Quinolones

FEBRUARY 1, 2002 / VOLUME 65, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 455

When used in combination with agents fromother antibiotic classes, such as beta-lactamsand aminoglycosides, the quinolones are notpredictably synergistic.1 Although the effects ofmost combinations are indifferent or additive,ciprofloxacin (Cipro) and rifampin (Rifadin)appear to be antagonistic against Staphylococ-cus aureus.5

Quinolones are well absorbed followingoral administration, with moderate to excel-lent bioavailability.1,4 Serum drug levelsachieved after oral administration are compa-rable to those with intravenous dosing, whichallows an early transition from intravenous tooral therapy and a potential reduction oftreatment costs.6

Food does not impair the absorption of mostquinolones. However, quinolones chelate withcations such as aluminum, magnesium, cal-cium, iron, and zinc. This interaction signifi-cantly reduces absorption and bioavailability,resulting in lower serum drug concentrationsand less target-tissue penetration.1,4

Elimination half-lives for the quinolonesvary from 1.5 to 16 hours. Therefore, most ofthese drugs are administered every 12 to 24 hours. The quinolones are eliminated byrenal and nonrenal routes. To avoid toxicity,dosages often need to be adjusted in patientswith renal or hepatic impairment.1,4 The

The first quinolone, nalidixic acid(NegGram), was introduced in1962. Since then, structural modi-fications have resulted in second-,third-, and fourth-generation

fluoroquinolones, which have improved cover-age of gram-positive organisms.

Mechanism of ActionQuinolones rapidly inhibit DNA synthesis

by promoting cleavage of bacterial DNA in theDNA-enzyme complexes of DNA gyrase andtype IV topoisomerase, resulting in rapid bac-terial death.1-3 As a general rule, gram-nega-tive bacterial activity correlates with inhibi-tion of DNA gyrase, and gram-positivebacterial activity corresponds with inhibitionof DNA type IV topoisomerase.1

PharmacokineticsLike aminoglycosides, the quinolones exhibit

concentration-dependent bacterial killing. Bac-tericidal activity becomes more pronounced asthe serum drug concentration increases to ap-proximately 30 times the minimum inhibitoryconcentration (MIC).1,4 Higher drug concen-trations paradoxically inhibit RNA and proteinsynthesis, thereby reducing bactericidal activ-ity.1 Quinolones have a postantibiotic effect ofabout one to two hours.1

With the recent introduction of agents such as gatifloxacin and moxifloxacin, the traditionalgram-negative coverage of fluoroquinolones has been expanded to include specific gram-positive organisms. Clinical applications beyond genitourinary tract infections include upperand lower respiratory infections, gastrointestinal infections, gynecologic infections, sexu-ally transmitted diseases, and some skin and soft tissue infections. Most quinolones haveexcellent oral bioavailability, with serum drug concentrations equivalent to intravenousadministration. 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-lineagents 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 Physician2002;65:455-64. Copyright© 2002 American Academy of Family Physicians.)

Quinolones: A Comprehensive ReviewCATHERINE M. OLIPHANT, PHARM.D., University of Wyoming School of Pharmacy, Casper, WyomingGARY M. GREEN, M.D., Kaiser Permanente, Santa Rosa Medical Center, Santa Rosa, California

Richard W. Sloan,M.D., R.PH.,coordinator of thisseries, is chairmanand residency program director of the Department of Family Medicine atYork (Pa.) Hospital andclinical associate pro-fessor in family andcommunity medicine at the Milton S. HersheyMedical Center, Pennsylvania StateUniversity, Hershey, Pa.

CLINICAL PHARMACOLOGY

majority of quinolones are excreted renally;however, sparfloxacin (Zagam), moxifloxacin(Avelox), and trovafloxacin (Trovan) areexcreted hepatically.

