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    Fluoroquinolone use in children: Resistance and safety implications

     

    Fluoroquinolone use in children:
    Resistance and safety implications

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    By Jeffrey L. Blumer, PhD, MD

    Increased use of fluoroquinolones during the past decade has been associated with some decreased susceptibility to these agents among Streptococcus pneumoniae. Pediatricians should consider the potential for a further increase in the prevalence of antimicrobial resistance, as well as safety concerns in children, when prescribing fluoroquinolones.

    Nalidixic acid, the first quinolone antimicrobial, has been used in the treatment of urinary tract infections since the 1960s.1 During the past 40 years, newer fluoroquinolones have been developed, with a spectrum of activity that covers both gram-positive and gram-negative pathogens.2 Despite extensive clinical use of the fluoroquinolone antimicrobials in adults for a range of infectious diseases, the data on the pharmacokinetics, efficacy, and safety of fluoroquinolones in children are limited.

    Fluoroquinolones have been used in pediatric patients in select cases. Available data in children are largely the result of ciprofloxacin use in select patients with pulmonary infection, such as children with cystic fibrosis. Fluoroquinolones have also been used in cases in which potential benefit was thought to outweigh risk, such as chronic suppurative otitis media, complicated urinary tract infection, uncomplicated gonorrhea, life-threatening salmonellosis and shigellosis, antimicrobial-resistant meningitis, multidrug-resistant tuberculosis, and central nervous system (CNS) infection.3,4 (Topical fluoroquinolones approved for pediatric use are indicated for ocular infections, otitis externa, and acute otitis media in patients with pressure-equalizing tubes.)

    This article reviews the published literature describing the low but increasing prevalence of Streptococcus pneumoniae isolates with reduced susceptibility to systemic fluoroquinolones that has been observed in Canada and Hong Kong, and the potential adverse effects of systemic fluoroquinolones that clinicians should consider when prescribing these agents for children.

    Antimicrobial resistance

    A major concern with expanding the scope of fluoroquinolone therapy to include pediatric indications is the potential problem of increased fluoroquinolone resistance among strains of S pneumoniae, a common community-acquired respiratory pathogen. (See "What causes fluoroquinolone resistance?") Streptococcus pneumoniae is the most commonly reported pathogen in acute otitis media,5 community-acquired pneumonia,6 and sinusitis.7 It is also commonly implicated in meningitis and bacteremia.8 Infections caused by S pneumoniae are responsible for more than 1 million deaths worldwide each year among children younger than 5 years of age.8

    Currently, fluoroquinolones are used as last-line treatment in pediatric patients who have failed therapy with other antimicrobials or in those allergic to other classes of antimicrobials. It may be important to preserve the efficacy of fluoroquinolones by thus limiting their use because of the increasing rates of resistance to more commonly used classes of antimicrobials—namely, ß-lactam and macrolide agents.

    Since the first case report of a penicillin-nonsusceptible S pneumoniae isolate in the United States in the mid 1970s,9 resistance among S pneumoniae has continued to increase. A hospital-based pneumococcal surveillance study from 1979 to 1987 reported that isolates of S pneumoniae resistant to penicillin increased from 1.8% in 1979 to 3.6% in 1987.10 By 1994–1995, results from a national surveillance study demonstrated that the rate of nonsusceptibility to penicillin had jumped to 23.6%.11 Of 1,531 isolates of S pneumoniae collected in the winter of 1999–2000, 34.2% were not susceptible to penicillin (minimum inhibitory concentration [MIC] >0.12 µg/mL).12 Results from a US surveillance study showed significant cross-resistance between penicillins and macrolides/ azalides among isolates of S pneumoniae, with 66% of penicillin-resistant strains also demonstrating resistance to macrolide/azalide antimicrobials.13

    For this reason, as resistance to ß-lactam antimicrobials has increased during recent years, reported rates of macrolide resistance have also jumped—from 10.3% in 1994–1995 to 26.2% by 1999–2000.12 A study in the US showed a 13% increase in macrolide use between 1993 and 1999, with a 320% increase in macrolide use among children younger than 5 years of age.14 The majority of macrolide prescriptions in this population were for azithromycin: Its use increased by 1.5 million prescriptions overall between 1996 and 1999. Macrolide resistance was found in 30.6% of patients younger than 5 years of age, compared with 16.0% of patients 5 years of age and older (P <.001), the latter being a population in which the total number of macrolide prescriptions did not change during that period. Antimicrobial resistance among strains of S pneumoniae to the many classes of antimicrobials has increased, and this increase may be linked to the exposure of children to new classes of antimicrobials, suggesting a possible weakening of the effectiveness of new agents.

