The Use of Systemic Fluoroquinolones

Nalidixic acid was the first quinolone antibacterial agent licensed for use in the United States. Since introduction of nalidixic acid in the 1960s, subsequent generations of fluoroquinolones have been licensed by the US Food and Drug Administration (FDA). Fluorination of quinolone compounds resulted in the introduction of norfloxacin in 1986 and ciprofloxacin in 1987, followed by other second-generation fluoroquinolones. Additional modifications resulted in third- and fourth-generation fluoroquinolones (Table 1). Some fluoroquinolones are no longer available, and others are of limited use clinically. Currently, ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are the most widely used fluoroquinolones.

Early in their development, fluoroquinolones were found to affect cartilage in juvenile animals, resulting in an arthropathy. Although the pathogenesis remains unknown, irreversible arthropathy in animals has been a consistent finding with most of the fluoroquinolones. The potential for arthropathy in children has limited the use of these drugs in pediatric patients.

Numerous reports describe use of fluoroquinolones to treat infections in children. Reported uses include treatment of exacerbations of bronchopulmonary disease in children with cystic fibrosis (CF) who have colonization with Pseudomonas aeruginosa, complicated urinary tract infections, chronic suppurative otitis media associated with P aeruginosa, osteochondritis attributable to P aeruginosa, shigellosis, invasive salmonellosis, and Campylobacter jejuni infections. In recent years, use has also included prophylaxis during periods of neutropenia; empiric therapy in febrile, neutropenic children with cancer; treatment of patients with multidrug-resistant Gram-negative bacillary septicemia or meningitis; and combination use with other agents to treat multidrug-resistant mycobacterial disease.¹ 

Reports on use of fluoroquinolones in children include retrospective studies, studies without control groups, and studies that include small numbers of children in selected populations. In these reports, arthropathy (as observed in animals) was not noted, or if a musculoskeletal event did occur, it was reversible.

Despite the fact that postexposure treatment for inhalation anthrax was the only licensed indication for use of systemic fluoroquinolones in patients younger than 18 years before 2004, there were approximately 520 000 prescriptions written for children and adolescents younger than 18 years in the United States in 2002. Approximately 13 800 of those prescriptions were written for children 2 to 6 years of age, and 2750 were written for infants younger than 2 years.

The increased use of fluoroquinolones in all age groups is resulting in a corresponding increase in bacterial resistance to fluoroquinolones. One study in adult patients with CF demonstrated that the proportion of susceptible P aeruginosa isolates decreased from 100% to 45% after 14 days of treatment.²  Studies from many countries have reported resistance to fluoroquinolones among C jejuni, Shigella species, Salmonella species, and shiga toxin-producing Escherichia coli. In many geographic areas of the world, including the United States, resistance patterns have demonstrated a consistent increase over the course of time, with resistance occurring to several classes of antimicrobial agents, including fluoroquinolones.³ 

Fluoroquinolones also are being used for empirical and prophylactic treatment in patients receiving chemotherapy for cancer, which might further contribute to increased resistance to these agents. A total of 122 stool samples were collected from 25 adult patients with hematologic malignancies who were receiving prophylactic norfloxacin. Stool isolates of E coli were tested for susceptibility to norfloxacin.⁴  Two patients had fluoroquinolone-resistant E coli isolates before beginning norfloxacin treatment, and 8 (35%) of the remaining 23 patients had fluoroquinolone-resistant E coli isolated from stool samples after a mean of 10 days (range: 3–35 days) of norfloxacin prophylaxis.⁴  Enterococcal isolates resistant to ciprofloxacin and trovafloxacin were recovered from hospitalized children who had never received fluoroquinolones, which raised the possibility of nosocomial infections with fluoroquinolone-resistant bacteria.⁵ 

Resistance to fluoroquinolones among isolates of Streptococcus pneumoniae is increasing. Susceptibility testing of 5640 strains of S pneumoniae isolated during the 1997–1998 respiratory illness season from 377 hospitals throughout the United States showed only 0.3% of isolates to be resistant to ciprofloxacin (minimum inhibitory concentration [MIC]: ≤4 μg/mL).⁶  However, S pneumoniae isolated in the United States from January 1999 through August 2000 showed resistance to ciprofloxacin at 3%, levofloxacin at 0.5%, and gatifloxacin at 0.4%.⁷  In Canada, 2% of 1844 S pneumoniae isolates from patients of all ages in all provinces were resistant to ciprofloxacin during the 1997–1998 respiratory illness season.⁸  In Hong Kong during the second half of 1998, 12% of S pneumoniae isolates had an MIC greater than 2 μg/mL for ciprofloxacin, 6% had an MIC greater than 2 μg/mL for levofloxacin, and 2% had an MIC greater than 1 μg/mL for trovafloxacin.⁹  Although it has been suggested that introduction of moxifloxacin and gatifloxacin, which require both typoisomerase and gyrase production for resistance, will circumvent the growing resistance to fluoroquinolones, there is evidence that resistance to fluoroquinolones is essentially a class effect.¹⁰  Thus, increased use of fluoroquinolones can be anticipated to result in an increase in strains of S pneumoniae that are resistant to all fluoroquinolones. Resistance of P aeruginosa, Pseudomonas mirabilis, E coli, and other common hospital pathogens has increased consistently as fluoroquinolone use has increased.¹¹ 

Several investigators have studied the empiric use of oral fluoroquinolones for outpatient treatment of children with cancer and fever and neutropenia who were considered at low risk of acquiring serious bacterial infections.¹²  These studies have shown the potential benefits of such therapy and have reported few drug-related adverse events.