Quinolones are widely distributed through-out the body. Tissue penetration is higherthan the concentration achieved in plasma,stool, bile, prostatic tissue, and lung tissue.Intracellular concentration is exceptional inneutrophils and macrophages. Quinolonesalso penetrate well in urine and kidneys whenrenal clearance is the route of drug elimina-tion. Penetration into prostatic fluid, saliva,bone, and cerebrospinal fluid does not exceedserum drug levels. Because cerebrospinal fluidlevels of quinolones are predictably poor,these agents are inadequate for first-line treat-ment of meningitis.1,4,7

Antimicrobial ActivityThe quinolones can be classified into four

generations based on antimicrobial activity(Table 1).8 First-generation agents, which areused less often today, have moderate gram-negative activity and minimal systemic distri-bution. Second-generation quinolones haveexpanded gram-negative activity and atypicalpathogen coverage, but limited gram-positiveactivity. These agents are most active againstaerobic gram-negative bacilli. Ciprofloxacinremains the quinolone most active againstPseudomonas aeruginosa.1,9,10 Third-genera-tion quinolones retain expanded gram-nega-tive and atypical intracellular activity but haveimproved gram-positive coverage. Finally,fourth-generation agents improve gram-posi-tive coverage, maintain gram-negative cover-age, and gain anaerobic coverage.10

Marginal susceptibility and acquired resis-tance limit the usefulness of second-genera-

tion quinolones in the treatment of staphylo-coccal, streptococcal, and enterococcal in-fections.9 The presently available fluoro-quinolones with in vitro activity againstStreptococcus pneumoniae (including currentpenicillin-resistant strains) are levofloxacin(Levaquin), sparfloxacin, gatifloxacin (Te-quin), moxifloxacin, and trovafloxacin. Levo-floxacin and sparfloxacin exhibit inferior invitro streptococcal activity compared withgatifloxacin, moxifloxacin, and trovafloxacin.Gatifloxacin is two to four times more activethan levofloxacin against S. pneumoniae invitro, and moxifloxacin is four to eight timesmore active.11 Compared with ciprofloxacinand levofloxacin, the fluoroquinolones gati-floxacin, moxifloxacin, and trovafloxacin havegreater in vitro activity against S. aureus andsome Enterococcus strains.11,12

Although gatifloxacin and moxifloxacinhave in vitro anaerobic activity, only trova-floxacin is labeled for the treatment of anaero-bic infections. Clinafloxacin, an investiga-tional fluoroquinolone, has the most potent invitro anaerobic activity.13

Ciprofloxacin, ofloxacin (Floxin), and thenewer fluoroquinolones have exceptionalintracellular concentrations. Moxifloxacin,gatifloxacin, levofloxacin, and the investiga-tional drug gemifloxacin have exceptional ac-tivity against Legionella, Chlamydia, Myco-plasma, and Ureaplasma species.9 Intracellularrespiratory pathogens such as Chlamydiapneumoniae, Mycoplasma pneumoniae, andLegionella pneumophila are predictably sus-ceptible to fluoroquinolones.1,9 These antibi-otics are regarded as second-line antitubercu-lous agents and should be reserved for thetreatment of resistant tuberculosis.

Resistance to QuinolonesQuinolone resistance has multiple mecha-

nisms and significant clinical impact. Muta-tions may occur rapidly during fluoro-quinolone therapy and may be the mostsignificant factor limiting the use of theseantimicrobials.

456 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 65, NUMBER 3 / FEBRUARY 1, 2002

Mutations may occur rapidly during fluoroquinolone therapyand may be the most significant factor limiting the use ofthese antimicrobials.

