BIOMIST® 3+15 ULV www.clarkemosquito.com For Use Outdoors as an Ultra-Low Volume (ULV) Application to Control Adult Mosquitoes in Residential andRecreational Areas. health determined by a state, tribal or local health or vector control agency on thebasis of documented evidence of disease causing agents in vector mosquitoes, or thePermethrin (3-Phenoxyphenyl) methyl (+/-) cis,occurrence
Quinolones: a comprehensive review -- american family physicianQuinolones: A Comprehensive Review
CATHERINE M. OLIPHANT, PHARM.D., University of Wyoming School of Pharmacy, Casper, Wyoming
GARY M. GREEN, M.D., Kaiser Permanente, Santa Rosa Medical Center, Santa Rosa, California
With the recent introduction of agents such as gatifloxacin and moxifloxacin, the traditional
gram-negative coverage of fluoroquinolones has been expanded to include specific gram-
positive organisms. Clinical applications beyond genitourinary tract infections include upper
and lower respiratory infections, gastrointestinal infections, gynecologic infections, sexu-
ally transmitted diseases, and some skin and soft tissue infections. Most quinolones have
excellent oral bioavailability, with serum drug concentrations equivalent to intravenous
administration. Quinolones have few adverse effects, most notably nausea, headache,
dizziness, and confusion. Less common but more serious adverse events include prolonga-
tion of the corrected QT interval, phototoxicity, liver enzyme abnormalities, arthropathy,
and cartilage and tendon abnormalities. The new fluoroquinolones are rarely first-line
agents and should be employed judiciously. Inappropriate use of agents from this impor-
tant class of antibiotics will likely worsen current problems with antibiotic resistance. Appli-
cations of fluoroquinolones in biologic warfare are also discussed. (Am Fam Physician
2002;65:455-64. Copyright 2002 American Academy of Family Physicians.)
When used in combination with agents from other antibiotic classes, such as beta-lactams and aminoglycosides, the quinolones are not series, is chairmanand residency program director of the Department (NegGram), was introduced in1962. Since then, structural modi-fications have resulted in second-, predictably synergistic.1 Although the effects of most combinations are indifferent or additive, fluoroquinolones, which have improved cover- ciprofloxacin (Cipro) and rifampin (Rifadin) appear to be antagonistic against Staphylococ- Mechanism of Action
oral administration, with moderate to excel- by promoting cleavage of bacterial DNA in the lent bioavailability.1,4 Serum drug levels achieved after oral administration are compa- type IV topoisomerase, resulting in rapid bac- rable to those with intravenous dosing, which terial death.1-3 As a general rule, gram-nega- allows an early transition from intravenous to tive bacterial activity correlates with inhibi- oral therapy and a potential reduction of bacterial activity corresponds with inhibition Food does not impair the absorption of most quinolones. However, quinolones chelate withcations such as aluminum, magnesium, cal- Pharmacokinetics
cium, iron, and zinc. This interaction signifi- Like aminoglycosides, the quinolones exhibit cantly reduces absorption and bioavailability, concentration-dependent bacterial killing. Bac- resulting in lower serum drug concentrations tericidal activity becomes more pronounced as the serum drug concentration increases to ap- Elimination half-lives for the quinolones proximately 30 times the minimum inhibitory vary from 1.5 to 16 hours. Therefore, most of concentration (MIC).1,4 Higher drug concen- these drugs are administered every 12 to trations paradoxically inhibit RNA and protein 24 hours. The quinolones are eliminated by synthesis, thereby reducing bactericidal activ- renal and nonrenal routes. To avoid toxicity, ity.1 Quinolones have a postantibiotic effect of dosages often need to be adjusted in patients tion quinolones in the treatment of staphylo- Mutations may occur rapidly during fluoroquinolone therapy coccal, streptococcal, and enterococcal in-fections.9 The presently available fluoro- and may be the most significant factor limiting the use of quinolones with in vitro activity against Streptococcus pneumoniae (including currentpenicillin-resistant strains) are levofloxacin(Levaquin), sparfloxacin, gatifloxacin (Te- majority of quinolones are excreted renally; quin), moxifloxacin, and trovafloxacin. Levo- however, sparfloxacin (Zagam), moxifloxacin floxacin and sparfloxacin exhibit inferior in vitro streptococcal activity compared with gatifloxacin, moxifloxacin, and trovafloxacin.
