Fluoroquinolones
Urs B. Schaad
Background
Despite class label warnings against use in children, prescriptions for quinolone antibiotics to treat infections in children have become increasingly prevalent. Many of the characteristics of the contemporary fluoroquinolones, the derivatives of the first quinolone antibiotic, nalidixic acid, are particularly appealign for certain pediatric populations. The fluoroquinolones are rapidly bactericidal and have an extended antimicrobial spectrum that includes Pseudomonas, gram-positive cocci, and intracellular pathogens. They have advantageous pharmacokinetic properties, such as absorption from the gastrointestinal tract, excellent penetration into many tissues, and good intracellular diffusion. These antimicrobials have been effective in the treatment or prevention of a variety of bacterial infections in adults, including infections of the respiratory and urinary tracts, skin and soft tissue, bone and joint, and eye and ear. Overall, fluoroquinolones are generally well tolerated; the most frequent adverse events during treatment are gastrointestinal disturbances, reactions of the central nervous system, and skin reactions (1,2).
The use of fluoroquinolones in children has been limited because of their potential to induce arthropathy in juvenile animals (3,4,5). This extraordinary form of age-related drug toxicity has been shown with all the fluoroquinolones tested so far and has led to important restrictions: Their use has been considered to be contraindicated in children, in growing adolescents, and in women during pregnancy and lactation. Since the mid-1980s, many children have received treatment with fluoroquinolones, however, because they are the only oral antimicrobials with potential activity against such multiple resistant and difficult-to-treat infections as Pseudomonas aeruginosa infections in children with cystic fibrosis, complicated urinary tract infections, and enteric infections in developing countries. Results of these trials indicate that prolonged therapy with the fluoroquinolones is effective and well tolerated in pediatric patients, with no significant evidence of arthropathy, bone abnormalities, or other serious adverse events (6). Besides feared arthrotoxicity, the second major concern regarding use of fluoroquinolones in children is the potential impact on bacterial resistance development (6).
Mechanism of Action and Antibacterial Spectrum
Quinolones inhibit bacterial DNA synthesis by targeting the enzymatic activities of DNA gyrase and topoisomerase IV (7). All quinolones have excellent activity against gram-negative bacteria, particularly Enterobacteriaceae, Haemophilus spp., Moraxella catarrhalis, and Neisseria spp. They also have activity against many strains of P. aeruginosa and methicillin-susceptible Staphylococcus aureus but weak activity against methicillin-resistant S. aureus and coagulase-negative staphylococci. Ciprofloxacin is the most potent available fluoroquinolone against gram-negative pathogens. Levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin are more active against gram-positive organisms, including Streptococcus pneumoniae. Atypical pathogens, including Mycoplasma spp., Chlamydia spp., Legionella spp. and Ureaplasma urealyticum, are susceptible to fluoroquinolones. The early fluoroquinolones had limited activity against anaerobes; however, the new compounds (e.g., moxifloxacin and gatifloxacin) have improved anaerobic activity. They also have activity against mycobacteria and excellent intracellular penetration.
Concentrations of fluoroquinolones in bile, lung, and urine are higher than in serum, whereas concentrations in saliva, bone, and cerebrospinal fluid are usually lower than in serum. However, cerebrospinal fluid concentrations are clinically useful for treatment of meningitis.
Quinolone Arthropathy
History
Soon after the marketing of nalidixic acid in 1962, a child with soreness in one wrist during therapy for urinary tract infection was described (8). Nalidixic acid was not initially contraindicated in children but approved for use in children with urinary tract infections in March 1964. Eight years later, another report described a 22-year-old woman who developed severe polyarthritis during a second course of nalidixic acid (9). These “incapacitating” cases of arthralgia/arthritis were considered as allergic manifestations. Data on file of the manufacturers were cited to contain “about a dozen
such reports.” These clinical observations with nalidixic acid prompted experimental exposure of laboratory animals to quinolone compounds. The first observations of quinolone-induced cartilage toxicity made with nalidixic, oxolinic, and pipemidic acid administration to young beagle dogs were reported by Ingham et al. in 1977 (10), Tatsumi et al. in 1978 (11), and Gough et al. in 1979 (3).
such reports.” These clinical observations with nalidixic acid prompted experimental exposure of laboratory animals to quinolone compounds. The first observations of quinolone-induced cartilage toxicity made with nalidixic, oxolinic, and pipemidic acid administration to young beagle dogs were reported by Ingham et al. in 1977 (10), Tatsumi et al. in 1978 (11), and Gough et al. in 1979 (3).