Quinolones


TABLE 1

Comparison of Quinolone Generations

Quinolone generations Microbiologic activity Administration and characteristics Indications

First generationNalidixic acid Enterobacteriaceae Oral administration Uncomplicated urinary tract infections

(NegGram) Low serum and tissue drug Not for use in systemic infectionsCinoxacin (Cinobac) concentrations

Narrow gram-negative coverage

Second generationClass I Enterobacteriaceae Oral administration Uncomplicated urinary tract infections

Lomefloxacin Low serum and tissue drug Not for use in systemic infections(Maxaquin) concentrations

Norfloxacin (Noroxin) Improved gram-negative coverage Enoxacin (Penetrex) compared with first-generation

quinolonesLimited gram-positive coverage

Class IIOfloxacin (Floxin) Enterobacteriaceae, Oral and intravenous administration Complicated urinary tract and Ciprofloxacin (Cipro) atypical pathogens; Higher serum, tissue, and intracellular catheter-related infections

Pseudomonas aeruginosa drug concentrations compared with Gastroenteritis with severe diarrhea(ciprofloxacin only) class I agents Prostatitis

Coverage of atypical pathogens Nosocomial infectionsSexually transmitted diseasesNot for use in community-acquired

pneumonia because of associations with pneumococcal bacteremia and meningeal seeding due to poorpneumococcal susceptibility)

Third generationLevofloxacin (Levaquin) Enterobacteriaceae, Oral and intravenous administration Similar indications as for second-Sparfloxacin (Zagam)* atypical pathogens, Similar to class II second-generation generation quinolonesGatifloxacin (Tequin) streptococci quinolones but with modest Community-acquired pneumonia in Moxifloxacin (Avelox) streptococcal coverage hospitalized patients or if atypical

Increased hepatic metabolism pathogens are strongly suspected(sparfloxacin and moxifloxacin) Community-acquired pneumonia in

nonhospitalized patients with risk factors for resistant pneumococcal infection†

Fourth generationTrovafloxacin (Trovan)* Enterobacteriaceae, Oral and intravenous administration Consider for treatment of

P. aeruginosa (reduced Similar to third-generation quinolones intra-abdominal infections.or absent), atypical but with improved gram-positive pathogens, methicillin- coverage and added anaerobic 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-tant S. aureus, methicillin-resistant Staphylo-coccus epidermidis, and vancomycin-resistantEnterococcus species is variable and unpre-dictable. Although the newer fluoroquino-lones have shown promising in vitro activityagainst gram-positive bacteria based on MICdata, physicians should be cautious whenusing quinolone antibiotics to treat life-threatening gram-positive infections. Con-tinued overuse of these antimicrobials in clin-ical medicine and agricultural feed willpromote gram-positive and gram-negativeresistance and is likely to limit the effectivenessof the quinolones in the near future. Overuseof a single agent will ultimately result in resis-tance to the entire class.1

Therapeutic Uses of QuinolonesGENITOURINARY INFECTIONS

Because of their extensive gram-negativecoverage, quinolone antibiotics were initiallyused to treat urinary tract infections. Thehigher genitourinary drug concentrationsthat occur with renally cleared quinolonespromote their effectiveness in the treatmentof genitourinary infections. Given in three- to10-day courses, most quinolones are as effec-tive as trimethoprim-sulfamethoxazole (Bac-trim, Septra) in treating uncomplicated uri-

nary tract infections caused by susceptibleEscherichia coli.14,15

Complicated urinary tract infections in-clude those in patients with stones or obstruc-tive uropathies and in patients with catheter-related infections. These infections are oftenassociated with nosocomial, antibiotic-resis-tant gram-negative pathogens and gram-posi-tive bacteria, and with Candida species.Because ciprofloxacin, ofloxacin, lomefloxacin(Maxaquin), enoxacin (Penetrex), levo-floxacin, and gatifloxacin have higher renalclearance and greater renal concentration, theyare optimal choices for the treatment of com-plicated urinary tract infections.1

Ciprofloxacin has been shown to be moreeffective than trimethoprim-sulfamethoxa-zole and aminoglycosides in seven- to 10-daycourses for the treatment of complicated uri-nary tract infections. However, few patientsmaintain sterile urine six weeks after anyantibiotic therapy.1,9 Bacterial resistance andCandida superinfection often limit treatmentin complicated urinary tract infections, withan estimated failure rate of at least 2 per-cent.15,16 Failure rates as high as 20 percentmay be encountered with infections causedby pathogens such as P. aeruginosa.1