Quinolones are widely distributed through- Gatifloxacin is two to four times more active out the body. Tissue penetration is higher than levofloxacin against S. pneumoniae in than the concentration achieved in plasma, vitro, and moxifloxacin is four to eight times stool, bile, prostatic tissue, and lung tissue.
more active.11 Compared with ciprofloxacin Intracellular concentration is exceptional in and levofloxacin, the fluoroquinolones gati- floxacin, moxifloxacin, and trovafloxacin have also penetrate well in urine and kidneys when greater in vitro activity against S. aureus and renal clearance is the route of drug elimina- tion. Penetration into prostatic fluid, saliva, bone, and cerebrospinal fluid does not exceed have in vitro anaerobic activity, only trova- serum drug levels. Because cerebrospinal fluid floxacin is labeled for the treatment of anaero- levels of quinolones are predictably poor, bic infections. Clinafloxacin, an investiga- these agents are inadequate for first-line treat- tional fluoroquinolone, has the most potent in Ciprofloxacin, ofloxacin (Floxin), and the Antimicrobial Activity
The quinolones can be classified into four intracellular concentrations. Moxifloxacin, generations based on antimicrobial activity gatifloxacin, levofloxacin, and the investiga- (Table 1).8 First-generation agents, which are tional drug gemifloxacin have exceptional ac- used less often today, have moderate gram- tivity against Legionella, Chlamydia, Myco- negative activity and minimal systemic distri- plasma, and Ureaplasma species.9 Intracellular bution. Second-generation quinolones have respiratory pathogens such as Chlamydia expanded gram-negative activity and atypical pneumoniae, Mycoplasma pneumoniae, and pathogen coverage, but limited gram-positive Legionella pneumophila are predictably sus- activity. These agents are most active against ceptible to fluoroquinolones.1,9 These antibi- aerobic gram-negative bacilli. Ciprofloxacin otics are regarded as second-line antitubercu- remains the quinolone most active against lous agents and should be reserved for the Pseudomonas aeruginosa.1,9,10 Third-genera- treatment of resistant tuberculosis.
tion quinolones retain expanded gram-nega-tive and atypical intracellular activity but have Resistance to Quinolones
improved gram-positive coverage. Finally, fourth-generation agents improve gram-posi- nisms and significant clinical impact. Muta- tive coverage, maintain gram-negative cover- Marginal susceptibility and acquired resis- significant factor limiting the use of these tance limit the usefulness of second-genera- Quinolones
Comparison of Quinolone Generations
Administration and characteristics Nosocomial infectionsSexually transmitted diseasesNot for use in community-acquired pneumonia because of associations with pneumococcal bacteremia and meningeal seeding due to poorpneumococcal susceptibility) nonhospitalized patients with risk factors for resistant pneumococcal infection† susceptible coverageStaphylococcus aureus, streptococci, anaerobes *—Sparfloxacin and trovafloxacin have significant nonrenal elimination pathways; these agents should not be used to treat urinary tractinfections.
†—Risk factors for penicillin-resistant pneumococcal infection include age younger than five years or older than 65 years, recent courseof antibiotics, comorbid disease or alcohol abuse, immunodeficiency state or human immunodeficiency virus infection, day-care atten-dance, recent hospitalization, and institutionalization (e.g., long-term care facility, prison). Adapted with permission from Owens RC Jr, Ambrose PG. Clinical use of the fluoroquinolones. Med Clin North Am 2000;84:1447-69. In vitro susceptibility to methicillin-resis- nary tract infections caused by susceptible tant S. aureus, methicillin-resistant Staphylo- coccus epidermidis, and vancomycin-resistant Enterococcus species is variable and unpre- clude those in patients with stones or obstruc- dictable. Although the newer fluoroquino- tive uropathies and in patients with catheter- lones have shown promising in vitro activity related infections. These infections are often against gram-positive bacteria based on MIC associated with nosocomial, antibiotic-resis- tant gram-negative pathogens and gram-posi- using quinolone antibiotics to treat life- tive bacteria, and with Candida species.
