Introduction: Urinary tract infections (UTIs) caused by antibiotic-resistant isolates have become a major health hazard in recent years as they are very difficult to treat, causing an increase in morbidity and mortality. Nitrofurantoin has been used successfully for decades for the prophylaxis and treatment of uncomplicated cystitis but the increased emergence of antibiotic resistance has made nitrofurantoin a suitable candidate for the treatment of UTI caused by multidrug-resistant pathogens. This study was taken up with the aim to determine the activity of nitrofurantoin against the wide range of resistant urinary gram-negative and gram-positive isolates. Materials and Methods: A total of 440 nonduplicate, gram-negative, and gram-positive uropathogens obtained between July 2013 and December 2014 from 3,780 fresh midstream urine samples were subjected to the VITEK-2 compact system for identification and antimicrobial susceptibility testing. Phenotypic methods for the detection of different beta-lactamases [extended spectrum beta-lactamases, AmpC beta-lactamases, metallo-beta-lactamases, and inhibitor-resistant beta-lactamases (IRT)] and methicillin-resistance staphylococci [methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS)] were employed. Results: High activity of nitrofurantoin was observed against MRCNS (96%) followed by MRSA (95%), extended spectrum beta-lactamases (ESBLs) (70%), IRT (66%), and vancomycin-resistant enterococci (VRE) (66%). However, the sensitivity rate was lowered to 38% and 32% for metallo-beta-lactamases (MBLs) and AmpC beta-lactamases, respectively. Conclusion: In view of the current incidence of antibiotic resistance among community uropathogens and based on efficacy, cost-effectiveness, and low impact on promoting resistance, nitrofurantoin should be considered as a reasonable alternative to trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones for the first-line therapy of uncomplicated UTIs. Keywords: Antimicrobial resistance, nitrofurantoin, urinary tract infections (UTIs)
A significant rise in the incidence of antimicrobial resistance, especially multidrug resistance (MDR), in pathogens isolated in urinary tract infections (UTI) is well documented. [1] This alarming widespread of antimicrobial resistance has not been paralleled by the development of novel antibiotics. Resistance to the scarce new antibiotics is also emerging. In this circumstance, the rational use of older antibiotics could represent an alternative to the treatment of MDR bacterial pathogens and this would help to optimize the armamentarium of antibiotics in the way to preserve new antibiotics, thereby avoiding the prescription of molecules known to promote the spread of resistance. For many years, trimethoprim-sulfamethoxazole (TMP-SMX) was the antibiotic of choice for the treatment of UTI, given its efficacy and low cost. [2] Following the development of a high occurrence of TMP-SMX resistance among uropathogens, use of this drug has been discouraged in many communities. [3] An effective alternative for many clinicians has been the fluoroquinolone class of antibiotics as they achieve high concentrations in the urine and have excellent activity against most uropathogens. [2] Experts are concerned about the overuse of fluoroquinolones leading to an increased prevalence of fluoroquinolone-resistant pathogens that has major implications for the treatment of more serious infections, such as community-acquired pneumonia, health-care-associated pneumonia, and complicated UTIs. Nitrofurantoin has been used for more than 50 years as an alternative treatment of uncomplicated UTIs. In contrast to the other classes of antimicrobial agents, acquired resistance to nitrofurantoin is said to be quite rare. [4] Since the macrocrystalline form was developed, the previously frequent gastrointestinal side effects have become less common, giving this drug a good safety profile. [5] This molecule has a broad-spectrum activity against the main uropathogens [ Escherichia More Details coli (E. coli), Citrobacter spp., group B streptococci, enterococci, Staphylococcus aureus (S. aureus), Staphylococcus epidermidis, Klebsiella pneumoniae (K. pneumoniae), and Enterobacter spp.] and has also been shown to be active against extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and vancomycin-resistant enterococci (VRE). However, it lacks activity against members of the genera Proteus, Providencia, Morganella, Serratia, Acinetobacter, and Pseudomonas. [1] In this study, we aimed to assess the in vitro activity of nitrofurantoin against the predominant urinary-resistant gram-positive and gram-negative bacteria.
