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Letter
Quinolone Safety and Efficacy
More Important than Potency
Richard Frothingham*
*Veterans Affairs Medical Center and Duke University Medical Center, Durham,
North Carolina, USA
Suggested citation
for this article:
Frothingham R. Quinolone safety and efficacy more important than potency.
Emerg Infect Dis [serial online] 2004 Jan [date cited]. Available
from: URL: http://www.cdc.gov/ncidod/EID/vol10no1/03-0307.htm
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 for known or
suspected Pseudomonas aeruginosa infection and moxifloxacin for
infections in which Streptococcus pneumoniae is likely, including
community-acquired pneumonia (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, moxifloxacin,
and gatifloxacin). On the basis of spontaneous reports to the U.S. Food
and Drug Administration (FDA), gatifloxacin is associated with a higher
rate of torsades de pointes 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 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 moxifloxacin (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 (U.S. National Library of Medicine, Bethesda, MD) search
in April 2003 provided the following raw numbers of peer-reviewed, randomized,
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 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 P. aeruginosa infections can be affirmed. Ciprofloxacin
has pharmacodynamic potency against P. 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 CAP. 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.
References
- Scheld WM. Maintaining
fluoroquinolone class efficacy: review of influencing factors. Emerg
Infect Dis 2003;9:1–9.
- Frothingham R. Rates
of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin,
gatifloxacin, and moxifloxacin. Pharmacotherapy 2001;21:1468–72.
- 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.
- Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor
DH. Timing
of new black box warnings and withdrawals for prescription medications.
JAMA 2002;287:2215–20.
- Shaffer DN, Singer SJ. Macrolide antibiotics and torsades de pointes
postmarketing analysis, slide 42. Presented at the FDA Center for Drug
Evaluation and Research Anti-Infective Drugs Advisory Committee, April
26, 2001. [cited 2003 April 24] Available from: URL: http://www.fda.gov/ohrms/dockets/ac/01/slides/3746s_02_Shaffer/sld042.htm
- Top 200 brand and generic drugs by units in 2001. Drug Topics 2002(5);38.
Available from: http://www.drugtopics.com
- Top 200 brand and generic drugs sold in 2002 by units. Drug Topics
2003(6);60. Available from: http://www.drugtopics.com
- Finch R, Schurmann D, Collins O, Kubin R, McGivern J, Bobbaers H,
et al. Randomized
controlled trial 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 treatment. Antimicrob Agents Chemother 2002;46:1746–54.
- 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 and/or cefuroxime axetil
in treatment of adults with community-acquired pneumonia. Antimicrob
Agents Chemother 1997;41:1965–72.
- 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. Scand J Infect Dis 1998;30:397–404.
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