Appropriate prescribing practices for fluoroquinolones are essential as evolving resistance patterns are considered, additional treatment indications are identified, and the toxicity profile of fluoroquinolones in children becomes better defined. Earlier recommendations for systemic therapy remain; expanded uses of fluoroquinolones for the treatment of certain infections are outlined in this report. Although fluoroquinolones are reasonably safe in children, clinicians should be aware of the specific adverse reactions. Use of fluoroquinolones in children should continue to be limited to treatment of infections for which no safe and effective alternative exists.

Fluoroquinolones are highly active in vitro against both Gram-positive and Gram-negative pathogens and have pharmacokinetic properties that are favorable for treating a wide array of infections. The prototype quinolone antibiotic agent, nalidixic acid, was approved by the US Food and Drug Administration (FDA) for adults in 1964 and generally is considered to be the first generation of such agents. For more than 2 decades, nalidixic acid also has been approved by the FDA and available for children aged 3 months and older. Subsequent chemical modifications of the first quinolone compounds resulted in the development of a series of fluoroquinolone agents with an increased antimicrobial spectrum of activity and better pharmacokinetic tissue-exposure characteristics.

Second-generation agents have a greater Gram-negative spectrum (with activity against Pseudomonas aeruginosa) and include ciprofloxacin, levofloxacin, norfloxacin, and ofloxacin. In 2004, ciprofloxacin became the first fluoroquinolone agent approved for use in children 1 through 17 years of age.

Gemifloxacin, a currently marketed third-generation agent, has been approved by the FDA for adults for the treatment of community-acquired pneumonia and acute exacerbations of chronic bronchitis. Compared with earlier agents, gemifloxacin provides substantially increased activity against Streptococcus pneumoniae (while retaining activity against many Gram-negative pathogens), Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

A fourth generation of fluoroquinolones, represented by moxifloxacin, displays increased activity against anaerobes while maintaining the Gram-positive and Gram-negative activity of the third-generation agents. Moxifloxacin also provides excellent activity against many mycobacteria including most strains of Mycobacterium tuberculosis currently isolated in the United States.

Animal toxicology data available with the first quinolone compounds documented their propensity to create inflammation and subsequent destruction of weight-bearing joints in juvenile animals.1,2  This observation effectively sidelined further development or large-scale evaluation of this class of antibiotic agents in children.

A policy statement summarizing the assessment of risks and benefits of fluoroquinolones in pediatric patients was published by the American Academy of Pediatrics in 2006.3  At that time, parenteral fluoroquinolones were believed to be appropriate for the treatment of infections caused by multidrug-resistant pathogens for which no alternative safe and effective parenteral agent existed. For outpatient management, oral fluoroquinolones were reasonable for treatment of infections when the only other options were intravenous treatment with other classes of antibiotic agents.

Since publication of the previous American Academy of Pediatrics policy statement, the clinical value of fluoroquinolones for the treatment of specific infections in children, particularly those caused by Gram-negative pathogens, has been further documented. The use of topical fluoroquinolone therapy for external otitis is now recommended by the American Association of Otolaryngology.4  In addition, results of the first randomized, prospective studies on the safety of the fluoroquinolones have been reported.5,6  No published reports exist of physician-diagnosed cartilage damage in children in the United States, either from controlled clinical trials of fluoroquinolones or from unsolicited reporting to the FDA or drug manufacturers. Quinolones that are currently approved by the FDA and available for use in children are nalidixic acid for urinary tract infections (UTIs), ciprofloxacin for inhalational anthrax and complicated UTI and pyelonephritis, and levofloxacin for inhalational anthrax. Only ciprofloxacin and levofloxacin are available in a suspension formulation. Moxifloxacin is currently under investigation for treatment of complicated intraabdominal infections in children.7  Other systemic quinolones that may be available in other countries but not the United States are not addressed in this report.

The original toxicology studies with quinolones documented cartilage injury in weight-bearing joints in juvenile animals; damage to the joint cartilage was proportional to the degree of exposure.1,2  Each quinolone may demonstrate a different potential to cause cartilage toxicity.8  However, given a sufficiently high exposure, cartilage changes will occur in all animal models with all quinolones, including nalidixic acid.

Although initial reports focused on articular cartilage, the results of subsequent studies suggested the possibility of epiphyseal plate cartilage injury,9  which led to fluoroquinolone clinical study designs that lasted several years to assess growth potential. Recent data suggest that quinolone toxicity occurs as a result of concentrations present in cartilage that are sufficiently high to form chelate complexes with divalent cations, particularly magnesium, that result in impairment of integrin function and cartilage matrix integrity in the weight-bearing joints, which undergo chronic trauma during routine use.10 

In studies of ciprofloxacin exposure to very young beagle puppies (one of the most sensitive animal models for quinolone toxicity), clinical evidence of arthrotoxicity was observed during a 14-day treatment course at 90 mg/kg per day but not at 30 mg/kg per day. Apparent joint tenderness at the higher exposure resolved 6 weeks after the last dose of ciprofloxacin.

Histopathologic evidence of cartilage injury was noted in virtually all animals given 90 mg/kg per day. At this exposure level, the observed clinical signs all occurred during and shortly after treatment but resolved by 2 months, with no recurrent signs noted during the 5-month follow-up period. In contrast, histopathologic evidence of cartilage injury was observed at 30 mg/kg per day, the dose currently recommended for children. Histopathologic evidence of inflammation occurred in fewer than half the animals at this dose but persisted for 5 months after treatment, at full skeletal maturation.5,11  The “no-observed-adverse-event level” was 10 mg/kg per day, a dose at which neither clinical nor histopathologic evidence of toxicity was present.

Similar data, which documented a no-observed-adverse-event level of 3 mg/kg per day for intravenous dosing for 14 days (approximately one-quarter the current FDA-approved dose of 16 mg/kg per day for children who weigh <50 kg), were documented before FDA approval of levofloxacin for adults. Levofloxacin has virtually 100% bioavailability; total drug exposure is equivalent between intravenous and oral formulations at the same milligram-per-kilogram dose.12 

Recent data from investigation of a lamb model, felt to approximate human growth rates and activity more closely than juvenile beagle dogs or rats, have been published. This study addressed epiphyseal cartilage and growth velocity after a 14-day drug exposure to either gatifloxacin or ciprofloxacin that was equivalent to that achieved in children receiving therapeutic doses. Gross examination of articular cartilage and microscopic examination of epiphyseal cartilage did not reveal abnormalities consistent with cartilage injury or inflammation.13 

Preclinical toxicology data are available for all FDA-approved fluoroquinolones. These data document differences in the animal species susceptible to cartilage effects as well as differences between each quinolone in the ability to create cartilage toxicity.

At the time of publication of the last American Academy of Pediatrics policy statement, retrospective studies, case-control series, and case reports represented the published data on fluoroquinolone safety in children available in the peer-reviewed literature.14,,17  Some reports included children with cystic fibrosis, who can develop disease-related arthropathy, and some included more toxic fluoroquinolone agents that were never approved in the United States. These data provided conflicting reports regarding the safety of fluoroquinolones in children. The results of 2 large, prospective safety studies are now available for review; 1 study was performed at the request of the FDA by Bayer for ciprofloxacin, and the second study was performed by Johnson & Johnson for levofloxacin as part of their FDA-coordinated program of pediatric drug development.

