Quinolone safety and efficacy more important than potency.
To the Editor: In a recent article, Scheld defines two principles for appropriate quinolone use based on the goal of maintaining class efficacy, namely avoiding unnecessary antimicrobial drug therapy and "using the agents with optimal activity against the expected pathogens" (1). He presents a large body of evidence supporting an inverse correlation between quinolone activity and the selection of antimicrobial drug resistance. On the basis of this concept, Scheld favors ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt.
n. for known or suspected Pseudomonas aeruginosa Pseudomonas aeruginosa A normal soil inhabitant and human saprophyte that may contaminate various solutions in a hospital, causing opportunistic infection in weakened Pts Clinical Infective endocarditis in IVDAs, RTIs, UTIs, bacteremia, meningitis, 'malignant' infection and moxifloxacin for infections in which Streptococcus pneumoniae Streptococcus pneu·mo·ni·ae
Streptococcus pneumoniae Microbiology A pathogenic streptococcus with 90 serotypes associated with pneumonia, bacteremia, meningitis Transmission Person to person Incidence is likely, including community-acquired pneumonia community-acquired pneumonia Pneumonia caused by an infection currently present in the community; CAP is the most common cause of infectious death–US, and number 6 killer overall; of the 57% of CAPs in which a pathogen is identified, S pneumoniae (CAP). Preventing the emergence of antimicrobial drug resistance is certainly an important goal in drug therapy decision-making. However, this goal should be balanced by the clinical criteria of safety and efficacy.
Serious adverse drug effects in patients led to the withdrawal or restriction of four quinolones in the past decade (temafloxacin, grepafloxacin, trovafloxacin, and sparfloxacin). Safety may differ substantially among the quinolones discussed in Scheld's review (ciprofloxacin, levofloxacin, moxilloxacin, and gatifloxacin). On the basis of spontaneous reports to the U.S. Food and Drug Administration (FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. ), gatifloxacin is associated with a higher rate of torsades de pointes Torsades de pointes or torsades is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific variety of ventricular tachycardia that exhibits distinct characteristics on the than ciprofloxacin or levofloxacin (p = 0.001) (2). Torsades cases have been reported in association with moxifloxacin, but their rate cannot be estimated with any precision by using FDA spontaneous reporting data because of the relatively small number of U.S. prescriptions (2). In a crossover study, a single oral dose of moxifloxacin 800 mg was associated with greater QT interval QT interval
the portion of an electrocardiogram between the onset of the Q wave and the end of the T wave, representing the total time for ventricular depolarization and repolarization. prolongation (16-18 milliseconds) than ciprofloxacin 1,500 mg (2-5 milliseconds) or levofloxacin 1,000 mg (4-5 milliseconds) (3). Gatifloxacin has been associated with alterations in glucose metabolism, both in prospective trials and in postmarketing surveillance. Gatifloxacin underwent two "safety-related drug labeling changes" in 2001 and is the only quinolone that carries a "warning" about disturbances in glucose metabolism. Gemifloxacin was approved after Scheld's review and has pharmacodynamic potency similar to moxifloxacin against S. pneumoniae. Gemifloxacin is associated with a high rate of rashes, especially in women <40 years of age.
Serious but uncommon adverse side effects may not be recognized until drugs are used in large populations (4). More than 100 million prescriptions were written for terfenadine and astemizole before they were withdrawn from the market because of torsades and sudden death. On the basis of the number of U.S. prescriptions in the past decade (January 1993-December 2002), patient experience with ciprofloxacin (119 million prescriptions) and levofloxacin (44 million) is larger than with gatifloxacin (8 million) or moxilloxacin (5 million) (5-7).
The clinical efficacy of ciprofloxacin and levofloxacin is better established for a broad range of indications in comparison to the newer agents. A full discussion of the literature is beyond the scope of this letter. A simple MEDLINE The online medical database of the U.S. National Library of Medicine (NLM) whose parent is the National Institutes of Health, Bethesda, MD. MEDLINE contains millions of articles from thousands of medical journals and publications. The consumer section of the site (http://medlineplus. (U.S. National Library of Medicine Noun 1. U.S. National Library of Medicine - the world's largest medical library
National Library of Medicine, United States National Library of Medicine , Bethesda, MD) search in April 2003 provided the following raw numbers of peer-reviewed, randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. , controlled trials reporting clinical outcomes: >200 trials using ciprofloxacin, 28 using levofloxacin, 13 using moxifloxacin, 7 using gatifloxacin, and 6 using gemifloxacin (search terms, inclusion criteria, and exclusion criteria available from the author). The quality of these studies is quite variable, and quality is certainly more important than quantity. Most trials of the newer agents were designed and funded by industry. In general, ciprofloxacin and levofloxacin have been studied in patient populations with more severe illnesses, including nosocomial infections, than the newer quinolones. With the exception of a single moxifloxacin trial (8), the trials of the newer quinolones have enrolled patients with predominantly mild or moderate community-acquired infections and low overall mortality rates.