    (The figure labled "Rising fluoroquinolone prescriptions, reduced susceptibility among pneumococci," is available in the print edition. Adapted with permission from: Chen DK, McGeer A, DeAzavedo JC, Low DE, for the Canadian Bacterial Surveillance Network: Decreased susceptibility of Streptococcus pneumoniae to fluoroquinoloes in Canada, N Engl J Med 1999;341:233.)

    Although fluoroquinolone resistance rates in the US are relatively stable at present,12 there have been several reports of increasing incidence of S pneumoniae with decreased fluoroquinolone susceptibility in adult patients in Canada and Hong Kong in recent years.15,16 Canadian susceptibility data from 7,551 S pneumoniae isolates demonstrated that, although the overall prevalence of S pneumoniae isolates with reduced fluoroquinolone susceptibility during the 10-year period was 1% (75/7,551), the prevalence of reduced fluoroquinolone susceptibility increased from 0% (0/327) in 1988 and 1993, to 1.7% (32/1,844) in 1997–1998 (P = .01).15 During this same period, the number of fluoroquinolone prescriptions (per 100 persons per year) increased from 0.8 to 5.5 (see figure). The total MIC range of selected fluoroquinolones against 75 ciprofloxacin-resistant S pneumoniae isolates collected from 1994 through 1998 is represented in Table 1 (Adapted with permission in the print issue from Chen DK, McGeer A, DeAzavedo JC, Low DE, for the Canadian Bacterial Surveillance Network: Decreased susceptibility of Streptococcus pneumoniae to fluoroquinoloes in Canada, N Engl J Med 1999;341:233). As ciprofloxacin use increased, along with reported resistance to this agent, decreased susceptibility to other fluoroquinolones manifested as increased MICs for those agents.

     


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    Results from a multicenter study in Hong Kong in 2000 demonstrated increasing resistance to levofloxacin compared with results from a 1998 study.16 Of 180 pneumococcal isolates, 13.3% were nonsusceptible (MIC >4 µg/mL) to levofloxacin,16 an increase from 5.5% in 1998.17 Isolates not susceptible to levofloxacin demonstrated cross-resistance to other fluoroquinolones, with median MICs for gatifloxacin and moxifloxacin that were 24- and 32-fold higher, respectively, than for isolates susceptible to levofloxacin.16 These newer agents may not be useful in the treatment of infection caused by levofloxacin-nonsusceptible strains. A recent study demonstrated that treatment with older fluoroquinolones (ciprofloxacin or levofloxacin) may preclude effective treatment with newer agents (moxifloxacin or gatifloxacin).18 In this study, prior therapy with fluoroquinolones was shown to be a risk factor (odds ratio, 10.6; P <.001) for infection with levofloxacin-resistant S pneumoniae.

    Fluoroquinolones and adverse events

    The safety profiles of fluoroquinolones in adults are well established. Although there are limited safety data in children, the incidence of adverse events with ciprofloxacin in pediatric patients is similar to that seen in adults19; it is, therefore, possible to extrapolate adverse events observed in adults to children. The most commonly reported adverse events associated with the fluoroquinolones for both pediatric and adult patients include gastrointestinal, CNS, dermatologic, and hepatic effects (Table 2, Adapted with permission in the print edition from Fish DN: Fluoroquinolone adverse effects and drug interactions. Pharmacotherapy 2001;21(10 pt 2):253S). The majority of these adverse events are mild and reversible. With regard to the pediatric population, it is the less common adverse events, such as arthropathy and tendon rupture, that are of concern to clinicians when prescribing fluoroquinolones.

