|Year : 2015 | Volume
| Issue : 4 | Page : 477-481
Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario
Laishram Shakti, Balaji Veeraraghavan
Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||25-Feb-2015|
|Date of Acceptance||06-Jul-2015|
|Date of Web Publication||16-Oct-2015|
Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Infections caused by antibiotic resistant pathogens are of significant concern and are associated with higher mortality and morbidity. Nitrofurantoin is a broad-spectrum bactericidal antibiotic and is effectively used to treat urinary tract infections (UTIs) caused by E. coli, Klebsiella sp., Enterobacter sp., Enterococcus sp. and Staphylococcus aureus. It interfere with the synthesis of cell wall, bacterial proteins and DNA of both Gram positive and Gram negative pathogens. Nitrofurantoin has been used successfully for treatment and prophylaxis of acute lower urinary tract infections. With the emergence of antibiotic resistance, nitrofurantoin has become the choice of agent for treating UTIs caused by multi-drug resistant pathogens.
Keywords: Nitrofurantoin, MDR, UTI
|How to cite this article:|
Shakti L, Veeraraghavan B. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario. Indian J Med Microbiol 2015;33:477-81
|How to cite this URL:|
Shakti L, Veeraraghavan B. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario. Indian J Med Microbiol [serial online] 2015 [cited 2020 Jul 13];33:477-81. Available from: http://www.ijmm.org/text.asp?2015/33/4/477/167350
| ~ Introduction|| |
Interest in nitrofurantoin, an old drug has increased as a solution to the ever increasing menace of antimicrobial resistance. This Review will highlight the potential and the limitation of this agent in the era of drug resistance, especially in India.
The major strength of nitrofurantoin is its action at multiple sites and levels. This includes inhibition of bacterial enzymes involved in carbohydrate synthesis and in higher concentration DNA, RNA, and total protein synthesis by the non-specific attack on bacterial ribosomal proteins.
, This is preceded by activation of nitrofurantoin by bacterial reductases to highly reactive electrophilic intermediates, and an inverse correlation exists with the bacterial reductase activity of the bacteria and its nitrofurantoin minimum inhibitory concentration (MIC). However, this reduction of nitrofurantoin is not an absolute requirement for its antibacterial activity.
Bioavailability and spectrum of activity
Nitrofurantoin formulation determine its pharmacokinetics (PK) whereas very little is known about its pharmacodynamics (PD). Different formulations of nitrofurantoin include microcrystals and macrocrystals. Macrocrystalline formulations have a slower rate of dissolution and lower bioavailability. Dual release capsules contain 25% microcrystal and 75% nitrofurantoin monohydrate, which allows sustained release and maintenance of plasma levels. Oral bioavailability is 40–50% and increases with food. Very low peak plasma level of <2 µg/mL is achieved after 1–4 h of oral administration., Nitrofurantoin is metabolised in renal tissue and rapidly excreted in the urine through both glomerular filtration, as well as tubular secretion, with a plasma half-life of 0.5–1 h. With this rapid excretion, the urinary concentration of nitrofurantoin is more than 100 µg/mL (up to 250 µg/mL). High concentration achievable in urine makes it an ideal choice for treatment of urinary tract infection (UTI). There is very limited information available on PK/PD property of nitrofurantoin. As a result, the optimal dosing schedule remains uncertain and different countries follow differing regimen.
There is only one study on the PD property of nitrofurantoin. Komp Lindgren et al. demonstrated rapid and complete killing of extended spectrum beta-lactamase (ESBL) and non-ESBL strain of Escherichia More Details coli in static time kill experiment while 99% killing was seen among vancomycin-resistant enterococcal (VRE) and non-VRE Enterococcus strains at 24 h. In the dynamic time kill assay for E. coli the PK/PD index that best correlated with antibacterial activity was T > MIC (time duration where the drug concentration is more than the MIC of the agent). This finding suggests need for more PK/PD studies with the urinary drug level assay at differing dosing regimens, which will help in determining the optimum dosing schedule.
Nitrofurantoin is usually well tolerated. Side-effects occur at rates <0.001%. Macrocrystal formulations reduce gastrointestinal effects such as nausea and vomiting. Haemolytic anaemia can occur in patients with glucose-6-phosphate deficiency. Serious adverse effects are rare and occur only with prolonged medication (>6 months). This includes chronic pulmonary reactions and interstitial fibrosis, peripheral neuropathy and hepatic injury. Nitrofurantoin also has good safety profile for use in pregnancy (pregnancy category B). Nitrofurantoin is contraindicated in patients with renal failure with creatinine clearance rate of 60 mL/min. However, recent studies indicate the use of nitrofurantoin can be expanded to creatinine clearance as low as 40 mL/min for infection with susceptible isolates.