In 2008, the FDA's analysis of study data for ciprofloxacin in the treatment of complicated UTI and pyelonephritis in children aged 1 through 17 years from 2004 was posted on the FDA Web site.5  A series of prospective, randomized, double-blinded studies was performed to compare (1) intravenous ceftazidime with intravenous ciprofloxacin, permitting oral step-down therapy, and (2) oral ciprofloxacin with oral cefixime or trimethoprim-sulfamethoxazole (TMP-SMX). These large studies were conducted in several countries (Table 1). Clinical end points were designed to capture any sign of cartilage or tendon toxicity by eliciting a detailed history of a wide variety of complaints referable to bones and joints (Table 2). Comparing complaints and physical findings between the ciprofloxacin-treated group and the group treated with comparator antimicrobial agents, a difference was detected only in the United States. The difference in rates of complaints varied between countries; the lowest rates were reported from Mexico (0% ciprofloxacin, 0% comparator), and the highest rates were reported from the United States (21% ciprofloxacin, 11% comparator). The study used a noninferiority design to assess musculoskeletal complaints between the 2 treatment groups across all countries, and as analyzed, the groups were sufficiently different to suggest potential musculoskeletal toxicity with ciprofloxacin (Table 2).

TABLE 1

Rate of FDA-Defined Arthropathy (See Table 2) 6 Weeks After Treatment With Ciprofloxacin or Comparator, According to Selected Baseline Characteristics

Ciprofloxacin (N = 335)Comparator (N = 349)
All patients, n/N (%) 31/335 (9.3) 21/349 (6.0) 
Country, n/N (%)   
    Argentina 8/77 (10.4) 7/79 (8.9) 
    Canada 1/8 (12.5) 1/11 (9.1) 
    Costa Rica 4/21 (19.0) 0/20 (0.0) 
    Germany 1/13 (7.7) 1/11 (9.1) 
    Mexico 0/56 (0.0) 0/60 (0.0) 
    Peru 2/87 (2.3) 3/88 (3.4) 
    United States 13/62 (21.0) 8/71 (11.3) 
    South Africa 2/11 (18.2) 1/9 (11.1) 
Race, n/N (%)   
    White 18/130 (13.8) 13/134 (9.75) 
    Black 0/5 (0.0) 1/7 (14.3) 
    Asian 0/3 (0.0) 1/6 (16.7) 
    Hispanic 8/102 (7.8) 3/109 (2.8) 
    Uncoded 5/95 (5.3) 3/93 (3.2) 
Gender, n/N (%)   
    Male 6/62 (9.7) 4/65 (6.2) 
    Female 25/273 (9.2) 17/284 (6.0) 
Ciprofloxacin (N = 335)Comparator (N = 349)
All patients, n/N (%) 31/335 (9.3) 21/349 (6.0) 
Country, n/N (%)   
    Argentina 8/77 (10.4) 7/79 (8.9) 
    Canada 1/8 (12.5) 1/11 (9.1) 
    Costa Rica 4/21 (19.0) 0/20 (0.0) 
    Germany 1/13 (7.7) 1/11 (9.1) 
    Mexico 0/56 (0.0) 0/60 (0.0) 
    Peru 2/87 (2.3) 3/88 (3.4) 
    United States 13/62 (21.0) 8/71 (11.3) 
    South Africa 2/11 (18.2) 1/9 (11.1) 
Race, n/N (%)   
    White 18/130 (13.8) 13/134 (9.75) 
    Black 0/5 (0.0) 1/7 (14.3) 
    Asian 0/3 (0.0) 1/6 (16.7) 
    Hispanic 8/102 (7.8) 3/109 (2.8) 
    Uncoded 5/95 (5.3) 3/93 (3.2) 
Gender, n/N (%)   
    Male 6/62 (9.7) 4/65 (6.2) 
    Female 25/273 (9.2) 17/284 (6.0) 
TABLE 2

Rate of FDA-Defined Arthropathy 6 Weeks and 1 Year After Treatment With Ciprofloxacin or a Comparator

Ciprofloxacin (N = 335)Comparator (N = 349)
Arthropathy rate at 6 wk of follow-up, n (%) 31 (9.3) 21 (6.0) 
    95% confidence intervala (−0.8 to 7.2) 
Cumulative arthropathy rate at 1 y of follow-up, n (%) 46 (13.7) 33 (9.5) 
    95% confidence intervala (−0.6 to 9.1) 
Selected musculoskeletal adverse eventsb in patients with arthropathy at 1 y of follow-up   
    No. of patients 46c 33c 
    Arthralgia, n (%) 35 (76) 20 (61) 
    Abnormal joint and/or gait exam, n (%) 11 (24) 8 (24) 
    Accidental injury, n (%) 6 (13) 1 (3) 
    Leg pain, n (%) 5 (11) 1 (3) 
    Back pain, n (%) 4 (9) 0 (0) 
    Arthrosis, n (%) 4 (9) 1 (3) 
    Bone pain, n (%) 3 (7) 0 (0) 
    Joint disorder, n (%) 2 (4) 0 (0) 
    Pain, n (%) 2 (4) 2 (6) 
    Myalgia, n (%) 1 (2) 4 (12) 
    Arm pain, n (%) 0 (0) 2 (6) 
    Movement disorder, n (%) 1 (2) 1 (3) 
Ciprofloxacin (N = 335)Comparator (N = 349)
Arthropathy rate at 6 wk of follow-up, n (%) 31 (9.3) 21 (6.0) 
    95% confidence intervala (−0.8 to 7.2) 
Cumulative arthropathy rate at 1 y of follow-up, n (%) 46 (13.7) 33 (9.5) 
    95% confidence intervala (−0.6 to 9.1) 
Selected musculoskeletal adverse eventsb in patients with arthropathy at 1 y of follow-up   
    No. of patients 46c 33c 
    Arthralgia, n (%) 35 (76) 20 (61) 
    Abnormal joint and/or gait exam, n (%) 11 (24) 8 (24) 
    Accidental injury, n (%) 6 (13) 1 (3) 
    Leg pain, n (%) 5 (11) 1 (3) 
    Back pain, n (%) 4 (9) 0 (0) 
    Arthrosis, n (%) 4 (9) 1 (3) 
    Bone pain, n (%) 3 (7) 0 (0) 
    Joint disorder, n (%) 2 (4) 0 (0) 
    Pain, n (%) 2 (4) 2 (6) 
    Myalgia, n (%) 1 (2) 4 (12) 
    Arm pain, n (%) 0 (0) 2 (6) 
    Movement disorder, n (%) 1 (2) 1 (3) 
a

The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the comparator group by more than 6.0%. At both evaluations, the 95% confidence interval indicated that it could not be concluded that ciprofloxacin had findings comparable to those of the comparator.

b

Events that occurred in 2 or more patients.

c

A patient with arthropathy may have had more than 1 event.

The levofloxacin safety data collection was prospective and randomized but not blinded. The published safety profile of levofloxacin included a large cohort of 2523 children from 3 large multicenter efficacy trials. Data were collected from a community-acquired pneumonia trial in children aged 6 months to 16 years (a randomized 3:1, prospective, comparative trial with 533 levofloxacin-exposed and 179 comparator-exposed evaluable subjects) and from 2 trials that assessed therapy of acute otitis media in children aged 6 months to 5 years (1 open-label noncomparative study with 204 evaluable subjects and another randomized 1:1, prospective, comparative trial with 797 levofloxacin-exposed and 810 comparator-exposed evaluable subjects).6  In addition, after completion of the treatment trials, all subjects from both treatment arms were also offered participation in an unblinded, long-term, 12-month follow-up study for safety assessments, and 2233 of 2523 families participated. From these trials, a selected group of children who were judged to benefit from additional follow-up because of the presence of tendon/joint abnormalities or failure to achieve expected vertical growth over the year of observation were continued in the musculoskeletal long-term follow-up study, which consisted of yearly visits for 4 additional years.