    Musculoskeletal. Pediatric fluoroquinolone use has been restricted because of the potential for these agents to induce cartilage toxicity in immature animals, including primates, rats, rabbits, mice, and dogs.20–25 In these animal models, fluoroquinolone use resulted in localized lesions in the cartilage of weight-bearing joints.26 Nalidixic acid, norfloxacin, ciprofloxacin, difloxacin, and ofloxacin have been associated with such cartilage changes in immature animals.20–25 The arthrogenic effects of the fluoroquinolones appear to be species-specific and drug-dependent. For example, 30 mg/kg/day of ciprofloxacin is required to induce cartilage damage in dogs, whereas 500 mg/kg/day is required to produce the same effect in rats.23

    The mechanism of fluoroquinolone-induced cartilage toxicity is unclear. It may be caused by inhibition of mitochondrial DNA synthesis within chondrocytes, direct cartilage toxicity with fluoride, or magnesium deficiency in the cartilage from chelation.27 Whatever the mechanism, histologic findings demonstrate blister formation, degeneration of the matrix, and erosion of cartilage. Approximately 1% of patients who are given a fluoroquinolone experience arthropathy, which manifests as joint pain, swelling, or stiffness in weight-bearing joints, such as the knees, elbows, or shoulders.28 Reported incidences of arthralgia associated with ciprofloxacin treatment in pediatric patients range from 1.3% to 3.2%.29–31 Note that many of these pediatric patients were given a fluoroquinolone for cystic fibrosis, and as many as 7% of patients with cystic fibrosis experience arthropathy.32 In addition, children with cystic fibrosis have a lower exercise tolerance than children who do not have this disease; this incidence may, therefore, be underrepresented.33

    Ten reports of possible fluoroquinolone-induced arthropathy in male and female patients between 14 and 17 years of age have been described in detail. These cases describe joint pain or swelling in the weight-bearing joints (knees, hips, shoulders).27,34–41 Joint swelling, pain, or both occurred after treatment with pefloxacin in the majority of these reports (7/10); two patients were treated with ciprofloxacin and one patient received nalidixic acid. However, pefloxacin is not available in the US and similar adverse events have not been reported with levofloxacin, gatifloxacin, or moxifloxacin.

    The possibility of tendinitis or tendon rupture is of even greater concern than arthropathy. Although rare (one case for every 175,000 to 800,000 daily doses), these are serious complications of fluoroquinolone use.19 Between 1985 and 1992, 100 cases of fluoroquinolone-induced tendon disorders, including 31 tendon ruptures, were reported in France.42 By 1994, the postmarketing spontaneous reporting system of the US Food and Drug Administration (FDA) had received 25 reports of tendon rupture in patients given a fluoroquinolone, three of which occurred in the US.43 These postmarketing reports of tendinitis and tendon rupture led the FDA to update the labeling on all fluoroquinolones to recommend discontinuation of treatment at the first sign of tendon discomfort or inflammation.

    Gastrointestinal. The estimated incidence of gastrointestinal adverse events following fluoroquinolone use is 2% to 20%.28 Most commonly, patients experience nausea, anorexia, or dyspepsia. Abdominal pain, vomiting, and diarrhea also occur and may be more severe. Gatifloxacin and moxifloxacin are associated with the highest incidence of nausea and diarrhea among the fluoroquinolones.

    A recent clinical trial evaluated gatifloxacin (10 mg/kg/day) for the treatment of recurrent acute otitis media in 254 children age 6 months to 7 years.44 Safety data were reported for 223 children, and the most common adverse events were vomiting (15%) and diarrhea (5%). The high rate of vomiting may have been a result of the liquid formulation, which was not very palatable. Pediatric clinical trials of ciprofloxacin have reported incidences of gastrointestinal adverse events, including nausea, vomiting, diarrhea, and abdominal pain, ranging from 4.3% to 16.4%.29,45–47

    Keep in mind that most antimicrobials cause gastrointestinal adverse events in children to a varying degree. The reported incidences of gastrointestinal adverse events in studies using common antimicrobials in pediatric patients are 11.1% (diarrhea) with amoxicillin-clavulanate (Augmentin ES-600),48 7.3% of patients treated with azithromycin (Zithromax) in phase II and phase III studies, and 15.5% of patients treated with clarithromycin (Biaxin) in phase III trials.49

    Central nervous system. CNS effects, the second most common adverse event reported in patients receiving fluoroquinolones, occur in 1% to 2% of adult patients, although this can range from 0.2% to 11% for individual agents within this class of antimicrobials.28 The most common symptoms among adult patients are headache, dizziness, and drowsiness. Other disturbances include sleep disorders (such as restlessness and insomnia), agitation, confusion, delirium, psychosis, tremor, seizure, and visual disturbances.28,50 The reported incidence of CNS adverse events with ciprofloxacin therapy among adolescents and children ranges from 0.8% to 4.8%.45–47 The potential for CNS adverse events in a pediatric population must be considered because there are many unanswered questions regarding how these effects influence school performance, language skills, and other learning processes.