In a randomized, open-label trial, oral cefixime for 7 days was compared with oral ofloxacin for 5 days in 82 Vietnamese children with culture-proven typhoid fever.¹³  Treatment failures were significantly fewer, and days of fever, poor eating, and immobility were significantly shorter in the ofloxacin-treated patients. The study was undertaken because the incidence of infections with fluoroquinolone-resistant S typhi is increasing in Vietnam. The authors concluded that cefixime can provide a useful alternative treatment for uncomplicated typhoid fever in children but is less effective than ofloxacin.¹³ 

The Zimbabwe, Bangladesh, South Africa (Zimbasa) Dysentery Study Group¹⁴  conducted a multicenter, randomized, double-blind controlled clinical trial in which 253 children between 1 and 12 years of age were randomly assigned to receive either a 3- or 5-day course of oral ciprofloxacin. S dysenteriae type I was isolated from stool specimens of 66 and 62 children in the short-course and standard-course groups, respectively. All isolates were susceptible to ciprofloxacin, and all children were microbiologically cured by day 5. Sixty-five percent of the children in the short-course group were cured clinically on day 5, compared with 69% in the standard-course group.¹⁴ 

Israeli children 6 months to 11 years of age with clinically defined invasive diarrhea were randomly assigned to receive either intramuscular ceftriaxone or oral ciprofloxacin in a double-blind controlled study.¹⁵  Enteric pathogens were isolated from 60% of the 201 children studied, and clinical cure or improvement was observed in 100% and 99% of the ciprofloxacin- and ceftriaxone-treated children, respectively. Although the study was carefully designed and executed, the empirical use of antibacterial agents to treat children with clinically defined invasive diarrhea is not indicated in most economically developed countries. The authors also did not address the potential for antibacterial treatment to increase the likelihood of hemolytic uremic syndrome in patients with invasive diarrhea caused by shiga toxin-producing E coli.¹⁶ 

The outcomes of 12 Swedish children with ulceroglandular tularemia treated with oral ciprofloxacin were reported in a retrospective study; all of them recovered without complication.¹⁷  All isolates were susceptible to other antibacterial agents, and no comparison group was studied.

An international multicenter trial compared the safety and efficacy of parenterally administered trovafloxacin with that of ceftriaxone with or without vancomycin for treatment of 203 evaluable patients with bacterial meningitis.¹⁸  No significant differences in clinical outcomes, including deaths, seizures, or severe sequelae, were detected at follow-up 5 to 7 weeks after treatment. Subsequently, trovafloxacin was associated with acute liver failure and death in adults. The FDA limited the indications for trovafloxacin to serious and life-threatening diseases, and the manufacturer decided to cease distribution of the drug. Thus, although a fluoroquinolone might have a role in the treatment of acute bacterial meningitis, no controlled trials in children have been reported using currently licensed drugs.

Two open-label, noncomparative trials of gatifloxacin to treat recurrent or nonresponsive acute otitis media have been published.¹⁹ ,²⁰  In a study conducted at a single center in Israel, 160 patients were enrolled, but 32 (20%) discontinued treatment prematurely, and an additional 14 (9%) were considered clinically unevaluable at the end of therapy.¹⁹  Of 114 patients clinically evaluable 12 to 14 days after commencing therapy, 90% were considered clinically cured. A multinational study enrolled 254 patients 6 months to 7 years of age with recurrent acute otitis media, treatment failure, or both.²⁰  Ultimately, 198 patients were evaluable clinically, and 58% had at least 1 pathogen isolated from their middle-ear fluid before treatment. The end-of-treatment clinical cure rate was 88%. Neither study used a precise clinical definition of acute otitis media, and neither enrolled a control group. The authors of both studies caution that fluoroquinolones should be used only in patients who do not respond to recommended antibacterial agents.

