Abstract
The activity of nitrofurantoin was tested against 300 isolates of Enterococcus faecium, Enterococcus faecalis, and Enterococcus gallinarum. No isolates tested were resistant to nitrofurantoin (MIC, ≥128 μg/ml), including vancomycin-resistant E. faecium isolates with vanA- and vanB-positive genotypes and vancomycin-resistant E. gallinarum isolates. We conclude that nitrofurantoin may provide effective treatment of urinary tract infections caused by vancomycin-resistant enterococci.
Enterococci are constitutive members of the intestinal flora of humans and animals but may also colonize the upper respiratory tracts, biliary tracts, and vaginas of otherwise healthy persons. The isolation of clinical isolates of enterococci generally denotes colonization rather than infection; however, enterococci may also cause infection, most commonly, urinary tract infection, but also cholecystitis, cholangitis, peritonitis, septicemia, endocarditis, meningitis, and simple wound infections (5). Although more than a dozen species of Enterococcus have been identified, two species, Enterococcus faecalis and Enterococcus faecium, account for approximately 85 to 90% and 5 to 10% of human enterococcal infections, respectively. The emergence of vancomycin resistance, most commonly in E. faecium, has introduced additional challenges to therapy, as these isolates are frequently resistant to additional antibiotics as well. The purpose of the current study was to assess the activities of nitrofurantoin and comparative antibiotics against isolates of E. faecium, E. faecalis, and Enterococcus gallinarum including vancomycin-resistant isolates.
The E. faecium, E. faecalis, and E. gallinarum stool isolates tested in this study were taken from previous and ongoing Canadian surveillance studies of vancomycin-resistant enterococci (VRE) (8, 17). In total, 100 vancomycin-susceptible E. faecium isolates, 100 vancomycin-susceptible E. faecalis isolates, 50 vancomycin-resistant E. faecium isolates, 25 vancomycin-susceptible E. gallinarum isolates, and 25 vancomycin-resistant E. gallinarum isolates were tested. Each stool isolate was from a different patient (8, 17) and had been identified to the species level by a conventional algorithm (4) supplemented with methyl-α-d-glycopyranoside testing (16). The identities of all discrepant organisms were determined by 16S rRNA gene sequencing (16). The genotypes of vancomycin-resistant isolates were determined by a previously described multiplex PCR protocol for vanA, vanB, vanC1 and vanC2-vanC3 (3).
Antibiotics for susceptibility testing were obtained from their various manufacturers as standard powders. Prior to antibiotic susceptibility testing all isolates were subcultured twice onto blood agar. MICs were determined by the standard broth microdilution method of NCCLS (M7-A4) with Mueller-Hinton broth (11) and were interpreted by using the breakpoints suggested by NCCLS (12).
None of the 300 isolates of enterococci tested were resistant to nitrofurantoin (MICs, ≥128 μg/ml) including vancomycin-resistant isolates of E. faecium with the vanA or vanB genotype and vancomycin-resistant E. gallinarum isolates with vanC genotypes (Table 1). Isolates of E. faecium positive for vanA and vanB demonstrated uniform phenotypic resistance to ampicillin, streptomycin, and ciprofloxacin, while they retained their susceptibility to quinupristin-dalfopristin. The percent susceptibilities for isolates of vancomycin-susceptible E. faecium, E. faecalis, and E. gallinarum are presented in Table 1. Rates of resistance to ampicillin, gentamicin, streptomycin, and ciprofloxacin were lower among vancomycin-susceptible enterococci than among vancomycin-resistant isolates. Quinupristin-dalfopristin demonstrated less potent activity against E. faecalis than against E. faecium and E. gallinarum, which is consistent with previously published data (8). The distributions of MICs of nitrofurantoin for all isolates of enterococci tested are presented in Table 2. Nitrofurantoin was less active against E. faecium than against E. faecalis and E. gallinarum. All isolates of E. faecalis and E. gallinarum were susceptible to nitrofurantoin, while 92 and 8% of E. faecium isolates were nitrofurantoin susceptible and nitrofurantoin intermediate, respectively.
TABLE 1.