A seven- to 10-day course of orally admin-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 ofacute uncomplicated pyelonephritis in non-pregnant women, similar efficacy has beenshown for levofloxacin, in a dosage of 250 mgper day for seven to 10 days, and cipro-floxacin, in a dosage of 500 mg twice daily for10 days. However, relapses were more com-mon with levofloxacin.1,9 Gatifloxacin, in adosage of 400 mg per day, has comparedfavorably with ciprofloxacin, in a dosage of500 mg twice daily, in the treatment of com-plicated urinary tract infections andpyelonephritis, with cure rates of 93 percentand 91 percent, respectively.11


The Authors

CATHERINE M. OLIPHANT, PHARM.D., is associate professor of pharmacy practice atthe University of Wyoming School of Pharmacy, Casper. Dr. Oliphant received her doc-tor of pharmacy degree from the University of Michigan College of Pharmacy, AnnArbor. She completed an American Society of Health System Pharmacists general res-idency and a fellowship in infectious diseases and microbiology at NorthwesternMemorial Hospital, Chicago.

GARY M. GREEN, M.D., is infectious diseases chief at Kaiser Permanente, Santa Rosa(Calif.) Medical Center. Dr. Green received his medical degree from Georgetown Uni-versity School of Medicine, Washington, D.C. He completed a residency in internalmedicine at the Medical Center of Delaware, Newark, Del., and St. Joseph’s Hospital,Phoenix, and a fellowship in infectious diseases at the University of California, LosAngeles, School of Medicine.

Address correspondence to Catherine M. Oliphant, Pharm.D., Wyoming Medical Center, Department of Pharmacy, 1233 E. 2nd St., Casper, WY 82601 (e-mail: [email protected]). Reprints are not available from the authors.

Fluoroquinolones, especially levofloxacinand ciprofloxacin, are valuable in the treatmentof complicated urinary tract infections andpyelonephritis. Yet bacterial resistance, relapseof infections, and recurrent infections remaincritical issues. Complex genitourinary tractinfections continue to be a niche for this antibi-otic class.

PROSTATITIS

Quinolones are effective in the treatment ofprostatitis because of their excellent penetra-tion into prostatic tissue. When taken for fourto six weeks, norfloxacin, ciprofloxacin, levo-floxacin, and ofloxacin have eradication ratesof 67 to 91 percent.1,17 Treatment failures havebeen associated with shorter treatmentcourses (e.g., two weeks) and less susceptiblebacteria, specifically P. aeruginosa and Ente-rococcus species.1,9,15,18

Levofloxacin is an excellent first-line agentin the treatment of prostatitis. Ciprofloxacinshould be reserved for use in patientswith resistant gram-negative, pseudomonal,and enterococcal prostatitis, because of itssuperior activity against P. aeruginosa andenterococci.

RESPIRATORY DISEASES

Acute bacterial sinusitis may be the compli-cation of an initial viral illness. The primarybacterial isolates are S. aureus, S. pneumoniae,Haemophilus influenzae, and Moraxellacatarrhalis.9 The U.S. Food and Drug Admin-istration (FDA) has labeled gatifloxacin,moxifloxacin, sparfloxacin, and levofloxacinfor use in the treatment of acute bacterialsinusitis. Clinical trials comparing fluoro-quinolones with amoxicillin–clavulanatepotassium (Augmentin), cefuroxime axetil(Ceftin), and clarithromycin (Biaxin) havedemonstrated the efficacy of the quinoloneantibiotics.9 However, we believe that quino-lones should not be used as first-line agents inthe treatment of acute bacterial sinusitisbecause of the potential for development ofbacterial resistance.

