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Vol 10, No 1, January/February 2002 1 The fluoroquinolones are a group of synthetic antimicrobial agents that are derived from nalidixic acid. The early generations of these broad-spectrum antibiotics were used predominantly for gastrointestinal and genitourinary tract infections with Gram-negative organisms. Use of ciprofloxacin, a second-generation fluoroquinolone, in the treatment of anthrax has recently been much publicized. The third- and fourth- generation agents have a much broader spectrum of action; they have been used in the treatment of pneumonia but also have excellent penetration into bones and joints. However, because of the extensive use of these drugs, resistant bacteria are becoming increas- ingly evident. As a result, they are now the drug of choice in only a few types of clinical situations. Their use in children is severely restricted because of the potential for cartilage damage and growth disturbance. Formulations such as ciprofloxacin are not sig- nificantly metabolized and are excreted unchanged by the kidneys, which raises some ecologic concerns. Structure and Mechanism of Action The feature that distinguishes the fluoroquinolones from nalidixic acid is the presence of a fluorine atom in position 6 (Fig. 1). These agents evolved with changes in their structure at positions 1, 5, 7, and 8. Second- generation agents, such as ciprofloxacin, ofloxacin, and lomefloxacin, are characterized by the addition of a cyclopropyl group at position 1. The third-generation agents, such as sparfloxacin and levofloxacin, also have changes at position 5 (methyl or amino groups) and position 8. In the fourth-generation fluoroquinolones, such as trovafloxacin, gatifloxacin, and moxifloxacin, the six-member piperazine ring at position 7 has been changed to a pyrrolidine group. The mechanism of action of these bactericidal agents is that they selectively target bacterial topoisomerases. The function of the topoisomerases in bacteria is to maintain the correct amount of supercoiling of DNA in both replicating and nonreplicating areas of the chromosomes. DNA gyrase (topoisomerase II) prevents the excessive amount of supercoiling that occurs in the DNA when enzymes cause it to replicate itself; without DNA gyrase, the excessive coiling would stop the DNA replication process. The fluoroquinolones stabilize the complex between the DNA gyrase and the DNA. The replicating fork of the DNA collides with this complex, thereby halting replication. Topoisomerase IV, which helps to separate the two daughter strands of DNA, is also targeted by the fluoroquinolones. If its action is blocked, the daughter strands remain linked, arresting cell replication. The fact that two separate functions of DNA replication are attacked by the fluoroquinolones may account for the differences in the spectrum of activity and the occurrence of resistance between various agents. For example, the activity of the fluoroquinolones against Staphylo- coccus aureus may be based on targeting topoisomerase IV, whereas the activity against Gram-negative bacteria is by targeting topoisomerase II. Mutations of the genes that code for the two topoisomerases in bacteria may vary from species to species. The development of resistance to the fluoroquinolones may also vary. Organisms with resistant mutations to protect both topoisomerase II and topoisomerase IV will have a higher level of resistance than organisms with mutations that protect only one or the other. Pharmacokinetics Many of the fluoroquinolones are available in both parenteral and oral forms (e.g., ciprofloxacin, ofloxacin, levofloxacin, and trovafloxacin). Absorption is excellent with oral administration, yielding blood concentrations similar to those achievable with parenteral administration and allowing early conversion to oral administration. Absorption of oral forms is blocked by decreased stomach acidity as well as by intake of alu- Dr. Levine is Director, Alvin and Lois Lapidus Cancer Institute, Sinai Hospital of Baltimore, Baltimore, Md. Dr. DiBona is Director of the Pharmacy, Lifebridge Health, Sinai Hospital of Baltimore. Reprint requests: Dr. Levine, Sinai Hospital of Baltimore, 2401 W Belvedere Avenue, Baltimore, MD 21215. Copyright 2002 by the American Academy of Orthopaedic Surgeons. J Am Acad Orthop Surg 2002;10:1-4 Fluoroquinolones Alan M. Levine, MD, and John R. DiBona, PharmD Advances in Therapeutics and Diagnostics minum, calcium, zinc, and iron. Ingestion with food delays arrival at the peak serum concentration by about 1 hour. Peak concentrations normally occur 1 to 2 hours after administration. Excretion of fluoroquinolones varies with the for- mulation. Second-generation agents, such as ciprofloxacin, are excreted predominantly by the renal route, whereas most fourth-generation agents are elim- inated by the hepatic route. The pharmacokinetics