The definitions of musculoskeletal events for tendinopathy (inflammation or rupture of a tendon as determined by physical examination and/or MRI or ultrasound), arthritis (inflammation of a joint as evidenced by redness and/or swelling of the joint), arthralgia (pain in the joint as evidenced by complaint), and gait abnormality (limping or refusal to walk) were determined before starting the studies. The identity of study medication was known by parents, study personnel, and the subject's care providers as reports of musculoskeletal events and any other adverse events were collected during the follow-up period. An analysis of these events occurred 1, 2, and 12 months after treatment. The analysis of disorders that involved weight-bearing joints revealed a statistically greater rate between the levofloxacin- and comparator-treated groups at 2 months (1.9% vs 0.7%; P = .025) and at 12 months (2.9% vs 1.6%; P = .047). A history of joint pain accounted for 85% of all events, and there were no findings of joint abnormality when assessed by physical examination. Computed tomography or MRI was performed for 5 of the patients with musculoskeletal symptoms; no signs of structural injury were identified. No evidence of joint abnormalities was observed at 12 months in the levofloxacin group.

A report on the 5-year safety assessment of the 2233 children who received levofloxacin treatment was recently completed by the manufacturer, Johnson & Johnson. Specified criteria for review included (1) documented height that was less than 80% of the expected height increase, (2) abnormal bone or joint findings, and (3) any other concerns for possible tendon/joint toxicity identified by the data safety monitoring board during treatment or in the 12 months after treatment. A total of 174 of 207 (84%) reviewed subjects were identified by the predetermined growth criteria (124 levofloxacin-treated and 83 comparator-treated subjects), and 49% of each group completed the entire 5-year follow-up. Although an increase in musculoskeletal events in the levofloxacin group had been noted 12 months after treatment, the cumulative long-term outcomes of children with musculoskeletal adverse events reported during the 5-year safety study (including ongoing arthropathy, peripheral neuropathy, abnormal bone development, scoliosis, walking difficulty, myalgia, tendon disorder, hypermobility syndrome, and pain in the spine, hip, and shoulder) were slightly higher in the comparator treatment group (2% levofloxacin, 4% comparator). Among all study participants identified by the growth criteria (n = 174), equal percentages of children from each treatment group were documented to fall into the previously defined categories at the 5-year visit: no change in height percentile; improvement; or deterioration in growth characteristics. This 5-year follow-up study enrolled 48% of study participants from US sites compared with 20% from US sites enrolled in the original clinical trials (unpublished data on file, J&J protocol LOFBO-LTSS-001, clinical study report, March 23, 2011).

A rare complication associated with quinolone antibiotic agents, tendon rupture, has a predilection for the Achilles tendon (often bilateral) and is estimated to occur at a rate of 15 to 20 per 100 000 treated patients in the adult population. Advanced age, along with antecedent steroid therapy and a particular subset of underlying diseases, including hypercholesterolemia, gout, rheumatoid arthritis, end-stage renal disease/dialysis, and renal transplantation, have been identified as risk factors and prompted an FDA warning about this serious adverse event for all quinolone agents. Achilles tendon rupture in the pediatric population, in general, is extremely rare, and although tendonitis in athletes is observed, this event usually follows overuse. To date, there have been no reports of this rare complication in a pediatric patient who was exposed to a quinolone, which precludes assessment of the risk of this complication in children.

Other potential toxicities of fluoroquinolone-class antibiotic agents do not occur commonly in children but include central nervous system adverse effects (seizures, headaches, dizziness, lightheadedness, sleep disorders), peripheral neuropathy, hypersensitivity reactions, photosensitivity and other rashes, disorders of glucose homeostasis (hypoglycemia and hyperglycemia), prolongation of QT interval, and hepatic dysfunction.

In the prospective ciprofloxacin study requested by the FDA, the rate of neurologic events was similar between ciprofloxacin- and comparator-treated children (Table 3).5  Reported rates of neurologic events in the levofloxacin safety database were statistically similar between fluoroquinolone- and comparator-treated children.18,19 

TABLE 3

Rate of FDA-Defined Neurologic Adverse Events by 6 Weeks After Treatment With Ciprofloxacin or Comparator

Neurologic Adverse EventsCiprofloxacin (N = 335), n (%)Comparator (N = 349), n (%)
Any event 9 (3) 7 (2) 
Dizziness 3 (<1) 1 (<1) 
Nervousness 3 (<1) 1 (<1) 
Insomnia 2 (<1) 0 (0) 
Somnolence 2 (<1) 0 (0) 
Abnormal dreams 0 (0) 2 (<1) 
Convulsion 0 (0) 2 (<1) 
Hypertonia 0 (0) 1 (<1) 
Abnormal gait 0 (0) 1 (<1) 
Neurologic Adverse EventsCiprofloxacin (N = 335), n (%)Comparator (N = 349), n (%)
Any event 9 (3) 7 (2) 
Dizziness 3 (<1) 1 (<1) 
Nervousness 3 (<1) 1 (<1) 
Insomnia 2 (<1) 0 (0) 
Somnolence 2 (<1) 0 (0) 
Abnormal dreams 0 (0) 2 (<1) 
Convulsion 0 (0) 2 (<1) 
Hypertonia 0 (0) 1 (<1) 
Abnormal gait 0 (0) 1 (<1) 

Quinolone resistance has been a concern since the first approval of these agents, given the broad spectrum of activity and the large number of clinical indications. Multiple mechanisms of resistance have been described, including mutations that lead to changes in the target enzymes DNA gyrase and DNA topoisomerase, as well as efflux pumps and alterations in membrane porins.20  Newly described plasmid-encoded quinolone-resistance proteins have the ability to spread rapidly.21 

Surveillance studies have tracked fluoroquinolone resistance in S pneumoniae strains isolated primarily from adult patients with respiratory tract infections and in Escherichia coli isolated from adult patients with UTIs. A number of studies also have assessed resistance in other enteric bacilli,22,,25 Pseudomonas aeruginosa,26 Neisseria gonorrhoeae,27 Neisseria meningitidis,28  and Streptococcus pyogenes.29,30  One recent study in North America addressed fluoroquinolone resistance in both Gram-negative and Gram-positive isolates, specifically from children younger than 7 years.31  Previous concerns that continuing widespread use of respiratory fluoroquinolones would lead to substantial increases in pneumococcal resistance and subsequent lack of usefulness of this class of agents for respiratory tract infections32,,34  have, fortunately, not been confirmed by current published surveillance data, particularly for pneumococcal isolates from children.31,35,36  The Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention documented virtually no levofloxacin resistance in children younger than 2 years between 1999 and 2004.37  In large-scale pediatric studies of levofloxacin for acute otitis media, emergence of levofloxacin-resistant pneumococci was not documented in children with persisting pneumococcal colonization after treatment, which suggests that emergence of resistance during treatment is not a common event.38  Possible reasons for the lack of increasing multidrug-resistant serotypes in both children and adults in populations in North America and Europe include the almost universal use of conjugate pneumococcal vaccine in children since 2000 as well as the lack of widespread use of fluoroquinolones in children.37,39,,41 

In adult patients, Pseudomonas resistance to both fluoroquinolones and other antimicrobial agents is problematic.42  Data on resistance in E coli isolated from adults with UTIs who were seen in emergency departments in the EMERGEncy ID NET, a network of 11 geographically diverse university-affiliated institutions, suggest a low but stable rate of resistance of approximately 5%,24  although in specific locations, rates of resistance for outpatients are closer to 10%.22,43  Similar published data do not exist for children, although in recent reports that included outpatient data, stratified according to age, the rates of fluoroquinolone resistance in E coli in children have been generally well below 3%.23,43 

For hospitalized children in a major tertiary care pediatric center, only 3% of 271 bloodstream isolates of E coli and Klebsiella species collected over 4 years (1999–2003) were resistant to fluoroquinolones.44  With the exception of children with cystic fibrosis, overall resistance in pediatric Gram-negative isolates, including P aeruginosa, has been lower than 5%.31  Data available from 3 large tertiary care children's hospitals document ciprofloxacin resistance for E coli to range from 4% to 7% for 2010 (B. Connelly, MD [Cincinnati Children's Hospital and Medical Center, Cincinnati, OH], M. A. Jackson, MD [Mercy Children's Hospital, Kansas City, MO], and J. Bradley, MD [Rady Children's Hospital, San Diego, CA], verbal communication, May 2011), and the rates have seemed stable for the last 3 years.