Nitrofurantoin is active against most common uropathogens including E. coli, Citrobacter spp. , Staphylococcus saprophyticus, and Enterococcus spp. whereas, Enterobacter spp. and Klebsiella spp. are only moderately inhibited, Proteus spp. , Providencia spp. , Morganella morgannii, Serratia spp. , Pseudomonas spp. , and Acinetobacter spp. are mostly resistant to nitrofurantoin.,
Preference and recommendation of nitrofurantoin
[Table 1] gives the breakpoints prescribed by Central Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoints for nitrofurantoin are based on urinary concentration. The EUCAST recommend the use of nitrofurantoin only for uncomplicated UTIs. The high urinary concentration achieved with nitrofurantoin is sufficient to eradicate the intraluminal bacteria, and the minimal intracellular invasion is possibly cleared by the innate immune response. However, complicated UTIs are associated with more tissue invasion and can develop urosepsis rapidly. Thus for a complicated UTI and UTI with tissue component like pyelonephritis, the plasma concentration and the tissue concentration is also important and thus the use of nitrofurantoin cannot be recommended because of inadequate tissue concentration., Nitrofurantoin may complement the primary therapy in urosepsis or as de-escalation choice.
|Table 1: Nitrofurantoin disc diffusion and MIC breakpoints recommendations from CLSI and EUCAST 2015|
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Nitrofurantoin is recommended as the first choice for the treatment of uncomplicated cystitis and pyelonephritis in women by Infectious Disease Society of America and the European Society for Microbiology and Infectious Disease. Another role for nitrofurantoin use is in UTI in pregnancy. Asymptomatic bacteriuria happens in 2–10% of pregnancies and acute cystitis in 1–4%. Among patients with asymptomatic bacteriuria, 20–40% eventually develops pyelonephritis later in pregnancy. Among multi-drug resistant (MDR) strains of E. coli causing UTI in pregnancy, resistance to nitrofurantoin is lower (7.7%) compared to ampicillin, trimethoprim-sulphamethoxazole, cephalothin or ciprofloxacin. Nitrofurantoin is also recommended as preventive therapy for recurrent UTI during pregnancy. However, its use is not recommended near term or during labour and delivery in patients with glucose-6-phosphate dehydrogenase deficiency because of the risk of haemolytic anaemia.
Dose and duration of nitrofurantoin
Dosage schedule for nitrofurantoin varies considerably in different countries ranging from 50 to 100 mg × 2–4 times/day [Table 2]. Infectious Diseases Society of America recommends a dosage of 100 mg BD for 5 days for uncomplicated cystitis and pyelonephritis in women. Pallett and Hand recommend 100 mg × 4 times daily for 7 days for uncomplicated or complicated lower UTIs. For children younger than 12 years, dosage of 3–5 mg/kg body weight per oral in two divided dosage for 7–14 days is recommended.
Similarly, though classically 10–14 days of therapy is recommended, the long duration compromises the compliance to treatment. Shorter duration of therapy has been investigated to overcome this limitation. Lumbiganon et al. compared the traditional 7 days regimen of nitrofurantoin to the 1-day regimen and found more treatment failure with shorter regimen though the rate of symptomatic infection and adverse pregnancy outcome was not significantly different. Systematic review on UTI in children showed 2–4 days course of therapy to be as effective as 7–14 days of therapy. However, Keren and Chan recommend treatment for the traditional 7–14 days as long-term therapy have fewer treatment failures in children. It is important to note that these systemic meta-analyses are based on treatment with different groups of antimicrobials. Thus, a generalisation of treatment duration across different groups of antimicrobial agents may not be advisable.