Acute bronchitis may follow a viral illness,but antimicrobial therapy generally is notwarranted unless the patient has underlyingpulmonary disease. Fluoroquinolone therapyfor acute bacterial bronchitis has been effec-tive against H. influenzae and M. catarrhalis,the primary pathogens.1,9 The use of cipro-floxacin for S. pneumoniae and P. aeruginosabronchitis has resulted in clinical treatmentfailures and the development of bacterialresistance.1 Generally, levofloxacin, spar-floxacin, ofloxacin, gatifloxacin, and moxi-floxacin have compared favorably withcefuroxime, cefaclor (Ceclor), amoxicillin-clavulanate potassium, and amoxicillin.1

Community-acquired pneumonia is thesixth leading cause of death in the UnitedStates. Even with optimal therapy, this illnessis associated with mortality rates of approxi-mately 14 percent in hospitalized patients andless than 1 percent in patients not requiringhospitalization.19,20 S. pneumoniae, H. influen-zae, and M. pneumoniae are the pathogensmost commonly identified in community-acquired pneumonia; less commonly isolatedpathogens include viruses, S. aureus, C. pneu-moniae, M. catarrhalis, Klebsiella pneumoniae,and L. pneumophila.19,20 The pathogens mostoften responsible for death in patients withcommunity-acquired pneumonia are S. pneu-moniae, S. aureus, and L. pneumophila.

Antibiotic choices for outpatient and in-patient treatment of pneumonia were stratifiedin a recent consensus statement from the Infec-tious Diseases Society of America (IDSA)19 andin guidelines formulated by the Centers forDisease Control and Prevention (CDC).20 Pref-erence was not given to a specific antibioticclass. Listed antibiotic choices for outpatienttreatment included macrolides, doxycycline(Vibramycin), and fluoroquinolones. Antibi-

Quinolones


Quinolones are effective in the treatment of prostatitisbecause of their excellent penetration into prostatic tissue.

otic choices for hospitalized patients includedfluoroquinolones or extended-spectrum peni-cillins (piperacillin [Pipracil], piperacillin-tazobactam [Zosyn], or ampicillin-sulbactam[Unasyn]), carbapenems (meropenem [Mer-rem] and imipenem-cilastatin [Primaxin]) andcephalosporins, plus adjunctive macrolides,aminoglycosides, clindamycin (Cleocin), ormetronidazole (Flagyl).19,20

For treatment of community-acquiredpneumonia in patients hospitalized in a gen-eral ward, IDSA19 recommends a macrolidewith an extended-spectrum cephalosporin(cefotaxime [Claforan] or ceftriaxone [Roceph-in]), or a beta-lactam/beta lactamase inhibitorcombined with a macrolide, or a fluoro-quinolone alone (levofloxacin, gatifloxacin, ormoxifloxacin [listed in order of improvedactivity against S. pneumoniae]). For the treat-ment of patients hospitalized in an intensivecare unit, the IDSA guidelines recommend amacrolide or a fluoroquinolone (levofloxacin,gatifloxacin, or moxifloxacin) plus anextended-spectrum cephalosporin (cefo-taxime or ceftriaxone) or a beta-lactam/beta-lactamase inhibitor.

We are cautious when using quinolones andmacrolides in elderly patients because of druginteractions and adverse effects. In addition,fluoroquinolones should not be used as first-line agents for empiric therapy unless a life-threatening or “atypical pneumonia” (e.g.,L. pneumophila infection) is suspected.

For the treatment of atypical pneumonias,macrolides are likely to be equivalent to fluoro-quinolones and are currently more cost-effec-tive. Quinolones provide exceptional cover-age against atypical pathogens when infectionwith these organisms is suspected in patientswith community-acquired pneumonia. How-ever, ofloxacin has been associated with treat-ment failures, and ciprofloxacin has displayedreduced activity against Chlamydia species.1,9

Compared with other quinolones, moxi-floxacin and gatifloxacin have been shown tohave superior in vitro activity against pneu-mococci. Although this activity may make

moxifloxacin or gatifloxacin an attractivechoice for pneumococcal infections, theseagents should probably be reserved for treat-ment of infections with atypical pathogens orfor life-threatening pneumonias.1,9,11,21,22