As fluoroquinolone use in pediatrics increases, it is expected that resistance will increase, as has been documented in adults. Appropriate use of fluoroquinolones in children should limit the development and spread of resistance.

An increasing number of topical fluoroquinolones have been investigated and approved by the FDA for treatment of acute conjunctivitis in adults and children older than 12 months, including levofloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and besifloxacin (Table 4). Conjunctival tissue pharmacokinetic evaluation was conducted in healthy adult volunteers; besifloxacin, gatifloxacin, and moxifloxacin were compared by using conjunctival biopsy. All 3 agents reached peak concentrations after 15 minutes.45  Bacterial eradication and clinical recovery of 447 patients aged 1 through 17 years with culture-confirmed bacterial conjunctivitis was evaluated in a posthoc multicenter study that investigated besifloxacin and moxifloxacin ophthalmic drops.46  Although better clinical and microbiological response was noted for besifloxacin compared with placebo, similar outcomes were noted when compared with moxifloxacin. Both agents were reported to be well tolerated. Although drug concentrations are only 1 indicator of potential clinical efficacy, the utility of agents with higher concentrations is tempered by the observation of a potential increase in ocular adverse events, such as eye pain,45  and slower corneal reepithelialization with specific agents.47 

TABLE 4

Most Common Infections for Which Fluoroquinolones Are Effective Therapy (See Text)

InfectionPrimary Pathogen(s)aFluoroquinolone
Systemic antibiotic requirementb   
    UTI Escherichia coli Ciprofloxacinc 
 Pseudomonas aeruginosa  
 Enterobacter species  
 Citrobacter species  
 Serratia species  
    Acute otitis media; sinusitis Streptococcus pneumoniae Levofloxacind 
 Haemophilus influenzae  
    Pneumonia Streptococcus pneumoniae Levofloxacin 
 Mycoplasma pneumoniae (macrolides preferred for Mycoplasma infections)  
    Gastrointestinal infections Salmonella species Ciprofloxacinc 
 Shigella species  
Topical antibiotic requiremente,f   
    Conjunctivitis Streptococcus pneumoniae Besifloxacin 
 Haemophilus influenzae Levofloxacin 
  Gatifloxacin 
  Ciprofloxacin 
  Moxifloxacin 
  Ofloxacin 
    Acute otitis externa; tympanostomy tube–associated otorrhea Pseudomonas aeruginosa Ciprofloxacing 
Staphylococcus aureus Ofloxacin 
 Mixed Gram-positive/Gram-negative organisms  
InfectionPrimary Pathogen(s)aFluoroquinolone
Systemic antibiotic requirementb   
    UTI Escherichia coli Ciprofloxacinc 
 Pseudomonas aeruginosa  
 Enterobacter species  
 Citrobacter species  
 Serratia species  
    Acute otitis media; sinusitis Streptococcus pneumoniae Levofloxacind 
 Haemophilus influenzae  
    Pneumonia Streptococcus pneumoniae Levofloxacin 
 Mycoplasma pneumoniae (macrolides preferred for Mycoplasma infections)  
    Gastrointestinal infections Salmonella species Ciprofloxacinc 
 Shigella species  
Topical antibiotic requiremente,f   
    Conjunctivitis Streptococcus pneumoniae Besifloxacin 
 Haemophilus influenzae Levofloxacin 
  Gatifloxacin 
  Ciprofloxacin 
  Moxifloxacin 
  Ofloxacin 
    Acute otitis externa; tympanostomy tube–associated otorrhea Pseudomonas aeruginosa Ciprofloxacing 
Staphylococcus aureus Ofloxacin 
 Mixed Gram-positive/Gram-negative organisms  
a

Assuming that the pathogen is either documented to be susceptible or presumed to be susceptible for fluoroquinolones.

b

If oral therapy is appropriate, use other classes of oral antibiotics if organisms are susceptible.

c

Dose of ciprofloxacin: oral administration, 20 to 40 mg/kg per day, divided every 12 hours (maximum dose: 750 mg per dose); intravenous administration, 20 to 30 mg/kg per day, divided every 8 to 12 hours (maximum dose: 400 mg per dose).

d

Dose of levofloxacin: oral or intravenous administration, 16 to 20 mg/kg per day divided every 12 hours (for children 6 months to 5 years of age) or 10 mg/kg per day once daily (for children 5 years of age and older) (maximum dose: 750 mg per dose).

e

Systemic toxicity of fluoroquinolones is not a concern with topical therapy; use of topical agents should be determined according to suspected pathogens, efficacy for mucosal infection, tolerability, and cost.

f

Other systemic therapy may be required for more severe infection.

g

Available with and without corticosteroid.

Recommendations for optimal care for patients with otitis externa were outlined in a review of 19 randomized controlled trials, including 2 from a primary care setting, which yielded 3382 participants. Topical antibiotic agents containing corticosteroids seemed to be more effective than acetic acid solutions. Aminoglycoside-containing otic preparations were reported to cause ototoxicity if the tympanic membrane was not intact; fluoroquinolone-containing preparations represent a safer alternative for treating both otorrhea associated with tympanic membrane perforation and tympanostomy tube otorrhea. Eleven trials included aural toilet as a routine intervention, but the authors acknowledged that this treatment is not likely to be available in a typical primary care office setting.48  The paucity of high-quality studies of antimicrobial-based topical therapy limited conclusions in this review. A small, prospective, randomized, open-label study of 50 patients with tympanostomy tube–associated otorrhea or a tympanic membrane perforation resulted in comparable outcomes with either topical antibiotic therapy or topical plus systemic antibiotic agents.49  For children with severe acute otitis externa, systemically administered antimicrobial agents should be considered in addition to topical therapy.50 

Which topical antibiotic agent is best for external otitis is unclear. High-quality studies that evaluated quinolone versus nonquinolone topical solutions have been limited. A systematic review of 13 meta-analyses confirmed that topical antibiotic agents were superior to placebo and noted a statistically significant advantage of quinolone agents over nonquinolone agents in the rate of microbiological cure (P = .035), although the clinical import of this advantage is likely of limited value. Safety profiles were similar between groups.50  A conclusion that quinolone and nonquinolone agents are similar in both microbiological and clinical cure rates was reached in a study of more than 200 children, 90 of whom were evaluated for microbiological response in a multicenter, randomized, parallel-group, evaluator-blinded study that compared once-daily ofloxacin drops to 4-times-daily neomycin sulfate/polymyxin B sulfate/hydrocortisone otic suspension. Microbial eradication was documented in 95% and 94%, respectively; clinical cure was achieved in 96% and 97%, respectively. Treatment was well tolerated with both regimens.51 

Newer fluoroquinolones display enhanced in vitro activity against S pneumoniae compared with ciprofloxacin. The clinical need for such agents to treat respiratory tract infections has largely been driven by the emergence of multidrug-resistant strains of this pathogen. Pharmacokinetic data for children 6 months of age and older are well defined for levofloxacin, the only currently available fluoroquinolone that has been studied for respiratory tract infections in children.52  The pharmaceutical manufacturer is currently not intending to present data to the FDA to obtain approval for the use of levofloxacin for acute bacterial otitis media or community-acquired pneumonia in children (S. Maldonado, Johnson & Johnson, written communication, May 2011).