Mechanism of resistance
Nitrofurantoin acts at multiple targets in the bacterial cell and resistance have not evolved as fast as other drugs with a single bacterial target. Resistance is developed through stepwise mutations. Sandegren et al. found the mutation frequency to be approximately 10−7/cell for E. coli. Mutations in the genes encoding bacterial nitroreductase nfsA and nfsB were responsible for high-level nitrofurantoin resistance (median MIC of 96 µg/mL)., However, the growth rate of the resistant mutants was lower than susceptible strains, and at the therapeutic urinary concentration of above 200 µg/mL the selection of resistant mutants is prohibited. This fitness cost conferred in resistant strains may render resistant strain with even moderately high MICs amenable to treatment with the normal dosing regimen. This may explain the lack of resistance to this drug even after 60 years of use. In patients with poor drug compliance or suboptimal dosing or PK altering condition (e.g., poor absorption) where the urinary drug concentration may be lower than expected, resistant mutants can, however, still be selected.
Though E. coli, in general, are highly susceptible to nitrofurantoin, susceptibility for ESBL producing strains are lower [Table 3]. Procop et al. in 2003 showed ESBL producing Klebsiella pneumoniae have significantly decreased susceptibility to nitrofurantoin compared to non-ESBL producer. Tasbakan et al. showed modest clinical and microbial success rates of 68% and 69% respectively, with nitrofurantoin therapy for infection with ESBL producing nitrofurantoin susceptible E. coli. The re-infection and relapse rates were 6.5% and 3.2%, respectively. However, 81% of the studied population had at least one complicating factors. The dosage of 50 mg 4 times/day for 14 days, may be suboptimal in this cohort with complicating factors.
Among VRE isolates, nitrofurantoin retain good activity [Table 3] and Heintz et al. recommends the use of empiric nitrofurantoin 100 mg 4 times daily for enterococcal cystitis and the first line therapy for nitrofurantoin susceptible VRE cystitis.
Nitrofurantoin resistance in India
In India, resistance rates among E. coli range from 5% to 24.4% [Table 4],,,,, with higher resistance rate seen in in-patients. In one of the large-scale study of more than 2000 isolates, Sahni et al. reported ESBL production among 47.6% of E. coli isolates studied of which 76.8% were MDR, with corresponding nitrofurantoin resistance of 20%., Shaifali et al. observed a resistance to third generation cephalosporin indicative of ESBL production was as high as 90% among female out-patient. The corresponding resistance to nitrofurantoin in this study was 13%. This finding is in contradiction with resistance rates of 1.1–1.8% in USA, Canada, and France.
Among Klebsiella sp. resistance rates vary from 9% to 17%., Shaifali et al., again reported third generation cephalosporin resistance of up to 90% among the Klebsiella spp. isolates studied with nitrofurantoin resistance of 9%. Among Enterococcus sp. the resistance rate is 6–17%.,
An agent is deemed unacceptable for empiric treatment where the rate of resistance exceeds 20%. Among oral agents used for out-patient therapy, high rates of resistance is seen in E. coli in India – 63.6–88% against aminopenicillins, 35–75% against ciprofloxacin, and 40–76% against trimethoprim-sulphamethoxazole.,,,,, Biswas et al. reported nitrofurantoin susceptibility of 87% among ciprofloxacin-resistant isolates.
While the rate of nitrofurantoin resistance is lower than any of the other oral agents, some studies have reported high levels of resistance. In a multi-centric study, Kothari and Sagar found resistance rates of 24.4%. The highest rate of nitrofurantoin resistance was reported from Aligarh against both E. coli and Klebsiella spp. with rates of 80% and 76%. The corresponding ESBL rates was 34.4% and 27.3% in E. coli and Klebsiella spp., respectively. This wide variation in the rates of resistance may be determined by the local prescribing practices, with the resistance higher among the most commonly prescribed agents.
There is very limited data on nitrofurantoin activity against carbapenem-resistant isolates or VRE in India. With the increasing drug resistance seen in this decade, there is a need to evaluate the activity of nitrofurantoin against such extensively drug-resistant strains.
| ~ Summary and Conclusion|| |
To surmise, among the various oral antimicrobials available for UTI the use of aminopenicillins and trimethoprim/sulphamethoxazole for UTI is restricted by high rates of resistance. The ever increasing resistance to ciprofloxacin, its contraindication during pregnancy and significant impact on gut flora compared to nitrofurantoin  has fallen out of favour as a choice for empirical therapy of UTI. While fosfomycin has good activity against E. coli, resistance rate is high among Klebsiella spp. (Chinnappan C. et al. Technical and interpretative issues of fosfomycin susceptibility testing. Indian Journal of Medical Microbiology 2015 - in the press.) Nitrofurantoin remains the only available alternative with almost equivalent activity against E. coli and Klebsiella spp. with high susceptibility rate among oral agents for UTI. To provide optimum use and to avoid misuse and overuse of this drug, culture, and susceptibility testing is the need of the time to preserve it for next generation.
| ~ References|| |
Guay DR. An update on the role of nitrofurans in the management of urinary tract infections. Drugs 2001;61:353-64.