of the fluoroquinolones are quantitatively altered in the elderly population as compared with younger age groups. As a result of decreased lean body mass and a decline in creatinine clearance in the elderly, these agents exhibit an increased maximal plasma drug concentration and an increase in the area under the plasma concentration curve (AUC) (i.e., a higher dose is available for a longer period). Only ofloxacin and levofloxacin re- quire dose alteration for very old or frail patients. Ofloxacin may be given twice daily rather than once daily. Most fluoroquinolones, particularly the newer agents (e.g., trovafloxacin and moxifloxacin), have some nonrenal clearance mechanism, such as metabolism and transintestinal secretion; therefore, the pharmacokinetics are not altered in the elderly. 1 Indications for Use The fluoroquinolones currently approved for treatment of bone and joint infections are ciprofloxacin, ofloxacin, levofloxacin, and trovafloxacin. These agents appear to have some advantages over other antibiotics in the treatment of osteomyelitis and infections involving prosthetic devices, such as total hip and knee implants. After an initial course of intravenous therapy, they can be administered orally with excellent bioavailability, and they penetrate bone in sufficient concentrations to be active against most Enterobacteriaceae and Pseudomonas species, as well as S aureus. Clinical studies of the serum concentrations of oral fluoroquinolones have shown that they are proportion- ate to the administered dose (in the range of 1 to 2 mg/mL for ciprofloxacin and ofloxacin and even higher for later-generation drugs). 2 The concentrations are also comparable to those achieved with parenteral cephalo- sporins. Peak bone concentrations are between 1 and 2 mg per kilogram of body weight for ciprofloxacin and ofloxacin and are higher for pefloxacin. 2 These values are higher than the MIC 90 (the minimal concentration of antibiotic that inhibits 90% of the growth of a tested strain) for many Gram-negative organisms (e.g., Entero- bacteriaceae), although the AUC-MIC ratio must be greater than 125:1 and in the therapeutic range in most cases for the drug to be effective against S aureus and Pseudomonas organisms. 3 Recent work in animal models has shown that even higher concentrations can be achieved when either methyl methacrylate or biode- gradable beads are used as carriers. Unfortunately, there are few well-controlled clinical studies in which the efficacy of fluoroquinolones in the treatment of chronic osteomyelitis has been assessed. Although fluoroquinolones are now often used for this purpose in patients with diabetes, there is little evidence to support their use. The cure rates in reported series range from 29% to 71%, 2 which is comparable to the results with other antibiotic regimens that provide broader-spectrum coverage. In a number of clinical studies of posttraumatic chronic osteomyelitis, ofloxacin (200 mg every 12 hr) and ciprofloxacin (750 mg every 12 hr) were compared with parenteral antibiotics. The cure rate for fluoroquinolones was approximately 80%, compared with 85% for parenteral regimens used to treat Pseudomonas and S aureus infection; the success rate in treating Enterobacteriaceae infections was even higher. 2 Thus, the fluoroquinolones can be considered to be opti- mal therapy for osteomyelitis due to Enterobacteriaceae infection; however, for Pseudomonas and S aureus, their value with relation to other agents is unclear. Innovative combination therapy with fluoroquinolones has been used to treat arthroplasty-related infections. Patients with S aureus infections develop resistance to rifampin early, but the addition of a fluoroquinolone seems to prevent the emergence of rifampin resistance if given concurrently. 3 In one series, 4 Fluoroquinolones Journal of the American Academy of Orthopaedic Surgeons 2 Figure 1 Relationship between quinolone structure and side effects (GABA = γ-aminobutyric acid; NSAID = nonsteroidal anti- inflammatory drug). (Adapted with permission from Mandell LA, Ball P, Tillotson G: Antimicrobial safety and tolerability: Dif- ferences and dilemmas. Clin Infect Dis 2001;32[suppl 1]:S72-S79.) F X 8 O R 2 R 1 R 5 R 7 COOH N Influences phototoxicity and genetic toxicity (CH 3 >H>NH 2 ) Metal binding and chelation; controls interaction with antacids, milk, iron, divalent cations No side effects associated with this position Controls theophylline interaction and genetic toxicity Effect has not been reported Controls GABA binding, theophylline and NSAID interaction Controls phototoxicity (CF>CCI>N>CH>OMe) patients with acute staphylococcal infections and sta- ble prostheses underwent irrigation and debridement and were then treated with parenteral flucloxacillin or vancomycin (with rifampin) for 2 weeks and then oral ciprofloxacin and rifampin for 3 to 6 months. The success rate was 100%. In