Clinical studies of levofloxacin and gatifloxacin have been conducted in children with recurrent or persistent otitis media but not simple acute bacterial otitis media. Although the results of studies of several fluoroquinolones have been reported, only levofloxacin is currently available in the United States. A prospective, open-label, noncomparative study of levofloxacin was performed in 205 children 6 months of age and older, 80% of whom were younger than 2 years. Tympanocentesis was performed at study entry and at least at 3 to 5 days into therapy for children for whom treatment failed or who had persistent effusion. Bacterial eradication of middle-ear pathogens occurred in 88% of children, including 84% infected by pneumococci and 100% infected by Haemophilus influenzae. Levofloxacin treatment was well tolerated; vomiting in 4% of the patients was documented as the most common adverse effect.53  An evaluator-blinded, active-comparator, noninferiority, multicenter study that involved 1305 evaluable children older than 6 months and compared levofloxacin to amoxicillin-clavulanate (1:1) found equivalent clinical cure rates of 75% in each treatment arm. However, because tympanocentesis was not required, microbiological cure rates could not be determined.19 

Although initially approved by the FDA for the treatment of pneumonia and acute exacerbation of chronic bronchitis in adults, ciprofloxacin therapy has not been uniformly successful in treatment of pneumococcal pneumonia in adults at dosages initially studied 30 years ago. Failures are most likely a result of the increasing pneumococcal resistance to ciprofloxacin and other fluoroquinolones documented since their first approval.54  Ciprofloxacin is currently not considered appropriate therapy for community-acquired pneumonia in adults.

Fluoroquinolones with enhanced activity against S pneumoniae compared with ciprofloxacin (levofloxacin, moxifloxacin, gemifloxacin) have been used in adults for single-drug treatment of community-acquired pneumonia. These “respiratory tract” fluoroquinolones have demonstrated in vitro activity against the most commonly isolated pathogens: S pneumoniae, Haemophilus influenzae (nontypeable), and Moraxella catarrhalis, as well as M pneumoniae, C pneumoniae, and Legionella pneumophila.55,,57  Although these agents are not the drugs of choice for pneumonia in previously healthy adults, they are recommended for adults with underlying comorbidities and for those who have been exposed to antibiotic agents within the previous 3 months and, therefore, are more likely to be infected with antibiotic-resistant pathogens.58  Failures in the treatment of pneumococcal pneumonia have been reported with levofloxacin at 500 mg daily as a result of emergence of resistance on therapy or resistance from previous exposures to fluoroquinolones.59  An increased dose of levofloxacin—750 mg daily, given for 5 days—is currently approved by the FDA for adults with pneumonia. The increase in drug exposure at the higher dose is designed to overcome the most common mechanism for the development of fluoroquinolone resistance.60 

Of the fluoroquinolones, only levofloxacin has been studied prospectively in children with community-acquired pneumonia; efficacy in a multinational, open-label, noninferiority-design trial compared with standard antimicrobial agents for pneumonia was documented. For children aged 6 months to 5 years, levofloxacin (oral or intravenous) was compared with amoxicillin/clavulanate (oral) or ceftriaxone (intravenous). For children 5 years of age and older, levofloxacin (oral) was compared with clarithromycin (oral), and levofloxacin (intravenous) was compared with ceftriaxone (intravenous) in combination with either erythromycin (intravenous) or clarithromycin (oral). Clinical cure rates were 94.3% in the levofloxacin-treated group and 94.0% in the comparator group, and there were similar rates of cure in both the younger and older age groups. Microbiological etiologies were investigated, and Mycoplasma was the most frequently diagnosed pathogen (by serologic testing), representing 32% of those receiving levofloxacin in both older and younger age groups and approximately 30% of those receiving comparator agents in both age groups. Pneumococci were infrequently documented to be the cause of pneumonia in study patients, representing only 3% to 4% of those who received levofloxacin and 3% to 5% of those receiving comparator. It should be noted that the clinical response rate of 83% in children younger than 5 years diagnosed by serologic testing with Mycoplasma infection and treated with amoxicillin/clavulanate was similar to that in children treated with levofloxacin (89%), which indicates a high rate of spontaneous resolution of disease caused by Mycoplasma species in preschool-aged children, poor accuracy of diagnosis by serologic testing, or a clinical end-point evaluation after a treatment course that could not identify possible differences in response that may have been present in the first days of therapy.18 

Although fluoroquinolones may represent effective therapy, they are not recommended for first-line therapy of respiratory tract infection in children, because other better-studied and safer antimicrobial agents are available to treat the majority of the currently isolated pathogens.

Alghasham and Nahata61  summarized the results of 12 efficacy trials that used a number of fluoroquinolone agents for infections caused by Salmonella and Shigella species. However, data from only 2 of the 12 trials that compared fluoroquinolones to nonquinolone agents were reported. Patients were treated for typhoid fever (8 studies, including 7 for multidrug-resistant strains), invasive nontyphoid salmonellosis (1 study), and shigellosis (3 studies). Clinical and microbiological success with fluoroquinolone therapy for these infections was similar for children and adults. A recent report suggested caution in the use of fluoroquinolones in visitors returning from India with typhoid fever, because antimicrobial-resistant Salmonella typhi strains, including strains with decreased susceptibility to fluoroquinolones, have been noted.62 

A prospective, randomized, double-blind comparative trial of acute, invasive diarrhea in febrile children was conducted by Leibovitz et al,63  who compared ciprofloxacin with intramuscular ceftriaxone in a double-dummy treatment protocol. Two hundred and one children were treated and evaluated for clinical and microbiological cure as well as for safety. Pathogens were isolated in 121 children, most commonly Shigella and Salmonella species. Clinical and microbiological cure were equivalent between groups. No arthropathy was detected during or up to 3 weeks after completion of therapy.63 

In the United States, although cases of typhoid fever and invasive salmonellosis are uncommon, there are up to 280 000 cases of shigellosis per year, most of which occur in preschool-aged children with relatively mild disease. Treatment is recommended primarily to prevent spread of infection. Ampicillin and TMP-SMX resistance is increasing, and multidrug-resistant strains are becoming common; the National Antimicrobial Resistance Monitoring System (NARMS) reported that 38% of the strains isolated from 1999–2003 were resistant to both ampicillin and TMP-SMX. A 2005 outbreak of multidrug-resistant Shigella sonnei infection involving 3 states was reported in the Morbidity and Mortality Weekly Report64 ; 89% of the strains were resistant to both agents, but 100% of the strains were susceptible to ciprofloxacin. Treatment options for multidrug-resistant shigellosis, depending on the antimicrobial susceptibilities of the particular strain, include ciprofloxacin, azithromycin, and parenteral ceftriaxone.

