that is specific to urinary tract infections. The common Macrobid capsule contains 100 mg in two forms: 25 mg as slow-dissolving macrocrystals and 75 mg as a monohydrate powder that forms a gel in the gut and releases the drug gradually. Blood levels stay low, usually under 1 mcg/mL, while the drug concentrates in urine, and it can turn urine brown. (Source 34)

What does it do in the body?

Bacteria in the urine use their own enzymes to convert nitrofurantoin into reactive fragments, which then damage several different bacterial systems at once: the ribosomal proteins that build proteins, plus energy metabolism, DNA, RNA and cell-wall production. Because it hits many targets rather than one, resistance has stayed rare since 1953, since a bacterium would need several simultaneous mutations. It kills bacteria in urine at the doses used. (Source 1)

Is it good or bad for you?

It depends almost entirely on how long it is taken for. For a short course for simple bladder infection the balance is clearly favourable: against placebo the number needed to treat for bacteriological cure in 3 days was 1.6, and a review of 27 trials in 4,807 patients found toxicity infrequent, mild and mostly stomach upset. Taken for months or years, which is how it is used to prevent recurrences, it is linked to lung fibrosis, liver injury that can progress to cirrhosis, and nerve damage that may not reverse. It is also the wrong drug for kidney infection, because it does not reach tissue outside urine. (Source 26)

How do you get more of it?

Does not apply in the nutrient sense. Nitrofurantoin is a prescription antibiotic, not a nutrient, so there is no dietary or behavioural way to increase it. One thing does change how much reaches the bloodstream: taking it with food raises absorption by about 40 percent, and the label tells people to take it with breakfast and dinner for that reason and for tolerance. (Source 35)

If it is harmful, what reduces it?

Stopping the drug is the main answer, and for the serious reactions the literature is unanimous that it should be stopped promptly. About 20 to 25 percent of a dose is excreted unchanged in urine within 24 hours, so it clears quickly; in overdose the label advises inducing vomiting and keeping fluid intake high, and notes nitrofurantoin can be removed by dialysis. Magnesium trisilicate antacids reduce how much is absorbed, but that is an interaction to avoid, not a treatment. (Source 36)

Why might someone be low in it or missing it?

Does not apply: nobody can be deficient in an antibiotic. What does happen is that nitrofurantoin can be the wrong drug or an unavailable one for a given person. It is contraindicated with little or no urine output or significant kidney impairment, in pregnancy at term and during labour, in babies under one month, and in anyone who has previously had nitrofurantoin-related jaundice or liver dysfunction. It also has no activity against most Proteus or Serratia species and none against Pseudomonas. (Source 5)

Which whole foods contain it or feed it?

No whole food contains nitrofurantoin; it is a manufactured chemical. Food does matter for absorption, though: any meal raises the bioavailability by about 40 percent, and the label advises taking capsules with breakfast and dinner. The one dietary product to avoid is an antacid containing magnesium trisilicate, which adsorbs the drug in the gut and reduces how much gets in. (Source 35)

What happens if you do not have it?

Nothing is lost physiologically, because it is not a body substance. For someone with a bladder infection who does not take an effective antibiotic, the placebo arm of the 2002 general-practice trial gives the closest answer: in the women with culture-confirmed infection, only 5 of 25 on placebo had cleared the bacteria after three days, against 21 of 25 on nitrofurantoin. Many simple bladder infections do settle on their own, which is why a fifth of the placebo group cleared anyway, and by seven days the gap had narrowed, but recovery is slower and less certain. (Source 25)

How can you test for it?

There is no blood test to measure nitrofurantoin levels in routine care, and none is described in the label. What is tested is the infection and the organ systems at risk: a urine culture with susceptibility testing before and after treatment, because susceptibility determines whether the drug will work at all, plus periodic liver blood tests and kidney function checks for anyone on long-term therapy. Nitrofurantoin can also make an old-style Benedict's or Fehling's urine sugar test read falsely positive. (Source 37)

References

1. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
2. The British journal of general practice : the journal of the Royal College of General Practitioners. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women.. 2002. PMID 12236276. Read the source
3. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
4. The Cochrane database of systematic reviews. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women.. 2004. PMID 15266443, DOI 10.1002/14651858.cd001209.pub2. Read the source
5. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
6. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
7. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
8. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
9. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
10. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
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17. Journal of hepatology. Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.. 2023. PMID 36152763, DOI 10.1016/j.jhep.2022.09.010. Read the source
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23. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
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25. The British journal of general practice : the journal of the Royal College of General Practitioners. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women.. 2002. PMID 12236276. Read the source
26. The Journal of antimicrobial chemotherapy. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials.. 2015. PMID 26066581, DOI 10.1093/jac/dkv147. Read the source
27. JAMA. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial.. 2018. PMID 29710295, DOI 10.1001/jama.2018.3627. Read the source
28. The Cochrane database of systematic reviews. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women.. 2004. PMID 15266443, DOI 10.1002/14651858.cd001209.pub2. Read the source
29. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women.. 2015. PMID 25918178, DOI 10.1503/cmaj.150067. Read the source
30. Lancet (London, England). Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.. 2024. PMID 38342126, DOI 10.1016/s0140-6736(23)02196-7. Read the source
31. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women.. 2015. PMID 25918178, DOI 10.1503/cmaj.150067. Read the source
32. European journal of clinical pharmacology. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care.. 2013. PMID 23660771, DOI 10.1007/s00228-013-1520-x. Read the source
33. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
34. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
35. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
36. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source
37. DailyMed / US Food and Drug Administration (RemedyRepack Inc.; Macrobid, Almatica Pharma LLC); SPL effective 9 February 2026 (version 9). MACROBID (nitrofurantoin monohydrate/macrocrystalline) capsule - FDA prescribing information (Structured Product Label). 2026. Read the source