another series, 5 patients were initially treated with ofloxacin (600 mg/day) and rifampin (900 mg/day) for 6 months. Prostheses were removed if they were unstable at 5 to 6 months in a one-stage exchange. The results were satisfactory in 76% of patients. The combination of quinolones and rifampin appears to be promising on the basis of these pilot studies; however, further study is clearly indi- cated. In addition to the recently much-publicized use of ciprofloxacin in the treatment of anthrax, there are some special circumstances for the use of fluoroquinolones, including the following 6 : (1) patients with urinary tract infections with Pseudomonas aeruginosa for whom oral ciprofloxacin is preferable to parenteral antibiotics; (2) patients with cystic fibrosis who have respiratory infections with sensitive organisms; (3) patients with multidrug-resistant tuberculosis or infection with atypical mycobacteria for whom a fluoroquinolone would be part of a multidrug regimen; and (4) patients who have serious infections, such as osteomyelitis or pneumonia, due to highly sensitive Gram-negative organisms whose only other alternative is an intravenous antibiotic. Ciprofloxacin is no longer a good empiric choice for hospitalized patients infected with Gram-negative organisms. Furthermore, in general, its use has been curtailed due to rapidly emerging resistance. Although the use of fluoroquinolones is restricted in children because of concerns about arthropathy and growth disturbance, ciprofloxacin, trovafloxacin, gatifloxacin, and moxifloxacin exhibit good activity against methicillin-susceptible S aureus and Staphylococcus pyo- genes, the organisms that most commonly cause acute osteomyelitis and joint infections in immunocompro- mised children. Other drugs are available for that purpose. However, high-dose oral ciprofloxacin for 14 days is an adequate alternative to parenteral therapy for Pseudomonas, methicillin-resistant Staphylococcus, and Salmonella infections. 7 Ciprofloxacin is available on a compassionate-use basis, especially for children with cystic fibrosis and multidrug-resistant infections. 8 Drug Interactions and Adverse Effects Absorption of oral fluoroquinolones is inhibited by divalent cations, such as calcium and aluminum, and can be as low as 10% if administered with either calcium supplements or antacids. 9 The drugs should be administered at least 2 hours before these cations. Cipro- floxacin inhibits the metabolism of both theophylline and caffeine, but later-generation agents do not seem to have the same effect. Nonsteroidal anti-inflammatory agents taken in combination with fluoroquinolones will potentiate central nervous system side effects. The nature and position of the substitutions at the various side-chain positions influence side effects (Fig. 1). There are a growing number of reports of serious side effects associated with the widespread use of ciprofloxacin as well as many of the newer related compounds. As with other antimicrobial agents, the most commonly reported side effects with the use of fluoroquinolones are gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. However, the incidence is related to both the dose and the particular compound. Severe neurotoxic reactions, such as con- vulsions and hallucinations, are rare (<0.5%), but unexplained symptoms such as light-headedness and dizziness are more common, especially in young women. 10 Cutaneous hypersensitivity reactions, such as rash, urticaria, pruritis, and erythema, are relatively uncommon, but photosensitivity has been observed with all of the quinolones. Those formulations with a halogen atom in position 8 (e.g., sparfloxacin and lomefloxacin) seem to have the highest occurrence. Prolongation of the QT interval has also been observed. There seems to be no increased incidence of side effects in the elderly. 1 Of interest to the orthopaedic community are the musculoskeletal side effects, such as arthralgia, chondrotoxicity, effects on growth, and tendinopathy. In animal studies of the quinolones, immature joint cartilage, especially the physeal plate, exhibited toxic effects. In some animal species, these effects can be elicited within the therapeutic range. It is assumed that the pathogenesis of the chondrotoxicity is chelation of magnesium within the joint, which causes radi- cal formation and irreversible cartilage lesions. The histologic changes observed with fluoroquinolones are blister formation on the cartilage surface, chondrocyte loss, matrix degeneration, and erosion of the cartilage followed by noninflammatory effusion in the involved joint. Arthralgias, most of which appear to be reversible with cessation of the drug, occur in about 1.0% to 1.5% of children who do not have cystic fibrosis. 