Although ciprofloxacin has been regarded as an effective agent for traveler's diarrhea in the past, resistance rates are increasing for specific pathogens in many parts of the world. Resistance in Campylobacter species is particularly problematic in countries such as Taiwan, Thailand, and Sweden, where rates of 57%, 84%, and up to 88%, respectively, have been reported.65,66 

Standard empiric therapy for uncomplicated UTI in the pediatric population continues to be a cephalosporin antibiotic agent, because TMP-SMX- and amoxicillin-resistant E coli are increasingly common. The fluoroquinolones remain a potential first-line agent only in the setting of pyelonephritis or complicated UTI when typically recommended agents are not appropriate on the basis of susceptibility data, allergy, or adverse-event history. The previous American Academy of Pediatrics policy statement (2006) supported the use of ciprofloxacin as oral therapy for UTI and pyelonephritis caused by P aeruginosa or other multidrug-resistant Gram-negative bacteria in children aged 1 through 17 years and remains current.3 

The fluoroquinolones are active in vitro against mycobacteria, including M tuberculosis and many nontuberculous mycobacteria.58,67  Increasing multidrug resistance in M tuberculosis has lead to the increased use of fluoroquinolones as part of individualized, multiple-drug treatment regimens; levofloxacin and moxifloxacin have demonstrated greater bactericidal activity than has ciprofloxacin.68  Treatment regimens that include fluoroquinolones for 1 to 2 years for multidrug-resistant and extensively drug-resistant tuberculosis have not been prospectively studied in children. However, the benefit of treatment of tuberculosis with an active compound when other active alternatives are not available is greater than the potential for arthropathy. No joint toxicity has yet been reported in children who have received long-term therapy for tuberculosis, but data on safety have not been collected systematically.

Ciprofloxacin is effective in eradicating nasal carriage of Neisseria meningitidis (single dose: 500 mg for adults and 20 mg/kg for children older than 1 month), is preferred in nonpregnant adult women, and can be considered for younger patients as an alternative to rifampin, depending on results of a risk/benefit assessment.

Good penetration into the cerebrospinal fluid by certain fluoroquinolones has been reported, and concentrations often exceed 50% of the corresponding plasma drug concentration. In cases of multidrug-resistant Gram-negative meningitis in which no other agents are suitable, fluoroquinolones may represent the only treatment option.69 

P aeruginosa can cause skin infections (including folliculitis) after exposure to inadequately chlorinated swimming pools or hot tubs. For children who require systemic therapy, fluoroquinolone agents offer an oral treatment option that may be preferred over parenteral nonfluoroquinolone antimicrobial therapy.

Use of a fluoroquinolone in a child or adolescent may be justified in special circumstances in which (1) infection is caused by a multidrug-resistant pathogen for which there is no safe and effective alternative and (2) the options for treatment include either parenteral nonfluoroquinolone therapy or oral fluoroquinolone therapy, and oral therapy is preferred. In other clinical situations outlined previously, fluoroquinolones may also represent a preferred option (eg, topical fluoroquinolones in the treatment of tympanostomy tube–associated otorrhea) or an acceptable alternative to standard therapy because of concerns for antimicrobial resistance, toxicity, or characteristics of tissue penetration.

No compelling published evidence to date supports the occurrence of sustained injury to developing bones or joints in children treated with available fluoroquinolone agents; however, FDA analysis of ciprofloxacin safety data, as well as posttreatment and 12-month follow-up safety data for levofloxacin, suggest the possibility of increased musculoskeletal adverse effects in children who receive fluoroquinolones compared with agents of other classes. Many drugs in common pediatric use lack specific FDA approval for children. In the case of fluoroquinolones, as is appropriate with all antimicrobial agents, practitioners should verbally review common, anticipated potential adverse events, and indicate why a fluoroquinolone is the most appropriate antibiotic agent for a child's infection.

John S. Bradley, MD

Mary Anne Jackson, MD

Michael T. Brady, MD, Chairperson

Henry H. Bernstein, DO

Carrie L. Byington, MD

Kathryn M. Edwards, MD

Margaret C. Fisher, MD

Mary P. Glode, MD

Mary Anne Jackson, MD

Harry L. Keyserling, MD

David W. Kimberlin, MD

Yvonne A. Maldonado, MD

Walter A. Orenstein, MD

Gordon E. Schutze, MD

Rodney E. Willoughby, MD

Former Committee Member

John S. Bradley, MD

Liaisons

Beth Bell MD, MPH

Centers for Disease Control and Prevention

Robert Bortolussi, MD

Canadian Paediatric Society

Marc A. Fischer, MD

Centers for Disease Control and Prevention

Bruce Gellin, MD

National Vaccine Program Office

Richard L. Gorman, MD

National Institutes of Health

Lucia Lee, MD

Food and Drug Administration

R. Douglas Pratt, MD

Food and Drug Administration

Jennifer S. Read, MD

National Institutes of Health

Jeffrey R. Starke, MD

American Thoracic Society

Jack Swanson, MD

Committee on Practice Ambulatory Medicine

Tina Q. Tan, MD

Pediatric Infectious Diseases Society

Carol J. Baker, MD

Red Book Associate Editor

Sarah S. Long, MD

Red Book Associate Editor

H. Cody Meissner, MD

Red Book Associate Editor

Larry K. Pickering, MD

Red Book Editor

Lorry G. Rubin, MD

Jennifer Frantz, MPH

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.