A total of 313 gram-negative and 127 gram-positive multidrug-resistant isolates among 3,780 urinary specimens from patients having clinical features of UTIs collected between July 2013 and December 2014 were included in this prospective and nonrandomized study. The inclusion criteria were clean catch midstream urine samples in a widemouthed container collected at the laboratory or received from the admitted patients within 2 h of collection irrespective of age, sex, or antibiotic administration. The urine specimens passed at home for which proper transport medium could not be ascertained or brought after 2 h of collection, growth of more than one isolate, and the presence of duplicate isolates were excluded from the study. The VITEK-2 calorimetric compact system with Advanced Expert System (AES) software (bioMιrieux, Marcy l’Etoile, France) was employed for the identification and the antimicrobial susceptibility testing of isolates following the presence of pure culture of isolated colonies of the microorganisms on blood agar and MacConkey agar. [6] Following the manufacturer’s instructions, the gram-negative bacteria were inoculated onto the GN ID and AST-N280 cards and the gram-positive bacteria onto the GP ID and AST-P628 cards. The following antibiotics were tested by this system: imipenem, meropenem, ertapenem, ampicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, cefuroxime, ceftriaxone, cefepime, amikacin, gentamicin, nalidixic acid, ciprofloxacin, tigecycline, nitrofurantoin, colistin, and TMP-SMX for gram-negative bacteria and benzylpenicillin, ciprofloxacin, levofloxacin, oxacillin, erythromycin, clindamycin, tetracycline, vancomycin, gentamicin, daptomycin, teicoplanin, linezolid, tigecycline, and TMP-SMX for gram-positive bacteria. The AES software has the capability of identifying antibiotic resistance mechanisms, even emerging and low-level resistance, and proved to be useful in calculating minimum inhibitory concentration (MIC) values. The identification of ESBL production was performed by combined disk test, AmpC beta-lactamases with AmpC disk test, metallo-beta-lactamases (MBLs) by disk enhancement test, and the coexistence phenotype of both ESBL and AmpC by modified double disk synergy test following the standard protocols. [7],[8],[9],[10] Agar disk-diffusion method (Kirby-Bauer) with cefoxitin (30 μg) was used for methicillin resistance of isolated staphylococci. [11] Quality control Quality control was achieved using K. pneumoniae (ATCC 700603); E. coli (ATCC 25922); Pseudomonas aeruginosa (ATCC 27853), known AmpC positive E. coli; S. aureus (ATCC 25923); and Enterococcus faecalis (ATCC 29212). Reference strains of carbapenemases positive K. pneumoniae. ATCC BAA-1705 and negative K. pneumoniae ATCC BAA-1706 were also included in the study. Statistical analysis Data obtained from this study were analyzed using descriptive statistics such as percentage and proportion. However, chi-square test was used to determine the significance between the sensitivity level of antimicrobials commonly used for both gram-negative and gram-positive microorganisms using SPSS 20 software (SPSS South Asia Pvt. Ltd. No.2353/1-4, 4th Floor, Dolphin, Hennur, Bengaluru, Karnataka, India). P ≤ 0.05 was considered significant.
Among the 313 resistant gram-negative isolates, ESBLs, AmpC, MBLs, and inhibitor-resistant beta-lactamases (IRT) were detected in 193 (61.66%), 42 (13.42%), 59 (18.85%), and 9 (2.88%) isolates, respectively. The coexistent phenotypes of ESBLs with AmpC and ESBLs with MBL were observed in five (1.6%) isolates each. From the 127 gram-positive resistant isolates, 41 (32.28%), 62 (48.82%), and 24 (18.9%) isolates were methicillin-resistant S. aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCNS), and VRE, respectively. The distribution of the microorganisms against the various resistant mechanisms is shown in [Table 1].
The age of the patients included in this study ranged from 7 months to 91 years, with 75% of them belonging to the age group of 15-50 years. Out of the 440 isolates, 366 (83.18%) were isolated from female patients and 74 (16.81%) from male patients. However, 68% of the isolates were recovered from the inpatient departments. Antimicrobial activity of nitrofurantoin against the various resistant patterns is shown in [Table 2]. The proportion of isolates sensitive to nitrofurantoin was substantially higher (90%) for gram-positive as compared to gram-negative (58%) isolates (P < 0.001). Nitrofurantoin showed better susceptibility pattern than gentamicin, ciprofloxacin, and TMP-SMX in both gram-positive and gram-negative isolates [Table 3].