8 The potential for cartilage damage and growth disturbance with these compounds has led to the restricted use of these antimicrobials in children, pregnant women, and nursing mothers, although its use in children with cystic fibrosis and in other study popula- tions 11 has not been associated with any particular problems. Alan M. Levine, MD, and John R. DiBona, PharmD Vol 10, No 1, January/February 2002 3 More than 1,000 cases of fluoroquinolone-induced tendinitis have been reported. 10 Achilles tendinitis and rupture are frequent complications of the use of ciprofloxacin and ofloxacin. Interestingly, 50% of cases are bilateral. The latency period for both tendinitis and rupture is usually between 2 and 60 days, with increased risk for those patients who are older (>60 years), have impaired renal function or diabetes, are receiving corticosteroids on a long-term basis, or are involved in strenuous sports activities. 12 Dosage and Cost The cost of the oral forms of these agents is consider- ably higher than that of many other drugs with similar spectrum coverage (Table 1). However, the dosing fre- quency and the equivalent effectiveness with oral administration make their use appealing. The cost of the intravenous forms may be as high as $60 a day. Summary Fluoroquinolones are a group of synthetic antibiotics that have evolved by means of combinations of addi- tions to various positions on the core quinolone ring structure. They are reasonably well tolerated and have the advantage that oral administration results in serum levels equivalent to those achieved with parenteral administration. They are currently not recommended for use in pediatric patients, pregnant women, or nursing mothers because of concerns about chondrotoxicity and growth arrest. They achieve a high concentration in bone and joint tissue, but the evidence for their effectiveness in treating osteomyelitis and prosthetic infections alone or in combination is not substantial except for P aeruginosa. Their increasing general use for conditions such as pneumonia and urinary tract infections has resulted in rapid emergence of resistant strains. There are ecologic concerns about second- generation agents, such as ciprofloxacin, which are excreted by the renal route and are slowly degraded in the environment. Fluoroquinolones Journal of the American Academy of Orthopaedic Surgeons 4 Table 1 Cost Comparisons for Fluoroquinolone and Other Antibiotics Oral Cost/ Cost/ Antibiotic Dosage * day † month † Levofloxacin (Levaquin) 500 mg qd $8.41 $252 Ciprofloxacin (Cipro) 500 mg bid $8.58 $258 Dicloxacillin (generic) 500 mg qid $1.81 $54 Doxycycline (generic) 100 mg bid $0.17 $5 Rifampin (Rifadin) 300 mg bid $4.06 $122 Clindamycin (generic) 300 mg tid $12.73 $382 * Abbreviations: bid = twice daily; qd = each day; qid = four times a day; tid = thrice daily. † Cost estimates from Epocrates for Palm Pilot and www.drug- store.com. References 1. Nicolle LE: Quinolones in the aged. Drugs 1999;58(suppl 2):49-51. 2. Lew DP, Waldvogel FA: Use of quinolones in osteomyelitis and infected orthopaedic prosthesis. Drugs 1999;58(suppl 2):85-91. 3. Widmer AF: New developments in diagnosis and treatment of infection in orthopedic implants. Clin Infect Dis 2001; 33(suppl 2):S94-S106. 4. Zimmerli W, Widmer AF, Blatter M, et al: Role of rifampin for treatment of orthopedic implant–related staphylococcal infections: A randomized controlled trial. JAMA 1998;279:1537-1541. 5. Drancourt M, Stein A, Argenson JN, Zannier A, Curvale G, Raoult D: Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants. Antimicrob Agents Chemother 1993;37:1214-1218. 6. Walker RC: The fluoroquinolones. Mayo Clin Proc 1999;74: 1030-1037. 7. Dagan R: Fluoroquinolones in paediatrics: 1995. Drugs 1995; 49(suppl 2):92-99. 8. Alghasham AA, Nahata MC: Clinical use of fluoroquinolones in children. Ann Pharmacother 2000;34:347-359. 9. Sanchez Navarro A, Martinez Carbarga M, Dominguez-Gil Hurle A: Comparative study of the influence of Ca2+ on absorption parameters of ciprofloxacin and ofloxacin. J Antimicrob Chemother 1994;34:119-125. 10. Stahlmann R, Lode H: Toxicity of quinolones. Drugs 1999;58 (suppl 2):37-42. 11. Bethell DB, Hien TT, Phi LT, et al: Effects on growth of single short courses of fluoroquinolones. Arch Dis Child 1996;74: 44-46. 12. Casparian JM, Luchi M, Mofffat RE, Hinthorn D: Quinolones and tendon ruptures. South Med J 2000;93:488-491. . mutations to protect both topoisomerase II and topoisomerase IV will have a higher level of resistance than organisms with mutations that protect only one or the other. Pharmacokinetics Many of the fluoroquinolones. re- quire dose alteration for very old or frail patients. Ofloxacin may be given twice daily rather than once daily. Most fluoroquinolones, particularly the newer agents (e.g., trovafloxacin and moxifloxacin),. weight for ciprofloxacin and ofloxacin and are higher for pefloxacin. 2 These values are higher than the MIC 90 (the minimal concentration of antibiotic that inhibits 90% of the growth of a tested strain)