threatening gram-positive infections. Con- Because ciprofloxacin, ofloxacin, lomefloxacin tinued overuse of these antimicrobials in clin- floxacin, and gatifloxacin have higher renal clearance and greater renal concentration, they resistance and is likely to limit the effectiveness are optimal choices for the treatment of com- of the quinolones in the near future. Overuse of a single agent will ultimately result in resis- effective than trimethoprim-sulfamethoxa-zole and aminoglycosides in seven- to 10-day Therapeutic Uses of Quinolones
courses for the treatment of complicated uri- GENITOURINARY INFECTIONS
nary tract infections. However, few patients maintain sterile urine six weeks after any coverage, quinolone antibiotics were initially antibiotic therapy.1,9 Bacterial resistance and used to treat urinary tract infections. The Candida superinfection often limit treatment in complicated urinary tract infections, with that occur with renally cleared quinolones an estimated failure rate of at least 2 per- promote their effectiveness in the treatment cent.15,16 Failure rates as high as 20 percent of genitourinary infections. Given in three- to may be encountered with infections caused 10-day courses, most quinolones are as effec- by pathogens such as P. aeruginosa.1 tive as trimethoprim-sulfamethoxazole (Bac- A seven- to 10-day course of orally admin- trim, Septra) in treating uncomplicated uri- istered norfloxacin (Noroxin) or ofloxacinhas been successful in the treatment ofuncomplicated pyelonephritis, with a bacteri-ologic cure rate equal to that for trimetho-prim-sulfamethoxazole.1 In the treatment of acute uncomplicated pyelonephritis in non- CATHERINE M. OLIPHANT, PHARM.D., is associate professor of pharmacy practice at pregnant women, similar efficacy has been the University of Wyoming School of Pharmacy, Casper. Dr. Oliphant received her doc-tor of pharmacy degree from the University of Michigan College of Pharmacy, Ann shown for levofloxacin, in a dosage of 250 mg Arbor. She completed an American Society of Health System Pharmacists general res- idency and a fellowship in infectious diseases and microbiology at Northwestern floxacin, in a dosage of 500 mg twice daily for 10 days. However, relapses were more com- GARY M. GREEN, M.D., is infectious diseases chief at Kaiser Permanente, Santa Rosa mon with levofloxacin.1,9 Gatifloxacin, in a (Calif.) Medical Center. Dr. Green received his medical degree from Georgetown Uni-versity School of Medicine, Washington, D.C. He completed a residency in internal medicine at the Medical Center of Delaware, Newark, Del., and St. Joseph’s Hospital, favorably with ciprofloxacin, in a dosage of Phoenix, and a fellowship in infectious diseases at the University of California, Los 500 mg twice daily, in the treatment of com- Address correspondence to Catherine M. Oliphant, Pharm.D., Wyoming Medical pyelonephritis, with cure rates of 93 percent Center, Department of Pharmacy, 1233 E. 2nd St., Casper, WY 82601 (e-mail: firstname.lastname@example.org). Reprints are not available from the authors. Quinolones
Fluoroquinolones, especially levofloxacin and ciprofloxacin, are valuable in the treatment Quinolones are effective in the treatment of prostatitis of complicated urinary tract infections and because of their excellent penetration into prostatic tissue. pyelonephritis. Yet bacterial resistance, relapseof infections, and recurrent infections remaincritical issues. Complex genitourinary tractinfections continue to be a niche for this antibi- Acute bronchitis may follow a viral illness, but antimicrobial therapy generally is notwarranted unless the patient has underlying PROSTATITIS