The rapid development and spread of antimicrobial resistance among bacteria is a growing threat and major public health concern. This study highlights an update on the susceptibility of resistant gram-negative and gram-positive uropathogens to nitrofurantoin and other commonly used antibiotics. In 1999, the Infectious Diseases Society of America (IDSA) published a clinical practice guideline on the treatment of women with acute uncomplicated cystitis and pyelonephritis mentioning TMP-SMX and fluoroquinolones as the first-line antimicrobial agents for the treatment of such infections. [12] However, the 2011 IDSA guidelines recommended nitrofurantoin as the first-line empirical therapy for uncomplicated UTIs. [13] Recently, there has been a new interest in rediscovering newer applications for older antibiotics due to alterations in pathogen distribution and resistance. Nitrofurantoin is a synthetic nitrofuran antimicrobial agent that has been used for years and still continues to be active against most of the uropathogens including the multiresistant strains, and prescribed especially in its macro-crystalline formulation, macrodantin, particularly in the ambulatory setting for uncomplicated UTIs. [14] The mechanism of action of nitrofurantoin is not well-understood but activity appears to require enzymatic reduction within the bacterial cell and the reduced derivatives appear to be capable of binding to ribosomal proteins. [15] Moreover, the antibacterial activity has also been observed under conditions in which nitroreductase activity was inhibited, suggesting that nitrofurantoin may act, in part, without reduction of active metabolites. [15] Absorption rate of oral nitrofurantoin is 40-50%, and this is enhanced when it is taken with food; serum concentrations are low to undetectable and urine concentrations are 50-250 mg/L. It should not be used in neonates and patients with renal failure. It can be safely used in pregnant women except at term. [4] The present study demonstrated that the rate of sensitivity to nitrofurantoin among the gram-negative isolates was maximum for ESBLs (70%) and least for ESBLs with MBLs (20%). The sensitivity rates for IRT, AmpC, and MBLs were 66%, 38%, and 32%, respectively. The rate of resistance to nitrofurantoin in recent surveys in the USA and Canada among the ESBL isolates was 1.1% among the 1,142 isolates of E. coli from outpatient urinary isolates. [16] Very similar results were found in France where 1.8% of all urinary E. coli isolates were resistant to nitrofurantoin in 2005. [17] High sensitivity rates of 88% and 90%, both against ESBL isolates, were obtained by Pai et al. (India) and Sire et al. (Senegal), respectively. [18],[19] E. coli resistance to nitrofurantoin has been reported to be high in a recent survey in Latin American hospitals and in Italy. [20],[21] In our study, the susceptibility rate of E. coli among the ESBL isolates for nitrofurantoin was 65% while that of K. pneumoniae was 5%. Liu et al. reported a sensitivity of 79% for ESBL-associated E. coli and high resistance rate (87%) for K. pneumoniae. [22] There is a paucity of data regarding the sensitivity to this antimicrobial for other types of beta-lactamases. Moreover, Pulcini et al. reported high activity for ESBL to this antibiotic and no activity for other beta-lactamases. [23] Nitrofurantoin is increasingly being used at present to treat VRE nosocomial UTIs (i.e., catheter-associated bacteria), and oral antibiotics are preferred for nosocomial vancomycin-sensitive Enterococcus (VSE) or VRE catheter-associated bacteriuria. [24] Pulcini et al. reported high activity of nitrofurantoin against MRSA and VRE. [23] Our study demonstrated high activity of nitrofurantoin against MRSA (95%) and MRCNS (96%) uropathogens. However, the sensitivity rate was lowered to 66% for VRE isolates. The present study reflected that the sensitivity rates of nitrofurantoin, ciprofloxacin, and TMP-SMX were significantly higher (P < 0.001) in gram-positive than gram-negative resistant isolates. The activity of gentamicin was slightly better for gram-negative isolates (57%). Among the commonly used antimicrobials for uropathogens, nitrofurantoin (67.5%) turned out to be the most effective followed by gentamicin (56.82%), TMP-SMX (32.73%), and ciprofloxacin (17.27%). Similar findings were shown by Pai et al. and Bhat et al. [18],[25] High fluoroquinolone resistance rates of 89.9% and 69% were reported by Francesco et al. and Tankhiwale et al. respectively. [26],[27] This study highlights nitrofurantoin as an important treatment option for uncomplicated UTIs in the current era of increasing fluoroquinolone and TMP-SMX resistance among uropathogens. The employment of nitrofurantoin as the first-line therapy may definitely contribute to a reduction in overall fluoroquinolone use, thereby helping to reduce selection pressure for increased resistance to fluoroquinolones. The limitation of this study was the lack of inclusion of fosfomycin due to the unavailability of this antimicrobial during the study period. This agent, used to treat UTI for nearly 40 years, is increasingly becoming important to treat UTI because the resistance rate of uropathogens to common antimicrobial agents is increasing and it is indeed necessary to assess the susceptibility status of this antibiotic. Other limitations include employment of the Vitek2 for IRT or VRE detection, inability to perform agar dilution method for VRE detection and molecular techniques for confirming the different antimicrobial resistances could not be accessed due to lack of infrastructure.
The emergence of antibiotic resistance and the decline in newly developed antibiotics have led to an increasing interest in the treatment and prophylaxis of bacterial UTI with nitrofurantoin because of its safety profile and resistance to this antibiotic remained virtually unchanged since its discovery. In this new microbiological era characterized by multidrug resistant pathogens, nitrofurantoin’s role is very crucial. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3] |
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