Scheld provides a table that lists case reports of clinical failures of levofloxacin for the treatment of pneumococcal pneumococcal /pneu·mo·coc·cal/ (-kok´al) pertaining to or caused by pneumococci. infections. Some cases were associated with primary or secondary levofloxacin resistance. These case reports should not be surprising, since CAP trials regularly identify clinical failures regardless of the therapy chosen. The rate of clinical failure is best determined by data from prospective trials rather than case reports. Both levofloxacin and moxifloxacin have performed well in patients with severe pneumococcal infections, on the basis of the rates of therapeutic success and death (8-10).
Scheld's choice of ciprofloxacin as a component of combination therapy for suspected R aeruginosa infections can be affirmed. Ciprofloxacin has pharmacodynamic potency against aeruginosa, a track record of safety in large populations, and a large published literature. Ciprofloxacin has demonstrated efficacy in patient populations with severe illnesses, including nosocomial infections.
Antimicrobial drug therapy decision-making for patients with CAP and other respiratory tract infections is much more complex. Individual patient factors should be considered, including the severity of illness, coexisting illnesses, risk factors for drug-resistant S. pneumoniae, and risk factors for specific adverse effects. A respiratory quinolone will be an appropriate choice for some patients with CAR Among the respiratory quinolones, a wholesale switch from levofloxacin to moxifloxacin, on the basis of pneumococcal potency alone, would be premature. Clinicians should use newer quinolones cautiously until their safety has been established in large patient populations.
(1.) Scheld WM. Maintaining fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid.
n. class efficacy: review of influencing factors. Emerg Infect Dis 2003;9:1-9.
(2.) Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy pharmacotherapy /phar·ma·co·ther·a·py/ (-ther´ah-pe) treatment of disease with medicines.
Treatment of disease through the use of drugs. 2001;21: 1468-72.
(3.) Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther 2003;73:292-303.
(4.) Lasser KE, Allen PD, Woolhandler SJ, Himmlelstein DU, Wolfe SM, Bur DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA JAMA
Journal of the American Medical Association 2002;287:2215-20.
(5.) Shatter DN, Singer SJ. Macrolide antibiotics and torsades de pointes postmarketing analysis, slide 42. Presented at the FDA Center for Drug Evaluation and Research The Center for Drug Evaluation and Research is a division of the FDA that deals with the approval of drugs. CDER reviews New Drug Applications to ensure that the drugs are safe and effective. It is one of five Centers at the United States Food and Drug Administration. Anti-Infective Drugs Advisory Committee, April 26, 2001. [cited 2003 April 24] Available from: URL URL
in full Uniform Resource Locator
Address of a resource on the Internet. The resource can be any type of file stored on a server, such as a Web page, a text file, a graphics file, or an application program. : http://www.fda. gov/ohrms/dockets/ac/01/slides/3746s_02_ Shaffer/sld042.htm
(6.) Top 200 brand and generic drugs by units in 2001. Drag Topics 2002(5);38. Available from: http://www.drugtopics.com
(7.) Top 200 brand and generic drugs sold in 2002 by units. Drug Topics 2003(6);60. Available from: http://www.drugtopics.com
(8.) Finch R, Schurmann D, Collins O, Kubin R, McGivern J, Bobbaers H, et al. Randomized controlled trial A randomized controlled trial (RCT) is a scientific procedure most commonly used in testing medicines or medical procedures. RCTs are considered the most reliable form of scientific evidence because it eliminates all forms of spurious causality. of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral parenteral /pa·ren·ter·al/ (pah-ren´ter-al) not through the alimentary canal, but rather by injection through some other route, as subcutaneous, intramuscular, etc.
1. treatment. Antimicrob Agents Chemother 2002;46:1746-54.
(9.) File TM Jr, Segreti J, Dunbar L, Player R, Kohler R, Williams RR, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone ceftriaxone /cef·tri·ax·one/ (cef?tri-ak´son) a semisynthetic, ß–resistant, third-generation cephalosporin effective against a wide range of gram-positive and gram-negative bacteria, used as the sodium salt. and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965-72.
(10.) Norrby SR, Petermann W, Willcox PA, Vetter N, Salewski E. A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia. Stand J Infect Dis 1998;30:397-404.
Richard Frothingham *
* Veterans Affairs Medical Center end Duke University Medical Center, Durham, North Caroline, USA
Address for correspondence: Richard Frothingham, Durham VA Medical Center, 508 Fulton St, Building 4, Durham, NC 27705, USA; fax: 919 286 0264; email: richard.frothingham @duke.edu