Table 31.1 Retrospective Matched Control Search for Cartilage Toxicity in Nalidixic Acid–Treated Pediatric Patients: Details of Patients and Therapies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Use of Nalidixic Acid in Children
Four groups performed retrospective matched control search for cartilage toxicity in pediatric patients who had received nalidixic acid therapy, in most cases for acute or recurrent urinary tract infections (12,13,14,15). Details of patients and therapies are shown in Table 31.1. History for symptoms and clinical/radiological examinations compatible with possible arthropathies were recorded, and at follow-up examination growth curves and functional and radiological joint findings were obtained. The results were similar in the index and control cases. All reports concluded that nalidixic acid does not cause arthropathy in children, even after long-term and high-dose therapy.
Animal Experiments
All quinolones tested, including the older compounds and the newer derivatives, have been shown to induce changes in immature cartilage of weight-bearing joints in all laboratory animals tested (mice, rats, dogs, marmosets, guinea pigs, rabbits, and ferrets) (2,4,5,16). Quinolone-induced arthropathy is limited to juvenile animals, except when pefloxacin has been used. Juvenile dogs are generally more sensitive to the arthropathic effects of quinolones than are other species. Healing of quinolone-induced arthropathy is incomplete even after complete clinical recovery; structural changes are at least in part irreversible.
Typical histopathological lesions after quinolone exposure include fluid-filled blisters, fissures, erosions, and clustering of chondrocytes, usually accompanied by noninflammatory joint effusion. Under the electron microscope, necrosis of the chondrocytes and swelling of the mitochondria are observed initially, followed by disruption of extracellular matrix (17). Loss of collagen and glycosaminoglycan is an early sequela to the degeneration of chondrocytes (18). When clinically manifested, the quinolone-induced joint lesions present as acute arthritis, including limping and swelling. The specific mechanism(s) responsible for the initiation of quinolone-induced arthropathy has not been determined. At present, inhibition of mitochondrial DNA replication (19) and the role of magnesium deficiency (20,21) are the most discussed hypotheses.
Neither pharmacokinetic nor pharmacodynamic data can explain the variable arthropathic “power” of different compounds. There is also no clear effect of the molecular structure of the given compound regarding its cartilage toxicity (e.g., quinolones that are fluorinated versus quinolones that are not fluorinated).
Possible Monitoring for Quinolone-Induced Cartilage Toxicity in Patients
The available methods for monitoring for quinolone-induced cartilage toxicity are the following:
Histopathology—the gold standard (22).
MRI—the parameters are surface, thickness, and structure of cartilage; presence of effusion (especially recessus suprapatellaris); and bone/cartilage integrity (23,24,25). Predictive value of MRI has been shown in studies with rabbits, pigs, and dogs (26).
Sonography—measurement includes presence/absence of effusion and thickness and surface of cartilage (24,25,26,27).
Clinical examination—indicating symptoms and signs would be arthralgia, limping, and joint swelling and for long-term follow-up growth rate; in many animal experiments, cartilage toxicity was documented without any clinical manifestation.
Review of Published Data
A comprehensive review of published reports including monitoring for quinolone-induced cartilage toxicity in patients was performed (28,29,30,31,32,33,34,35). The reviewed studies included all case reports of suspected quinolone-associated arthralgia/arthropathy in children and adolescents and all multipatient studies on the use of quinolone compounds
in skeletally immature patients (open-label and controlled trials) in which there were data on safety, especially regarding potential arthropathy. Most of the data were based on clinical findings—musculoskeletal complaints and joint examination. Such findings do not allow one to distinguish between coincidental joint problems and quinolone-induced arthropathy. Only rarely MRI, ultrasonography, and growth curve have been used for either short-term or long-term evaluation. With the exception of the findings in two cystic fibrosis patients (22), the gold standard parameter “histopathology” is lacking. There are four conclusions:
in skeletally immature patients (open-label and controlled trials) in which there were data on safety, especially regarding potential arthropathy. Most of the data were based on clinical findings—musculoskeletal complaints and joint examination. Such findings do not allow one to distinguish between coincidental joint problems and quinolone-induced arthropathy. Only rarely MRI, ultrasonography, and growth curve have been used for either short-term or long-term evaluation. With the exception of the findings in two cystic fibrosis patients (22), the gold standard parameter “histopathology” is lacking. There are four conclusions:
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