pulmonary disease. Fluoroquinolone therapy Quinolones are effective in the treatment of for acute bacterial bronchitis has been effec- prostatitis because of their excellent penetra- tive against H. influenzae and M. catarrhalis, tion into prostatic tissue. When taken for four the primary pathogens.1,9 The use of cipro- to six weeks, norfloxacin, ciprofloxacin, levo- floxacin for S. pneumoniae and P. aeruginosa floxacin, and ofloxacin have eradication rates bronchitis has resulted in clinical treatment of 67 to 91 percent.1,17 Treatment failures have failures and the development of bacterial resistance.1 Generally, levofloxacin, spar- courses (e.g., two weeks) and less susceptible floxacin, ofloxacin, gatifloxacin, and moxi- bacteria, specifically P. aeruginosa and Ente- cefuroxime, cefaclor (Ceclor), amoxicillin- Levofloxacin is an excellent first-line agent in the treatment of prostatitis. Ciprofloxacin sixth leading cause of death in the United with resistant gram-negative, pseudomonal, States. Even with optimal therapy, this illness and enterococcal prostatitis, because of its is associated with mortality rates of approxi- superior activity against P. aeruginosa and mately 14 percent in hospitalized patients and less than 1 percent in patients not requiringhospitalization.19,20 S. pneumoniae, H. influen- RESPIRATORY DISEASES
zae, and M. pneumoniae are the pathogens Acute bacterial sinusitis may be the compli- cation of an initial viral illness. The primary acquired pneumonia; less commonly isolated bacterial isolates are S. aureus, S. pneumoniae, pathogens include viruses, S. aureus, C. pneu- Haemophilus influenzae, and Moraxella moniae, M. catarrhalis, Klebsiella pneumoniae, catarrhalis.9 The U.S. Food and Drug Admin- and L. pneumophila.19,20 The pathogens most istration (FDA) has labeled gatifloxacin, often responsible for death in patients with moxifloxacin, sparfloxacin, and levofloxacin community-acquired pneumonia are S. pneu- for use in the treatment of acute bacterial moniae, S. aureus, and L. pneumophila.
sinusitis. Clinical trials comparing fluoro- Antibiotic choices for outpatient and in- quinolones with amoxicillin–clavulanate patient treatment of pneumonia were stratified in a recent consensus statement from the Infec- (Ceftin), and clarithromycin (Biaxin) have tious Diseases Society of America (IDSA)19 and demonstrated the efficacy of the quinolone in guidelines formulated by the Centers for antibiotics.9 However, we believe that quino- Disease Control and Prevention (CDC).20 Pref- lones should not be used as first-line agents in erence was not given to a specific antibiotic the treatment of acute bacterial sinusitis class. Listed antibiotic choices for outpatient because of the potential for development of treatment included macrolides, doxycycline (Vibramycin), and fluoroquinolones. Antibi- otic choices for hospitalized patients included moxifloxacin or gatifloxacin an attractive fluoroquinolones or extended-spectrum peni- choice for pneumococcal infections, these cillins (piperacillin [Pipracil], piperacillin- agents should probably be reserved for treat- tazobactam [Zosyn], or ampicillin-sulbactam ment of infections with atypical pathogens or for life-threatening pneumonias.1,9,11,21,22 rem] and imipenem-cilastatin [Primaxin]) and Of the fluoroquinolones, ciprofloxacin and cephalosporins, plus adjunctive macrolides, trovafloxacin have been studied most exten- aminoglycosides, clindamycin (Cleocin), or sively in the treatment of nosocomial pneu- monia. Ciprofloxacin has been found to be pneumonia in patients hospitalized in a gen- statin in mechanically ventilated patients, especially those infected with pathogens from the Enterobacteriaceae family, but it has also (cefotaxime [Claforan] or ceftriaxone [Roceph- been associated with poorer responses and in]), or a beta-lactam/beta lactamase inhibitor higher clinical failure rates in patients with nosocomial pneumonia caused by S. aureus quinolone alone (levofloxacin, gatifloxacin, or or P. aeruginosa.1 The efficacy of the newer moxifloxacin [listed in order of improved quinolones (moxifloxacin and gatifloxacin) activity against S. pneumoniae]). For the treat- in the treatment of nosocomial pneumonia is ment of patients hospitalized in an intensive currently being assessed in clinical trials.
care unit, the IDSA guidelines recommend a macrolide or a fluoroquinolone (levofloxacin, combination antimicrobial therapy for noso- therapy may worsen the increasing problem of taxime or ceftriaxone) or a beta-lactam/beta- antibiotic resistance in the nosocomial setting.