    Dermatologic. Fluoroquinolones cause dermatologic adverse effects in 0.5% to 3% of patients.28,51 In pediatric clinical trials studying ciprofloxacin, dermatologic adverse events, including rash, urticaria, and pruritus, occurred in 2.4% to 15% of patients younger than 18 years.29,45–47 Although rare, phototoxic reactions, ranging from mild erythema to bullous eruptions, are more common with ciprofloxacin and levofloxacin than with moxifloxacin or gatifloxacin.27 This reaction is an important consideration for children, who often spend more time outdoors than adults. Less common dermatologic adverse effects include edema, erythema multiforme, hemorrhagic bullae, vasculitis, and dermatitis.45,50

    Clinical implications

    For the pediatric patient, the fluoroquinolones represent a new class of antimicrobials with a number of inherent advantages. They are bactericidal agents with a broad spectrum of antimicrobial activity, excellent tissue penetration, and availability in both oral and parenteral formulations. As such, they offer a therapeutic alternative to the commonly used antimicrobials in a number of clinical situations for which there have heretofore been limited options (Table 3). These drugs have been used in a number of these clinical scenarios in infants and children, with beneficial effects reported.3,29–31,45–47,52–65 The most commonly used agents have been ciprofloxacin and levofloxacin, both administered as 20 to 30 mg/kg/day in two or three divided doses. More recently, clinical trials have been reported with the 8-methoxyfluoroquinolone gatifloxacin, demonstrating effectiveness and tolerability at a dose of 10 mg/kg administered once a day. Nevertheless, caution persists with regard to the potential for bacteria to develop resistance to these agents, as well as to their safety profile in infants and children.

     

    TABLE 3
    When might you consider a fluoroquinolone for a child?

    • Pulmonary exacerbations in patients with cystic fibrosis
    • Osteomyelitis caused by Pseudomonas aeruginosa or other gram-negative bacteria
    • Acute otitis externa
    • Drug allergy (ß-lactams, macrolides)
    • Complicated urinary tract infection
    • Sexually transmitted disease
    • Persistent fever in an immunocompromised patient treated with a ß-lactam antimicrobial with or without an aminoglycoside
    • Recurrent or persistent infection despite seemingly adequate treatment with more conventional agents
    • Life-threatening salmonellosis or shigellosis

     

    Data suggest that increased use of a given class of antimicrobials leads to increased resistance in that class.15,16 There have been several reports in recent years of growing bacterial resistance to fluoroquinolones, which may be associated with increased fluoroquinolone use. This resistance may continue if widespread fluoroquinolone use extends to the pediatric population.

    In terms of the safety of fluoroquinolones in pediatric patients, data are limited. What is needed is a well-designed, prospective, clinical trial of adequate sample size that evaluates the long-term safety of fluoroquinolone use in children. The safety profiles of these agents are well established in adults, however, and may be extrapolated to the pediatric population. Fluoroquinolones are associated with a high incidence of gastrointestinal adverse events, ranging from 2% to 20% depending on the agent. CNS and dermatologic adverse events occur with measurable frequency. The potential for detrimental musculoskeletal effects, including cartilage toxicity in pediatric patients, is of special concern. Isolated cases of fluoroquinolone-induced arthropathy in children have been reported with pefloxacin, an agent unavailable for use in the US, and animal data have demonstrated that fluoroquinolones can induce cartilage damage in juvenile animals.

    Serious adverse effects, notably musculoskeletal disturbances, should be a major determining factor when considering fluoroquinolone use in the pediatric population. Exposure to a fluoroquinolone may subject a child to unnecessary risks when safe and effective alternatives are available. Because safety data in this population are limited, the International Society of Chemotherapy recommends the use of alternative effective antimicrobials for pediatric infections.65 Alternatives to fluoroquinolones, such as amoxicillin-clavulanate,5,66,67 cefprozil,68 cefixime,69 cefpodoxime,70 clarithromycin, and azithromycin,49 have a long history of efficacy and safety in children.