Antibiotic susceptibilities for isolates of E. faecium, E. faecalis, and E. gallinaruma
| Organism | No. of isolates | MIC90 (μg/ml [% resistant])
|
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Nitrofurantoin | Vancomycin | Teicoplanin | Ampicillin | Gentamicin | Streptomycin | Ciprofloxacin | Q-D | ||
| VS E. faecium | 100 | 32 (0) | 1 (0) | 1 (0) | 64 (38) | 1,000 (15) | 4,000 (36) | >32 (46) | 1 (3) |
| VS E. faecalis | 100 | 8 (0) | 2 (0) | 0.5 (0) | 1 (2) | >2,000 (26) | >4,000 (11) | >32 (23) | 8 (57) |
| VS E. gallinarum | 25 | 8 (0) | 2 (0) | 0.5 (0) | 1 (0) | ≤50 (0) | ≤125 (4) | 2 (8) | 2 (8) |
| VR E. faecium | |||||||||
| VanA | 40 | 32 (0) | 256 (100) | 32 (100) | 64 (100) | >2,000 (50) | >4,000 (100) | >32 (100) | 0.5 (0) |
| VanB | 10 | 32 (0) | 16 (100) | 1 (0) | 64 (100) | 2,000 (50) | >4,000 (100) | >32 (100) | 0.5 (0) |
| VR E. gallinarum VanC | 25 | 8 (0) | 8 (100) | 0.5 (0) | 1 (0) | ≤50 (4) | ≤125 (0) | 2 (4) | 2 (8) |
VS, vancomycin-susceptible; VR, vancomycin-resistant; Q-D, quinupristin-dalfopristin; MIC90, MIC at which 90% of isolates are inhibited.
TABLE 2.
Distribution of nitrofurantoin MICs for isolates of E. faecium, E. faecalis, and E. gallinarum
| Organisma | No. of isolates | No. of isolates for which nitrofurantoin MICs (μg/ml) were as follows:
|
||||
|---|---|---|---|---|---|---|
| 4 | 8 | 16 | 32 | 64 | ||
| VS E. faecium | 100 | 1 | 9 | 2 | 80 | 8 |
| VS E. faecalis | 100 | 1 | 93 | 3 | 3 | 0 |
| VS E. gallinarum | 25 | 3 | 21 | 1 | 0 | 0 |
| VR E. faecium | ||||||
| VanA | 40 | 0 | 2 | 5 | 30 | 3 |
| VanB | 10 | 0 | 3 | 4 | 3 | 0 |
| VR E. gallinarum VanC | 25 | 3 | 21 | 1 | 0 | 0 |
VS, vancomycin-susceptible; VR, vancomycin-resistant.
The prevalence of VRE has been increasing in the United States in the past 10 years (5, 10). Approximately 70% of all vancomycin-resistant isolates of E. faecium and E. faecalis in the United States exhibit the vanA phenotype, which is characterized by resistance to vancomycin and teicoplanin and which is frequently associated with a multidrug resistance phenotype (5, 10). However, these isolates are frequently susceptible to quinupristin-dalfopristin (6, 7). Of the remaining 30% of vancomycin-resistant isolates, most exhibit a vanB phenotype, which is characterized by resistance to vancomycin and susceptibility to teicoplanin (5, 10). Vancomycin-resistant enterococci not only colonize the gastrointestinal tract but also have been associated with various infections including bacteremias, surgical site infections, peritonitis, pelvic abscesses, skin and soft tissue infections, and urinary tract infections including chronic prostatitis (1, 9, 13, 15, 17). Recently, seven cases of urinary tract infection caused by VRE were characterized (9). The urinary tract infections in five of the seven patients resolved in the absence of therapy or by removal of the Foley catheter or nephrostomy tube. The remaining two patients received nitrofurantoin, the infection resolved clinically, and negative urine cultures were documented (9). More recently, Taylor and coworkers (15) reported on a case of chronic prostatitis caused by VRE in which the organism was resistant to vancomycin, ampicillin, ciprofloxacin, and doxycycline. This organism retained susceptibility to rifampin (MIC, ≤1 μg/ml), chloramphenicol (MIC, ≤4 μg/ml), and nitrofurantoin (MIC, ≤32 μg/ml). The patient was treated with oral rifampin (600 mg/day for 6 weeks) and nitrofurantoin (200 mg four times daily for 2 weeks, followed by 100 mg four times daily for 4 weeks). The patient improved clinically, and all subsequent urine cultures were negative (15). As it is known that nitrofurantoin penetrates the prostate poorly, its exact role in the cure of this patient's infection is unclear (2). As well, clinicians should be reminded that because nitrofurantoin is retained in the blood of uremic patients, it should not be used in patients with moderate to severe renal impairment (creatinine clearance, ≤50 ml/min) (14).
Our study has demonstrated that nitrofurantoin is active against E. faecium and E. faecalis. More importantly, nitrofurantoin retained its activity against vanA- and vanB-positive isolates. Our in vitro data are consistent with the very limited clinical studies that suggest that nitrofurantoin may be effective in the treatment of VRE infections associated with the urinary tract.
Acknowledgments
George G. Zhanel is supported by a Merck Frosst Chair in Pharmaceutical Microbiology. This study was funded by Procter Gamble Inc., Cincinnatti, Ohio.
We thank M. Wegrzyn for expert secretarial assistance.
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