We are cautious when using quinolones and SEXUALLY TRANSMITTED DISEASES
macrolides in elderly patients because of drug interactions and adverse effects. In addition, ceftriaxone is the agent of choice for treat- fluoroquinolones should not be used as first- ment of uncomplicated Neisseria gonorrhoeae line agents for empiric therapy unless a life- urethritis and cervicitis. A single dose of threatening or “atypical pneumonia” (e.g., ciprofloxacin or ofloxacin should be consid- L. pneumophila infection) is suspected.
ered as alternative treatment in, for example, For the treatment of atypical pneumonias, patients with penicillin allergy.23 Recently, macrolides are likely to be equivalent to fluoro- gatifloxacin was reported to be as effective as quinolones and are currently more cost-effec- ofloxacin against N. gonorrhoeae.11 A seven- tive. Quinolones provide exceptional cover- day course of ofloxacin or sparfloxacin has age against atypical pathogens when infection been found to be as effective as doxycycline in with these organisms is suspected in patients the treatment of C. trachomatis infections.
Finally, ciprofloxacin has been reported to be ever, ofloxacin has been associated with treat- as effective as trimethoprim-sulfamethoxa- ment failures, and ciprofloxacin has displayed reduced activity against Chlamydia species.1,9 Pelvic inflammatory disease is a polymicro- floxacin and gatifloxacin have been shown to bial infection. Quinolone treatment options have superior in vitro activity against pneu- include ofloxacin plus metronidazole, ofloxa- Quinolones
floxacin plus clindamycin.1,9 Fluoroquin-olone monotherapy is incomplete.
Gastrointestinal and central nervous system effects (e.g., headaches, dizziness, drowsiness) are the most GASTROENTERITIS
frequent adverse events with quinolone therapy. Prophylactic antimicrobial therapy is not recommended for the prevention of diarrheain travelers.9 Norfloxacin or ciprofloxacin hasbeen found to be comparable to trimetho- prim-sulfamethoxazole in the treatment of activity; thus, they should not be considered traveler’s diarrhea caused by Shigella species, first-line agents for skin and soft tissue infec- enterotoxigenic E. coli, or Campylobacter tions. Diabetic foot infections, which are polymicrobial, can be treated with quinolones Ciprofloxacin and ofloxacin are the agents in combination with other antibiotics.9 We of choice for treatment of enteric typhoid exercise caution when S. aureus is isolated.
fever.1 Norfloxacin has been found to besuperior to both trimethoprim-sulfamethox- Adverse Events
azole and doxycycline in the treatment of Vib- Although quinolones are well tolerated and relatively safe, certain adverse effects are com-mon with all agents in this antibiotic class SKIN AND SOFT TISSUE INFECTIONS
(Table 2).5,6,11,24-35 Gastrointestinal and cen- Because of limited data, the role of fluoro- tral nervous system (CNS) effects are the quinolones in the treatment of skin and soft most frequent adverse events, occurring in tissue infections remains uncertain. Most flu- 2 to 20 percent of patients treated withquinolones.3,5,6,33-35 Prolongation of the corrected QT interval Adverse Effects of Quinolones*
arrhythmias such as torsades de pointes. Sec-ondary to its effects in prolonging the QTc, Gastrointestinal: nausea, vomiting, diarrhea, grepafloxacin (Raxar) was withdrawn from the U.S. market in 1999. Because of reported QTc CNS: headache, dizziness, drowsiness, confusion, prolongation, sparfloxacin and moxifloxacin should not be used in patients with a known somnolence, seizures, vertigo, lightheadedness, restlessness, tremor predisposition to arrhythmias (e.g., hypoka- Dermatologic: rash, photosensitivity reactions, lemia, bradycardia) or in patients who are receiving antiarrhythmic drugs or other med- Other: QTc prolongation, hepatotoxicity, abnormal ications that might prolong the QTc.11,24-27,33,34 Drug Interactions
