Letters to the Editor

Possible Drug Interactions Among Quinolones

TO THE EDITOR: The article1 on quinolones by Drs. Oliphant and Green was an excellent review of this important, yet often overly prescribed, class of antibiotics. We would like to commend the authors for increasing awareness of the emerging resistance to these agents. However, we would like to further elucidate some of the other issues addressed in the article.

The article1 states that levofloxacin is an effective first-line agent for the treatment of prostatitis, but that "ciprofloxacin should be reserved for use in patients with resistant gram-negative, pseudomonal, and enterococcal prostatitis, because of its superior activity against [Pseudomonas] aeruginosa and enterococci." The minimum inhibitory concentration (MIC) of levofloxacin (MIC = 4) is usually greater than the activity of ciprofloxacin (MIC = 16). In 2001, we found at our institution that 57 percent of all enterococcal isolates were susceptible to levofloxacin, while only 30 percent were susceptible to ciprofloxacin.

Another issue concerns the penetration of fluoroquinolones into the cerebrospinal fluid (CSF). We agree with the authors' statement that these agents should not be considered as first-line treatment for meningitis. However, CSF concentrations of fluoroquinolones are approximately 20 to 50 percent those of serum in noninflamed meninges.2 In comparison, CSF concentrations of third-generation ceph-a-losporins range from 10 to 40 percent those of serum in inflamed meninges. High-dose ciprofloxacin has been used to treat multidrug-resistant gram-negative meningitis with favorable outcomes.2

Also, the information on the potential interactions between quinolones and other drugs presented in Table 3 of the article1 could possibly be misleading to some readers. Although four case reports have suggested a possible pharmacokinetic or pharmacodynamic drug interaction between cyclo-sporine and cipro-floxacin, many pharma-cokinetic studies have refuted this suspicion.3 Literature discussing the interaction implies that cipro-floxacin has an antagonistic action on the immunosuppressive effect of cyclosporine.4 The significance of this interaction remains controversial. In addition, levofloxacin does not seem to interact pharmacokinetically with cyclosporine.5

Ciprofloxacin may cause an average increase in serum theophylline levels of 50 to 60 percent.2 However, the newer fluoroquinolones (moxifloxacin, gemifloxacin, gatifloxacin, levofloxacin, and trova-floxacin), appear to have no significant effect on theophylline metabolism.2 Ciprofloxacin also has been shown to interact unpredictably with warfarin. Apparently, if warfarin is used concomitantly with one of the newer fluoroquinolones, the combination does not usually result in an increased international normalized ratio (INR).2 Though one pharmacokinetic study states that no interaction exists between levofloxacin and warfarin, three publications describing eight patients (75 percent were elderly with age greater than 70 years and co-morbidities) have reported an enhanced anticoagulant effect of warfarin when levofloxacin was added (INR up to 11.5). More research is needed to determine the true nature and significance of the interactions between warfarin and levofloxacin.2,6

Beata M. DomagalA, Pharm.D.
Simon Leung, Pharm.D.
Randolph E. Regal, B.S., Pharm.D.
University of Michigan Health System
1500 E. Medical Center Dr.
UH B2D 301 Box 0008
Ann Arbor, MI 48109

REFERENCES

1. Oliphant CM, Green GM. Quinolones: a comprehensive review. Am Fam Physician 2002;65:455-64.

2. Aminimanizani A, Beringer P, Jelliffe R. Com-parative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001;40:169-87.

3. Hoey LL, Lake KD. Does ciprofloxacin interact with cyclosporine? Ann Pharmacother 1994;28:93-6.

4. Wrishko RE, Levine M, Primmett DR, Kim S, Partovi N, Lewis S, et al. Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients. Transplantation 1997;64:996-9.

5. Doose DR, Walker SA, Chien SC, Williams RR, Nayak RK. Levofloxacin does not alter cyclosporine disposition. J Clin Pharmacol 1998;38:90-3.

6. Jones CB, Fugate SE. Levofloxacin and warfarin interaction. Ann Pharmacother 2002;36:1554-7.

Herbal Products Should Be Regulated for Quality Control

TO THE EDITOR: The excellent review1 of the dietary supplement valerian by Drs. Hadley and Petry will be very helpful for family physicians. However, physicians are still faced with the confusing process of determining which particular manufacturer and product of these herbal preparations to recommend to their patients.