All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

     
  • FDA

    Food and Drug Administration

  •  
  • UTI

    urinary tract infection

  •  
  • TMP-SMX

    trimethoprim-sulfamethoxazole

1.
Tatsumi
H
,
Senda
H
,
Yatera
S
,
Takemoto
Y
,
Yamayoshi
M
,
Ohnishi
K
.
Toxicological studies on pipemidic acid. V. Effect on diarthrodial joints of experimental animals
.
J Toxicol Sci
.
1978
;
3
(
4
):
357
367
2.
Gough
A
,
Barsoum
NJ
,
Mitchell
L
,
McGuire
EJ
,
de la Iglesia
FA
.
Juvenile canine drug-induced arthropathy: clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids
.
Toxicol Appl Pharmacol
.
1979
;
51
(
1
):
177
187
3.
American Academy of Pediatrics, Committee on Infectious Diseases
.
The use of systemic fluoroquinolones
.
Pediatrics
.
2006
;
118
(
3
):
1287
1292
4.
Rosenfeld
RM
,
Brown
L
,
Cannon
CR
, et al
;
American Academy of Otolaryngology–Head and Neck Surgery Foundation
.
Clinical practice guideline: acute otitis externa
.
Otolaryngol Head Neck Surg
.
2006
;
134
(
4 suppl
):
S4
S23
5.
US Food and Drug Administration
.
Drug approval package [ciprofloxacin]
. . Accessed June 30, 2010
6.
Noel
GJ
,
Bradley
JS
,
Kauffman
RE
, et al
.
Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders
.
Pediatr Infect Dis J
.
2007
;
26
(
10
):
879
891
7.
ClinicalTrials.gov
.
Moxifloxacin in Pediatric Subjects With Complicated Intra-abdominal Infection (MOXIPEDIA)
. . Accessed June 30, 2010
8.
Patterson
DR
.
Quinolone toxicity: methods of assessment
.
Am J Med
.
1991
;
91
(
6A
):
35S
37S
9.
Riecke
K
,
Lozo
E
,
ShakiBaei
M
,
Baumann-Wilschke
I
,
Stahlmann
R
.
Fluoroquinolone-induced lesions in the epiphyseal growth plates of immature rats
.
Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy
;
September 17–20, 2000
;
Toronto, Ontario, Canada
10.
Sendzik
J
,
Lode
H
,
Stahlmann
R
.
Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data
.
Int J Antimicrob Agents
.
2009
;
33
(
3
):
194
200
11.
von Keutz
E
,
Ruhl-Fehlert
C
,
Drommer
W
,
Rosenbruch
M
.
Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period
.
Arch Toxicol
.
2004
;
78
(
7
):
418
424
12.
US Food and Drug Administration
.
Review and evaluation of pharmacology and toxicology data
. . Accessed June 30, 2010
13.
Sansone
JM
,
Wilsman
NJ
,
Leiferman
EM
,
Conway
J
,
Hutson
P
,
Noonan
KJ
.
The effect of fluoroquinolone antibiotics on growing cartilage in the lamb model
.
J Pediatr Orthop
.
2009
;
29
(
2
):
189
195
14.
Burkhardt
JE
,
Walterspiel
JN
,
Schaad
UB
.
Quinolone arthropathy in animals versus children
.
Clin Infect Dis
.
1997
;
25
(
5
):
1196
1204
15.
Chalumeau
M
,
Tonnelier
S
,
D'Athis
P
, et al
;
Pediatric Fluoroquinolone Safety Study Investigators
.
Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France
.
Pediatrics
.
2003
;
111
(
6 pt 1
).
16.
Schaad
UB
,
Wedgwood-Krucko
J
.
Nalidixic acid in children: retrospective matched controlled study for cartilage toxicity
.
Infection
.
1987
;
15
(
3
):
165
168
17.
Yee
CL
,
Duffy
C
,
Gerbino
PG
,
Stryker
S
,
Noel
GJ
.
Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin
.
Pediatr Infect Dis J
.
2002
;
21
(
6
):
525
529
18.
Bradley
JS
,
Arguedas
A
,
Blumer
JL
,
Saez-Llorens
X
,
Melkote
R
,
Noel
GJ
.
Comparative study of levofloxacin in the treatment of children with community-acquired pneumonia
.
Pediatr Infect Dis J
.
2007
;
26
(
10
):
868
878
19.
Noel
GJ
,
Blumer
JL
,
Pichichero
ME
, et al
.
A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media
.
Pediatr Infect Dis J
.
2008
;
27
(
6
):
483
489
20.
Hooper
DC
.
Mechanisms of quinolone resistance
. In:
Hooper
DC
,
Rubenstein
E
Quinolone Antimicrobial Agents
. 3rd ed.
Washington, DC
:
American Society for Microbiology Press
;
2003
:
41
67
21.
Robicsek
A
,
Jacoby
GA
,
Hooper
DC
.
The worldwide emergence of plasmid-mediated quinolone resistance
.
Lancet Infect Dis
.
2006
;
6
(
10
):
629
640
22.
Johnson
L
,
Sabel
A
,
Burman
WJ
, et al
.
Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates
.
Am J Med
.
2008
;
121
(
10
):
876
884
23.
Qin
X
,
Razia
Y
,
Johnson
JR
, et al
.
Ciprofloxacin-resistant Gram-negative bacilli in the fecal microflora of children
.
Antimicrob Agents Chemother
.
2006
;
50
(
10
):
3325
3329
24.
Talan
DA
,
Krishnadasan
A
,
Abrahamian
FM
,
Stamm
WE
,
Moran
GJ
.
Prevalence and risk factor analysis of trimethoprim-sulfamethoxazole- and fluoroquinolone-resistant Escherichia coli infection among emergency department patients with pyelonephritis
.
Clin Infect Dis
.
2008
;
47
(
9
):
1150
1158
25.
Wang
A
,
Yang
Y
,
Lu
Q
, et al
.
Presence of qnr gene in Escherichia coli and Klebsiella pneumoniae resistant to ciprofloxacin isolated from pediatric patients in China
.
BMC Infect Dis
.
2008
;
8
:
68
26.
Rhomberg
PR
,
Jones
RN
.
Summary trends for the Meropenem Yearly Susceptibility Test Information Collection program: a 10-year experience in the United States (1999–2008)
.
Diagn Microbiol Infect Dis
.
2009
;
65
(
4
):
414
426
27.
Morris
SR
,
Moore
DF
,
Hannah
PB
, et al
.
Strain typing and antimicrobial resistance of fluoroquinolone-resistant Neisseria gonorrhoeae causing a California infection outbreak
.
J Clin Microbiol
.
2009
;
47
(
9
):
2944
2949
28.
Wu
HM
,
Harcourt
BH
,
Hatcher
CP
, et al
.
Emergence of ciprofloxacin-resistant Neisseria meningitidis in North America
.
N Engl J Med
.
2009
;
360
(
9
):
886
892
29.
Smeesters
PR
,
Vergison
A
,
Junior
DC
,
Van Melderen
L
.
Emerging fluoroquinolone-non-susceptible group A streptococci in two different paediatric populations
.
Int J Antimicrob Agents
.
2009
;
34
(
1
):
44
49
30.
Yan
SS
,
Schreckenberger
PC
,
Zheng
X
, et al
.
An intrinsic pattern of reduced susceptibility to fluoroquinolones in pediatric isolates of Streptococcus pyogenes
.
Diagn Microbiol Infect Dis
.
2008
;
62
(
2
):
205
209
31.
Fedler
KA
,
Jones
RN
,
Sader
HS
,
Fritsche
TR
.
Activity of gatifloxacin tested against isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (North America, 1998–2003)
.
Diagn Microbiol Infect Dis
.
2006
;
55
(
2
):
157
164
32.
Adam
HJ
,
Hoban
DJ
,
Gin
AS
,
Zhanel
GG
.
Association between fluoroquinolone usage and a dramatic rise in ciprofloxacin-resistant Streptococcus pneumoniae in Canada, 1997–2006
.
Int J Antimicrob Agents
.
2009
;
34
(
1
):
82
85
33.
Pletz
MW
,
McGee
L
,
Jorgensen
J
, et al
.
Levofloxacin-resistant invasive Streptococcus pneumoniae in the United States: evidence for clonal spread and the impact of conjugate pneumococcal vaccine
.
Antimicrob Agents Chemother
.
2004
;
48
(
9
):
3491
3497
34.
Pletz
MW
,
Shergill
AP
,
McGee
L
,
Beall
B
,
Whitney
CG
,
Klugman
KP
.
Prevalence of first-step mutants among levofloxacin-susceptible invasive isolates of Streptococcus pneumoniae in the United States
.
Antimicrob Agents Chemother
.
2006
;
50
(
4
):
1561
1563
35.
Morrissey
I
,
Colclough
A
,
Northwood
J
.
TARGETed surveillance: susceptibility of Streptococcus pneumoniae isolated from community-acquired respiratory tract infections in 2003 to fluoroquinolones and other agents
.
Int J Antimicrob Agents
.
2007
;
30
(
4
):
345
351
36.
Patel
SN
,
Melano
R
,
McGeer