CNS = central nervous system; QTc = corrected QT Clinically significant drug interactions are known to occur with all quinolones (Table *—Because quinolones have been associated with 3).6,7,11,24-32 When products containing multi- arthropathy and chondrotoxicity in immature ani- valent cations (calcium, aluminum, magne- mals, they are not recommended for use in childrenand adolescents younger than 18 years of age, or in sium, iron, zinc), including sucralfate (Cara- fate), antacids, nutritional supplements, and Information from references 5, 6, 11, and 24 multivitamin and mineral supplements, are taken within two to four hours of an orallyadministered quinolone, the maximum in the United States. Fluoroquinolones have a be reduced by 25 percent to approximately chemotherapy for specific agents that couldbe used in biologic warfare (Table 4).37 Spe- Applications of Fluoroquinolones
cific fluoroquinolones are indicated for pro- in Biologic Warfare
phylaxis or treatment of anthrax, cholera, Bacillus anthracis (anthrax) spores have plague, brucellosis, and tularemia. Cipro- recently been deployed as a biologic weapon floxacin is the drug of choice for postexpo- TABLE 3
Potential Interactions Between Quinolones and Other Drugs
Decreased absorption of quinolones if didanosine (Videx) or multivalent cations are administered
concomitantly or less than two hours before or after a quinolone.† May increase anticoagulant effects of warfarin (Coumadin)‡May increase caffeine levels§May increase cyclosporine (Sandimmune) levels§May increase theophylline levels§May prolong QTc if used concomitantly with antiarrhythmics (e.g., class IA and III agents) or with May increase risk of CNS stimulation and convulsions if used concomitantly with nonsteroidal May lead to hypoglycemia and/or hyperglycemia if used concomitantly with antidiabetic agents Gatifloxacin (Tequin)
Increased serum digoxin (Lanoxin) levels#
Decreased absorption if used concomitantly with sodium citrate and citric acid oral solution (Bicitra)
Decreased effect of orally administered trovafloxacin if used concomitantly with intravenously administered
QTc = corrected QT interval; CNS = central nervous system. *—Listed as interactions with quinolones as a class; interactions may be more likely with some quinolonesthan others. †—Products that contain multivalent cations (calcium, aluminum, magnesium, iron, and zinc) include antacids,nutritional supplements, and multivitamin and mineral supplements. Newer fluoroquinolones, such as gati-floxacin (Tequin), moxifloxacin (Avelox), and trovafloxacin (Trovan), may not interact significantly with calcium-containing products. Avoid concomitant use of fluoroquinolones and sucralfate (Carafate). ‡—Because some fluoroquinolones are known to enhance the effects of warfarin, the prothrombin time andInternational Normalized Ratio should be monitored closely if warfarin or a warfarin derivative is used con-comitantly with any quinolone.
§—Monitor for toxicity.
||—Although cisapride has been removed from the market, it can still be obtained from the manufacturer.
¶—Monitoring of blood glucose levels may be recommended.
#—Clinical significance is unknown. Information from references 6, 7, 11, and 24 through 32. Quinolones
Selected Potential Biologic Pathogens: Postexposure Prophylaxis and Treatment
Agent of choice: ciprofloxacin (Cipro)* Agents of choice: ciprofloxacin, doxycycline Agents of choice: oral rehydration therapy, tetracycline, doxycycline, ciprofloxacin, norfloxacin (Noroxin) Agents of choice: streptomycin, gentamicin, Agents of choice: doxycycline plus rifampin Alternative: ofloxacin (Floxin) plus rifampin Francisella tularensis Agent of choice: doxycycline Alternatives: tetracycline, ciprofloxacin Alternatives: gentamicin, ciprofloxacin *—Levofloxacin (Levaquin) and ofloxacin are alternatives for postexposure prophylaxis in mass casualty settings. Adapted from Kortepeter M, et al., eds. USAMRIID’s Medical management of biological casualties handbook.
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PUBLICATIONS 43) E. Kogut, A. Zeller, T.H. Warren*, T. Strassner*, Structure and Dynamics of Neutral β- Agostic Nickel-Alkyls A Combined Experimental and Theoretical Study', submitted. 42) L.D. McPherson, M. Drees, S.I. Khan, T. Strassner*, M.M. Abu-Omar*, 'Multielectron Atom Transfer Reactions of Perchlorate and Other Substrates Catalyzed by Rhenium Oxazoline and Thiazoline Complexes: R