Unfortunately, studies conducted by objective investigators have concluded that quality control standards for dietary supplements in the United States range from good to nonexistent. The most disturbing evidence comes from studies2 demonstrating the adulteration of dietary supplements with pharmaceuticals. Other studies2 have discovered products that are contaminated with heavy metals or pesticides.

Another significant problem with dietary supplements in the United States is the substantial discrepancies between the labeled contents and the actual amounts found in the dosage units. Such inaccuracies have been demonstrated for many dietary supplements,2 including valerian.3 In addition, supplement content, even from the same manufacturer, can vary widely from lot to lot.2

This information illustrates an apparent lack of interest in product quality by many dietary supplement manufacturers or, in the worst cases, fraudulent behavior. In either case, the prevalence of low-quality products increases the risks of ineffective supplements or adverse reactions to supplements.

We believe that quality testing of these products is in the best interest of public safety. Only one independent group has tested valerian. In 2000, www. ConsumerLab.com tested 17 valerian products purchased off the shelf in the United States.3 Five products listed one or more additional herbs. The products were analyzed for their total valeric acid content to determine if they possessed the type and amount of valerian stated on the label. The testing method and passing scores are available on the Web site. Only nine of the 17 products passed. Unfortunately, a 47 percent failure rate is not unusual for these products. For example, www.ConsumerLab.com has tested over 700 brands of dietary supplements; 30 to 40 percent of the herbal products did not pass. Of the eight valerian products that failed quality testing, four had no detectable levels of the expected valeric acids, and the other four had only one half the expected or claimed amounts.

The World Health Organization4 and the American Medical Association5 have called for significant regulatory changes for dietary supplements. The U.S. Food and Drug Admini-stration has expressed concern about the increasing incidence of adverse reactions to impure or contaminated dietary supplements and is developing plans to improve the regulation regarding both quality manufacturing practices and truth in labeling.6

We recommend that physicians writing reviews on dietary supplements guide their readers on how to find and recommend safe and high-quality dietary supplements to their patients. Under the current lack of regulatory oversight in the United States, otherwise excellent dietary supplement reviews run the risk of being less helpful to family physicians and even dangerous to our patients.

Walter L. Larimore, M.D.
University of Colorado, Denver
8605 Explorer Dr.
Colorado Springs, CO 80920-1051

Donal p. O'Mathúna, Ph.D., M.A.
Mount Carmel College of Nursing
127 S. Davis Ave.
Columbus, OH 43222-1564

REFERENCES

1. Hadley S, Petry JJ. Valerian. Am Fam Physician 2003; 67:1755-8.

2. Larimore WL, O'Mathúna DP. Quality assessment programs for dietary supplements. Ann Pharmaco-ther 2003;37:893-8.

3. Product review: Valerian. Accessed January 14, 2004 at: http://www.consumerlab.com/results/valerian.asp.

4. WHO looks to monitor safety of traditional medicines. Reuters News, June 25, 2002.

5. An assurance of safety: Treat supplements like drugs. Am Med News. November 11, 2002. Accessed January 14, 2004, at: http://www.ama-assn.org/amednews/2002/11/11/edsa1111.htm.

6. Levitt JA. Regulation of dietary supplements: FDA's strategic plan. Food Drug Law J 2002;57:1-13.

Correction

The editorial "Clinical Inquiries from the Family Practice Inquiries Network" (Decem-ber 15, 2003, page 2340) contained an error in the description of the network's online database of clinical answers. The database is accessible to member institutions of the network, rather than to paid subscribers.

Send letters to Jay Siwek, M.D., Editor, American Family Physician, 11400 Tomahawk Creek Pkwy., Leawood, KS 66211-2672; fax: 913-906-6080; e-mail: afplet@ aafp.org. Please include your complete address, telephone number, and fax number. Letters should be submitted on disk, double-spaced, fewer than 500 words, and limited to one table or figure and six references. Please submit a word count. Letters submitted for publication in AFP must not be submitted to any other publication. Possible conflicts of interest must be disclosed at time of submission. Submission of a letter will be construed as granting the AAFP permission to publish the letter in any of its publications in any form. The editors may edit letters to meet style and space requirements.