McOsker CC, Fitzpatrick PM. Nitrofurantoin: Mechanism of action and implications for resistance development in common uropathogens. J Antimicrob Chemother 1994;33 Suppl A: 23-30.
Garau J. Other antimicrobials of interest in the era of extended-spectrum beta-lactamases: Fosfomycin, nitrofurantoin and tigecycline. Clin Microbiol Infect 2008;14 Suppl 1:198-202.
Mazzei T, Cassetta MI, Fallani S, Arrigucci S, Novelli A. Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections. Int J Antimicrob Agents 2006;28 Suppl 1:S35-41.
Komp Lindgren P, Klockars O, Malmberg C, Cars O. Pharmacodynamic studies of nitrofurantoin against common uropathogens. J Antimicrob Chemother 2015;70:1076-82.
Munoz-Davila MJ. Role of old antibiotics in the era of antibiotic resistance. Highlighted nitrofurantoin for the treatment of loweer urinary tract infections. Antibiotics 2014;3:39-48.
Duff P. Antibiotic selection in obstetrics: Making cost-effective choices. Clin Obstet Gynecol 2002;45:59-72.
Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: Looking for the evidence. Ann Pharmacother 2013;47:106-11.
Ronald AR, Turck M. Comparison of oxafuradene and nitrofurantoin in vitro
and clinical assessment of oxafuradene in bacteriuria. Antimicrob Agents Chemother (Bethesda) 1967;7:506-9.
Barry AL. Nitrofurantoin susceptibility test criteria. J Antimicrob Chemother 1990;25:711-3.
Wagenlehner FM, Naber KG. Antibiotic treatment for urinary tract infections: Pharmacokinetic/pharmacodynamic principles. Expert Rev Anti Infect Ther 2004;2:923-31.
Richards WA, Riss E, Kass EH, Finland M. Nitrofurantoin; clinical and laboratory studies in urinary tract infections. AMA Arch Intern Med 1955;96:437-50.
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al.
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103-20.
Le J, Briggs GG, McKeown A, Bustillo G. Urinary tract infections during pregnancy. Ann Pharmacother 2004;38:1692-701.
Schneeberger C, Geerlings SE, Middleton P, Crowther CA. Interventions for preventing recurrent urinary tract infection during pregnancy. Cochrane Database Syst Rev 2012;11:CD009279.
Pallett A, Hand K. Complicated urinary tract infections: Practical solutions for the treatment of multiresistant Gram-negative bacteria. J Antimicrob Chemother 2010;65 Suppl 3:iii25-33.
Beetz R, Westenfelder M. Antimicrobial therapy of urinary tract infections in children. Int J Antimicrob Agents 2011;38 Suppl: 42-50.
Lumbiganon P, Villar J, Laopaiboon M, Widmer M, Thinkhamrop J, Carroli G, et al.
One-day compared with 7-day nitrofurantoin for asymptomatic bacteriuria in pregnancy: A randomized controlled trial. Obstet Gynecol 2009;113:339-45.
Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database Syst Rev 2003;1:CD003966.
Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children. Pediatrics 2002;109:E70.
Sandegren L, Lindqvist A, Kahlmeter G, Andersson DI. Nitrofurantoin resistance mechanism and fitness cost in Escherichia coli
. J Antimicrob Chemother 2008;62:495-503.
Whiteway J, Koziarz P, Veall J, Sandhu N, Kumar P, Hoecher B, et al.
Oxygen-insensitive nitroreductases: Analysis of the roles of nfsA and nfsB in development of resistance to 5-nitrofuran derivatives in Escherichia coli
. J Bacteriol 1998;180:5529-39.
Liu HY, Lin HC, Lin YC, Yu SH, Wu WH, Lee YJ. Antimicrobial susceptibilities of urinary extended-spectrum beta-lactamase-producing Escherichia coli
and Klebsiella pneumoniae
to fosfomycin and nitrofurantoin in a teaching hospital in Taiwan. J Microbiol Immunol Infect 2011;44:364-8.