    Bottom line: Use appropriately and cautiously

    Fluoroquinolones should be used prudently in children, who are often colonized with respiratory pathogens such as S pneumoniae. These agents should be reserved for treatment in patients who have failed other antimicrobial therapies or in those who are allergic to ß-lactams or macrolides. Further, it may be best to reserve their use for treatment of severe infections, such as infectious exacerbations of cystic fibrosis or gastrointestinal infections caused by Salmonella or Shigella, for which few alternative antimicrobial agents are available. Pediatricians may feel constrained in their use of these agents even in these situations, because of both the absence of labeling for these drugs in pediatric patients and the warning that appears on some existing labels concerning the development of arthropathy in young animals. Although these concerns are genuine, the off-label use of drugs in pediatric patients is common and often justifiable.71

    Widespread use of fluoroquinolone antimicrobials by large groups of pediatric outpatients would open the door to adverse events and may help promote the development of antimicrobial resistance—and, ultimately, may limit the usefulness of these agents. We are fortunate, though: We already have an armamentarium of safe and effective antimicrobials for pediatric patients that precludes the need to introduce fluoroquinolones as first-line treatment of non-life-threatening infection. When conventional therapy fails or cannot be tolerated by a particular patient, however, the potential benefit of fluoroquinolone use may outweigh concerns about safety and antimicrobial resistance. In this way, the fluoroquinolones make an effective addition to our anti-infective armamentarium.

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    70. Cohen R: Clinical experience with cefpodoxime proxetil in acute otitis media. Pediatr Infect Dis J 1995;14(suppl 4):S12

    71. Blumer JL: Off-label uses of drugs in children. Pediatrics 1999;104(3 Pt 2):598

    DR. BLUMER is chief, pediatric pharmacology and critical care medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio. He receives grant/research support from, is a consultant for, and is a member of the speakers' bureau of Bristol-Myers Squibb, GlaxoSmithKline, Bayer, and Johnson & Johnson. He received editorial assistance in, and payment for, creating the manuscript of this article from Scientific Therapeutics Information, Inc, on behalf of GlaxoSmithKline.

    What causes fluoroquinolone resistance?

    Fluoroquinolones act by targeting two bacterial enzymes involved in DNA replication: DNA gyrase and topoisomerase IV.1 Resistance to fluoroquinolones increases when bacterial genes undergo mutations, specifically the gyrA and gyrB genes of gram-negative bacteria and the parC or parE of gram-positive organisms.2 The first-step mutation, which affects the primary drug target, slightly decreases antimicrobial susceptibility. When mutations occur in additional targets, susceptibility is reduced further.1 Mutations in these genes, especially mutations at two or more targets, can reduce susceptibility to all available fluoroquinolones.

    In addition to genetic mutations, fluoroquinolone resistance can result from expression of efflux mechanisms within bacteria that pump antimicrobial agents out of the cell. Piddock and colleagues3 reported that the presence of an efflux pump among S pneumoniae decreases the in vitro activity of the fluoroquinolones, including the newer agents moxifloxacin and gatifloxacin. These mechanisms have been implicated in levofloxacin treatment failures.4–7 Treatment failures have not been reported with gatifloxacin or moxifloxacin.

    REFERENCES

    1. Hooper DC: Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 2000;31(suppl 2):S24

    2. Hooper DC: Mechanisms of action of antimicrobials: Focus on fluoroquinolones. Clin Infect Dis 2001;32 (suppl 1):S9

    3. Piddock LJV, Johnson M, Ricci V, et al: Activities of new fluoroquinolones against fluoroquinolone-resistant pathogens of the lower respiratory tract. Antimicrob Agents Chemother 1998;42:2956

    4. Davidson R, Cavalcanti R, Brunton JL, et al: Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;36:747

    5. Empey PE, Jennings HR, Thornton AC, et al: Levofloxacin failure in a patient with pneumococcal pneumonia. Ann Pharmacother 2001;35:687

    6. Kays MB, Smith DW, Wack ME, et al: Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacotherapy 2002;22:395

    7. Urban C, Rahman N, Zhao X, et al: Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J Infect Dis 2001;184:794

     

    Jeffrey Blumer. Fluoroquinolone use in children: Resistance and safety implications. Contemporary Pediatrics November 2003;20:97.

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