A
,
Green
K
,
Low
DE
.
Characterization of the quinolone resistant determining regions in clinical isolates of pneumococci collected in Canada
.
Ann Clin Microbiol Antimicrob
.
2010
;
9
:
3
37.
Kyaw
MH
,
Lynfield
R
,
Schaffner
W
, et al
;
Active Bacterial Core Surveillance of the Emerging Infections Program Network
.
Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae
.
N Engl J Med
.
2006
;
354
(
14
):
1455
1463
38.
Davies
TA
,
Leibovitz
E
,
Noel
GJ
,
McNeeley
DF
,
Bush
K
,
Dagan
R
.
Characterization and dynamics of middle ear fluid and nasopharyngeal isolates of Streptococcus pneumoniae from 12 children treated with levofloxacin
.
Antimicrob Agents Chemother
.
2008
;
52
(
1
):
378
381
39.
de la Campa
AG
,
Ardanuy
C
,
Balsalobre
L
, et al
.
Changes in fluoroquinolone-resistant Streptococcus pneumoniae after 7-valent conjugate vaccination, Spain
.
Emerg Infect Dis
.
2009
;
15
(
6
):
905
911
40.
Farrell
DJ
,
Klugman
KP
,
Pichichero
M
.
Increased antimicrobial resistance among nonvaccine serotypes of Streptococcus pneumoniae in the pediatric population after the introduction of 7-valent pneumococcal vaccine in the United States
.
Pediatr Infect Dis J
.
2007
;
26
(
2
):
123
128
41.
Fenoll
A
,
Aguilar
L
,
Granizo
JJ
, et al
.
Has the licensing of respiratory quinolones for adults and the 7-valent pneumococcal conjugate vaccine (PCV-7) for children had herd effects with respect to antimicrobial non-susceptibility in invasive Streptococcus pneumoniae?
J Antimicrob Chemother
.
2008
;
62
(
6
):
1430
1433
42.
Mesaros
N
,
Nordmann
P
,
Plésiat
P
, et al
.
Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium
.
Clin Microbiol Infect
.
2007
;
13
(
6
):
560
578
43.
Boyd
LB
,
Atmar
RL
,
Randall
GL
,
Hamill
RJ
,
Steffen
D
,
Zechiedrich
L
.
Increased fluoroquinolone resistance with time in Escherichia coli from >17,000 patients at a large county hospital as a function of culture site, age, sex, and location
.
BMC Infect Dis
.
2008
;
8
:
4
44.
Kim
JY
,
Lautenbach
E
,
Chu
J
, et al
.
Fluoroquinolone resistance in pediatric bloodstream infections because of Escherichia coli and Klebsiella species
.
Am J Infect Control
.
2008
;
36
(
1
):
70
73
45.
Torkildsen
G
,
Proksch
JW
,
Shapiro
A
,
Lynch
SK
,
Comstock
TL
.
Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration
.
Clin Ophthalmol
.
2010
;
4
:
331
341
46.
Comstock
TL
,
Paterno
MR
,
Usner
DW
,
Pichichero
ME
.
Efficacy and safety of besifloxacin ophthalmic suspension 0.6% in children and adolescents with bacterial conjunctivitis: a post hoc, subgroup analysis of three randomized, double-masked, parallel-group, multicenter clinical trials
.
Paediatr Drugs
.
2010
;
12
(
2
):
105
112
47.
Wagner
RS
,
Abelson
MB
,
Shapiro
A
,
Torkildsen
G
.
Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue
.
Arch Ophthalmol
.
2005
;
123
(
9
):
1282
1283
48.
Kaushik
V
,
Malik
T
,
Saeed
SR
.
Interventions for acute otitis externa
.
Cochrane Database Syst Rev
.
2010
;(
1
):
CD004740
49.
Granath
A
,
Rynnel-Dagoo
B
,
Backheden
M
,
Lindberg
K
.
Tube associated otorrhea in children with recurrent acute otitis media; results of a prospective randomized study on bacteriology and topical treatment with or without systemic antibiotics
.
Int J Pediatr Otorhinolaryngol
.
2008
;
72
(
8
):
1225
1233
50.
Rosenfeld
RM
,
Singer
M
,
Wasserman
JM
,
Stinnett
SS
.
Systematic review of topical antimicrobial therapy for acute otitis externa
.
Otolaryngol Head Neck Surg
.
2006
;
134
(
4 suppl
):
S24
S48
51.
Schwartz
RH
.
Once-daily ofloxacin otic solution versus neomycin sulfate/polymyxin B sulfate/hydrocortisone otic suspension four times a day: a multicenter, randomized, evaluator-blinded trial to compare the efficacy, safety, and pain relief in pediatric patients with otitis externa
.
Curr Med Res Opin
.
2006
;
22
(
9
):
1725
1736
52.
Chien
S
,
Wells
TG
,
Blumer
JL
, et al
.
Levofloxacin pharmacokinetics in children
.
J Clin Pharmacol
.
2005
;
45
(
2
):
153
160
53.
Arguedas
A
,
Dagan
R
,
Pichichero
M
, et al
.
An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media
.
Pediatr Infect Dis J
.
2006
;
25
(
12
):
1102
1109
54.
Richter
SS
,
Heilmann
KP
,
Beekmann
SE
,
Miller
NJ
,
Rice
CL
,
Doern
GV
.
The molecular epidemiology of Streptococcus pneumoniae with quinolone resistance mutations
.
Clin Infect Dis
.
2005
;
40
(
2
):
225
235
55.
DailyMed
.
Factive (gemifloxacin mesylate) table [Oscient Pharmaceuticals] [package insert]
. . Accessed June 30, 2010
56.
DailyMed
.
Avelox (moxifloxacin hydrochloride) injection, solution; Avelox (moxifloxacin hydrochloride) tablet, film coated [Schering Plough Corporation] [package insert]
. . Accessed June 30, 2010
57.
DailyMed
.
Levaquin (levofloxacin) tablet, film coated; Levaquin (levofloxacin) solution; Levaquin (levofloxacin) injection, solution, concentrate; Levaquin (levofloxacin) injection, solution [Ortho-McNeil-Janssen Pharmaceuticals Inc] [package insert]
. . Accessed June 30, 2010
58.
Mandell
LA
,
Wunderink
RG
,
Anzueto
A
, et al
;
Infectious Diseases Society of America, American Thoracic Society
.
Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults
.
Clin Infect Dis
.
2007
;
44
(
suppl 2
):
S27
S72
59.
Davidson
R
,
Cavalcanti
R
,
Brunton
JL
, et al
.
Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia
.
N Engl J Med
.
2002
;
346
(
10
):
747
750
60.
Drusano
GL
,
Louie
A
,
Deziel
M
,
Gumbo
T
.
The crisis of resistance: identifying drug exposures to suppress amplification of resistant mutant subpopulations
.
Clin Infect Dis
.
2006
;
42
(
4
):
525
532
61.
Alghasham
AA
,
Nahata
MC
.
Clinical use of fluoroquinolones in children
.
Ann Pharmacother
.
2000
;
34
(
3
):
347
359
62.
Lynch
MF
,
Blanton
EM
,
Bulens
S
, et al
.
Typhoid fever in the United States, 1999–2006
.
JAMA
.
2009
;
302
(
8
):
859
865
63.
Leibovitz
E
,
Janco
J
,
Piglansky
L
, et al
.
Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children
.
Pediatr Infect Dis J
.
2000
;
19
(
11
):
1060
1067
64.
Centers for Disease Control and Prevention
.
Outbreaks of multidrug-resistant Shigella sonnei gastroenteritis associated with day care centers: Kansas, Kentucky, and Missouri, 2005
.
MMWR Morb Mortal Wkly Rep
.
2006
;
55
(
39
):
1068
1071
65.
Shlim
DR
.
Update in traveler's diarrhea
.
Infect Dis Clin North Am
.
2005
;
19
(
1
):
137
149
66.
Engberg
J
,
Aarestrup
FM
,
Taylor
DE
,
Gerner-Smidt
P
,
Nachamkin
I
.
Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates [published correction appears in Emerg Infect Dis. 2001;7(3):491]
.
Emerg Infect Dis
.
2001
;
7
(
1
):
24
34
67.
American Thoracic Society; CDC; Infectious Diseases Society of America
.
Treatment of tuberculosis [published correction appears in MMWR Recomm Rep. 2005;53(51):1203]
.
MMWR Recomm Rep
.
2003
;
52
(
RR-11
):
1
77
68.
Mitnick
CD
,
Shin
SS
,
Seung
KJ
, et al
.
Comprehensive treatment of extensively drug-resistant tuberculosis
.
N Engl J Med
.
2008
;
359
(
6
):
563
574
69.
Nau
R
,
Sörgel
F
,
Eiffert
H
.
Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections
.
Clin Microbiol Rev
.
2010
;
Oct
;
23
(
4
):
858
83