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Abstract & Commentary
Synopsis: Nitrofurantoin still appears uniformly active against vancomycin-resistant enterococci in cystitis.
Source: Zhanel GG, et al. Antimicrob Agents Chemother. 2001;45:324-326.
Zhanel and colleagues tested 300 strains of enterococci collected in an ongoing Canadian surveillance study and tested them for susceptibility to nitrofurantoin. These included 100 strains of vancomycin-susceptible Enterococcus faecalis, 100 strains of vancomycin-susceptible E faecium, 50 strains of vancomycin-resistant E faecium, 25 strains of vancomycin-susceptible E gallinarum, and 25 strains of vancomycin-resistant E gallinarum. All were from stool samples from different patients and carefully identified and confirmed to be enterococci.
The 300 isolates were tested using NCCLS criteria with a panel of antibiotics including ampicillin, streptomycin, teicoplanin, ciprofloxacin, quinupristin-dalfopristin, and nitrofurantoin. The vancomycin-susceptible E faecium strains were highly resistant to ampicillin and the aminoglycosides, but the E faecalis strains were susceptible. Both were usually resistant to ciprofloxacin and some were resistant to quinupristin-dalfopristin as well. Remarkably, all isolates were susceptible to nitrofurantoin with MICs less than 1:128.
Comment by Alan D. Tice, MD, FACP
Enterococci have gone from being commensal, colonizing bacteria of the upper intestinal tract to one of the most feared and resistant organisms humans are faced with. They have clearly increased associated mortality and morbidity in hospitals and oncology units. They were the first of the common Gram-positive pathogens to become resistant to essentially all antibiotics available for systemic infections. Fortunately, they are not as inherently virulent and toxic as many of the other Gram-positive bacteria and may lie dormant in a normal host unless disturbed by alterations in the local microflora or by tissue trauma. Unfortunately, the stimuli for growth and the opportunities to cause disease are frequent and becoming more so with increasing use of potent antibiotics and immunosuppressives as well as surgery.
In the relatively normal host, enterococci play little role in disease. The exceptions are endocarditis and the urinary tract where they find their way into the bladder and sometimes the prostate or a kidney when the opportunities arise with faulty collecting systems. They account for about 5% of the bacteria causing uncomplicated cystitis in women and were commonly treated with ampicillin until they took a quantum leap in antibiotic resistance mechanisms that now may include enzyme production, aminoglycoside resistance, and the presence of Van A, B, or C coding for vancomycin resistance. While many E faecalis strains remain susceptible to ampicillin, an increasing number are resistant to gentamicin at high levels. E faecium is less frequently encountered but much more likely to be associated with ampicillin, gentamicin, and vancomycin resistance. E gallinarum is even less frequently a pathogen but is "intrinsically resistant" to vancomycin along with E cassiflavus. They can carry the VanC gene for vancomycin resistance although many strains retain their susceptibility to gentamicin and even ampicillin. There are some reports of a small percentage of enterococci with resistance to nitrofurantoin in the literature but most laboratory employees I have spoken with have not seen a strain.1
How frequently enterococci cause significant disease and what percentage of them are vancomycin resistant is unknown. It is clear, however, that the frequency of vancomycin resistance varies geographically. A recent report suggests half of enterococci isolated from patients in Santa Monica, Calif, are resistant to vancomycin.2
Nitrofurantoin offers an unusual opportunity to fight a new super bug with an old, cheap, and effective agent—almost a David and Goliath situation. Unfortunately, the circumstances for success are limited to infection of the urinary tract and, then, even further to the bladder. There are, nevertheless, reasons to keep the sling shot in your pocket and be ready to use it when a possible enterococci UTI appears in your office.
Exactly why nitrofurantoin has not fallen to the resistance mechanisms of enterococci after more than 20 years is unknown. It is a cousin of both furzolidone and fusidic acid, which is used for resistant Gram-positive infections in some countries. Although its mechanism of action remains unclear, it appears to act in the nucleic acid replication process. That is thought to be why it is antagonistic with the quinolones. Its resistance could also be related to its limited use in humans and possibly animal feed as well.
Although nitrofurantoin has a long and successful career in UTIs, there are a number of limitations and cautions in regard to its use. It does not reach effective concentrations other than in the urine so it should not be used for systemic infections and is of doubtful value in even kidney and prostate disease. It may be used in pregnancy but not during the third trimester as delivery may expose the immature renal system of the fetus to an agent it cannot metabolize. Although it is assumed that in vitro activity correlates with in vivo success with nitrofurantoin for VRE UTIs, the studies have not been done to prove it with actual clinical trials.
Nitrofurantoin also has side effects, some of which can be severe. Gastrointestinal upset and headache are not unusual. It may cause a hemolytic anemia—especially with G6PD deficiency. It may also cause a neuropathy, leukopenia, hepatitis, and, at times, an unusual but classic pneumonitis that may be life threatening and associated with fever and often eosinophilia.
For uncomplicated cystitis, it should be given for 7 instead of 3 days to avoid relapses and to be sure of eradication. It may also be used for prophylaxis or, perhaps, suppression of UTIs, but the likelihood of adverse effects such as the pulmonary syndrome increases with time.
While nitrofurantoin will remain a mainstay for the therapy of cystitis, it may be worth considering alternatives, especially with increasing resistance of the Gram-positive organisms such as the enterococci. As mentioned, some of even the VRE may remain susceptible to ampicillin. Cipro may also be active despite susceptibility testing. Linezolid may also be considered and is now FDA approved for therapy. Intravenous therapy with quinupristin-dalfopristin is an added consideration for recalcitrant or systemic infections due to susceptible E faecium.
1. Moellering RC. Clin Infect Dis. 1998;26:1196-1199.
2. Message on the Emerging Infections Network from Ellie Goldstein in Santa Monica, Calif.