Maina D, Makau P, Nyerere A, Revathi G. Antimicrobial resistance patterns in extended-spectrum β-lactamase producing Escherichia coli
and Klebsiella pneumoniae
isolates in a private tertiary hospital, Kenya. Microbiol Discov 2013;1: www.hoajonline.com/microbiology/.5 Vol. 1- ISSN 2052-6180.
Auer S, Wojna A, Hell M. Oral treatment options for ambulatory patients with urinary tract infections caused by extended-spectrum-beta-lactamase-producing Escherichia coli
. Antimicrob Agents Chemother 2010;54:4006-8.
Puerto AS, Fernández JG, del Castillo Jde D, Pino MJ, Angulo GP.In vitro
activity of beta-lactam and non-beta-lactam antibiotics in extended-spectrum beta-lactamase-producing clinical isolates of Escherichia coli
. Diagn Microbiol Infect Dis 2006;54:135-9.
Zhanel GG, Hoban DJ, Karlowsky JA. Nitrofurantoin is active against vancomycin-resistant enterococci. Antimicrob Agents Chemother 2001;45:324-6.
Zhanel GG, Laing NM, Nichol KA, Palatnick LP, Noreddin A, Hisanaga T, et al.
Antibiotic activity against urinary tract infection (UTI) isolates of vancomycin-resistant enterococci (VRE): Results from the 2002 North American Vancomycin Resistant Enterococci Susceptibility Study (NAVRESS). J Antimicrob Chemother 2003;52:382-8.
Rahbar M, Hajia M, Farzanehkhah M. Activity of nitrofurantoin against Urinary Tract Infection (UTI) isolates of Vancomycin-Resistant Entreococci (VRE): A three-year survey in an Iranian hospital. Iran J Pathol 2007;2:171-4.
Procop GW, Tuohy MJ, Wilson DA, Williams D, Hadziyannis E, Hall GS. Cross-class resistance to non-beta-lactam antimicrobials in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
. Am J Clin Pathol 2003;120:265-7.
Tasbakan MI, Pullukcu H, Sipahi OR, Yamazhan T, Ulusoy S. Nitrofurantoin in the treatment of extended-spectrum ß-lactamase-producing Escherichia coli
-related lower urinary tract infection. Int J Antimicrob Agents 2012;40:554-6.
Heintz BH, Halilovic J, Christensen CL. Vancomycin-resistant enterococcal urinary tract infections. Pharmacotherapy 2010;30:1136-49.
Kaur N, Sharma S, Malhotra S, Madan P, Hans C. Urinary tract infection: Aetiology and antimicrobial resistance pattern in infants from a tertiary care hospital in northern India. J Clin Diagn Res 2014;8:DC01-3.
Niranjan V, Malini A. Antimicrobial resistance pattern in Escherichia coli
causing urinary tract infection among inpatients. Indian J Med Res 2014;139:945-8.
Shaifali I, Gupta U, Mahmood SE, Ahmed J. Antibiotic susceptibility patterns of urinary pathogens in female outpatients. N Am J Med Sci 2012;4:163-9.
Sahni RD, Balaji V, Varghese R, John J, Tansarli GS, Falagas ME. Evaluation of fosfomycin activity against uropathogens in a fosfomycin-naive population in South India: A prospective study. Future Microbiol 2013;8:675-80.
Biswas D, Gupta P, Prasad R, Singh V, Arya M, Kumar A. Choice of antibiotic for empirical therapy of acute cystitis in a setting of high antimicrobial resistance. Indian J Med Sci 2006;60:53-8.
Gupta V, Yadav A, Joshi RM. Antibiotic resistance pattern in uropathogens. Indian J Med Microbiol 2002;20:96-8.
Kothari A, Sagar V. Antibiotic resistance in pathogens causing community-acquired urinary tract infections in India: A multicenter study. J Infect Dev Ctries 2008;2:354-8.
Akram M, Shahid M, Khan AU. Etiology and antibiotic resistance patterns of community-acquired urinary tract infections in J N
M C Hospital Aligarh, India. Ann Clin Microbiol Antimicrob 2007;6:4.
Stewardson AJ, Gaïa N, François P, Malhotra-Kumar S, Delémont C, Martinez de Tejada B, et al.
Collateral damage from oral ciprofloxacin versus nitrofurantoin in outpatients with urinary tract infections: A culture-free analysis of gut microbiota. Clin Microbiol Infect 2015;21:344.
[Table 1], [Table 2], [Table 3], [Table 4]