Despite statements to the contrary, fluoroquinolones have been associated with musculoskeletal adverse events in children. Pefloxacin was used extensively in France and was found to cause arthralgia/arthritis in children and adults. Ciprofloxacin pediatric labeling by the FDA includes data regarding musculoskeletal adverse events in pediatric patients 1 to 17 years of age who received ciprofloxacin or a control agent to treat complicated E coli urinary tract infections and pyelonephritis attributable to E coli. The rates of musculoskeletal adverse events occurring within 6 weeks of treatment were 9.3% (31 of 335) in patients receiving ciprofloxacin compared with 6.0% (21 of 349) in control patients.²¹  To date, most reported musculoskeletal events associated with fluoroquinolone use were of moderate intensity and were transient.²² ,²³  Study of a large database did not demonstrate a difference in musculoskeletal toxicity between patients receiving ciprofloxacin or ofloxacin and azithromycin.²⁴  Fluoroquinolone-associated tendinopathy in adults is more likely to occur in older patients, patients receiving systemic corticosteroids, and patients with renal disease.²⁵ 

The inappropriate use of fluoroquinolones in children and adults is likely to be associated with increasing bacterial resistance to these agents.

The use of a fluoroquinolone in a child or adolescent may be justified in special circumstances after careful assessment of the risks and benefits for the individual patient. Although there is no compelling evidence supporting the occurrence of sustained injury to developing joints in humans by a fluoroquinolone, the possibility that it occurs infrequently has not been excluded.

Circumstances in which fluoroquinolones may be useful include those in which (1) infection is caused by multidrug-resistant pathogens for which there is no safe and effective alternative and (2) parenteral therapy is not feasible and no other effective oral agent is available. Appropriate uses should be limited to the following:

• exposure to aerosolized Bacillus anthracis to decrease the incidence or progression of disease (FDA licensed) (evidence grade III; see Table 2);

• urinary tract infections caused by P aeruginosa or other multidrug-resistant, Gram-negative bacteria (FDA licensed for complicated E coli urinary tract infections and pyelonephritis attributable to E coli in patients 1–17 years of age) (evidence grade II-2);

• chronic suppurative otitis media or malignant otitis externa caused by P aeruginosa (evidence grade II-3);

• chronic or acute osteomyelitis or osteochondritis caused by P aeruginosa (not for prophylaxis of nail puncture wounds to the foot) (evidence grade III);

• exacerbation of pulmonary disease in patients with CF who have colonization with P aeruginosa and can be treated in an ambulatory setting (evidence grade II-2);

• mycobacterial infections caused by isolates known to be susceptible to fluoroquinolones (evidence grade III);

• Gram-negative bacterial infections in immunocompromised hosts in which oral therapy is desired or resistance to alternative agents is present (evidence grade II-1);

• gastrointestinal tract infection caused by multidrug-resistant Shigella species, Salmonella species, Vibrio cholerae, or C jejuni (evidence grade II-2);

• documented bacterial septicemia or meningitis attributable to organisms with in vitro resistance to approved agents or in immunocompromised infants and children in whom parenteral therapy with other appropriate antimicrobial agents has failed (evidence grade III); and

• serious infections attributable to fluoroquinolone-susceptible pathogen(s) in children with life-threatening allergy to alternative agents (evidence grade III).

Keith R. Powell, MD, Chairperson

Robert S. Baltimore, MD

Henry Bernstein, DO

Joseph A. Bocchini, Jr, MD

John S. Bradley, MD

Michael Brady, MD

Penelope H. Dennehy, MD

Robert W. Frenck, Jr, MD

David Kimberlin, MD

Sarah S. Long, MD

Julia A. McMillan, MD

Lorry G. Rubin, MD

Carol J. Baker, MD

Caroline B. Hall, MD

H. Cody Meissner, MD

Margaret B. Rennels, MD

Richard D. Clover, MD

American Academy of Family Physicians

Steven Cochi, MD

Centers for Disease Control and Prevention

Joanne Embree, MD

Canadian Paediatric Society

Marc A. Fischer, MD

Centers for Disease Control and Prevention

Benjamin Schwartz, MD

National Vaccine Program Office

Mamodikoe Makhene, MD

National Institutes of Health

Douglas Pratt, MD

Food and Drug Administration

Jeffrey R. Starke, MD

American Thoracic Society

Jack Swanson, MD

Practice Action Group

Larry K. Pickering, MD

Red Book Editor

Edgar O. Ledbetter, MD

Alison Siwek, MPH

Margaret B. Rennels, MD, Chairperson

H. Cody Meissner, MD, Vice Chairperson

Carol J. Baker, MD

Robert S. Baltimore, MD

Joseph A. Bocchini, Jr, MD

John S. Bradley, MD

Penelope H. Dennehy, MD

Robert W. Frenck, Jr, MD

Caroline B. Hall, MD

Sarah S. Long, MD

Julia A. McMillan, MD

^*Keith R. Powell, MD

Lorry G. Rubin, MD

Thomas N. Saari, MD

Richard D. Clover, MD

American Academy of Family Physicians

Steven Cochi, MD

Centers for Disease Control and Prevention

Joanne Embree, MD

Canadian Paediatric Society

Marc Fischer, MD

Centers for Disease Control and Prevention

Bruce Gellin, MD, MPH

National Vaccine Program Office

Mamodikoe Makhene, MD

National Institutes of Health

Douglas Pratt, MD

Food and Drug Administration

Jeffrey R. Starke, MD

American Thoracic Society

Larry K. Pickering

Red Book Editor

Martha Cook, MS