Of the fluoroquinolones, ciprofloxacin andtrovafloxacin have been studied most exten-sively in the treatment of nosocomial pneu-monia. Ciprofloxacin has been found to becomparable in efficacy to imipenem-cila-statin in mechanically ventilated patients,especially those infected with pathogens fromthe Enterobacteriaceae family, but it has alsobeen associated with poorer responses andhigher clinical failure rates in patients withnosocomial pneumonia caused by S. aureusor P. aeruginosa.1 The efficacy of the newerquinolones (moxifloxacin and gatifloxacin)in the treatment of nosocomial pneumonia iscurrently being assessed in clinical trials.

At present, quinolones are best used incombination antimicrobial therapy for noso-comial pneumonia. Fluoroquinolone mono-therapy may worsen the increasing problem ofantibiotic resistance in the nosocomial setting.

SEXUALLY TRANSMITTED DISEASES

Based on 1998 guidelines from the CDC,23

ceftriaxone is the agent of choice for treat-ment of uncomplicated Neisseria gonorrhoeaeurethritis and cervicitis. A single dose ofciprofloxacin or ofloxacin should be consid-ered as alternative treatment in, for example,patients with penicillin allergy.23 Recently,gatifloxacin was reported to be as effective asofloxacin against N. gonorrhoeae.11 A seven-day course of ofloxacin or sparfloxacin hasbeen found to be as effective as doxycycline inthe treatment of C. trachomatis infections.Finally, ciprofloxacin has been reported to beas effective as trimethoprim-sulfamethoxa-zole for treating chancroid caused byHaemophilus ducreyi.1

Pelvic inflammatory disease is a polymicro-bial infection. Quinolone treatment optionsinclude ofloxacin plus metronidazole, ofloxa-cin plus cefoxitin (Mefoxin), and cipro-


floxacin plus clindamycin.1,9 Fluoroquin-olone monotherapy is incomplete.

GASTROENTERITIS

Prophylactic antimicrobial therapy is notrecommended for the prevention of diarrheain travelers.9 Norfloxacin or ciprofloxacin hasbeen found to be comparable to trimetho-prim-sulfamethoxazole in the treatment oftraveler’s diarrhea caused by Shigella species,enterotoxigenic E. coli, or Campylobacterjejuni.1

Ciprofloxacin and ofloxacin are the agentsof choice for treatment of enteric typhoidfever.1 Norfloxacin has been found to besuperior to both trimethoprim-sulfamethox-azole and doxycycline in the treatment of Vib-rio cholerae infection.1

SKIN AND SOFT TISSUE INFECTIONS

Because of limited data, the role of fluoro-quinolones in the treatment of skin and softtissue infections remains uncertain. Most flu-

oroquinolones have limited gram-positiveactivity; thus, they should not be consideredfirst-line agents for skin and soft tissue infec-tions. Diabetic foot infections, which arepolymicrobial, can be treated with quinolonesin combination with other antibiotics.9 Weexercise caution when S. aureus is isolated.

Adverse EventsAlthough quinolones are well tolerated and

relatively safe, certain adverse effects are com-mon with all agents in this antibiotic class(Table 2).5,6,11,24-35 Gastrointestinal and cen-tral nervous system (CNS) effects are themost frequent adverse events, occurring in 2 to 20 percent of patients treated withquinolones.3,5,6,33-35

Prolongation of the corrected QT interval(QTc) may precipitate fatal ventriculararrhythmias such as torsades de pointes. Sec-ondary to its effects in prolonging the QTc,grepafloxacin (Raxar) was withdrawn from theU.S. market in 1999. Because of reported QTcprolongation, sparfloxacin and moxifloxacinshould not be used in patients with a knownpredisposition to arrhythmias (e.g., hypoka-lemia, bradycardia) or in patients who arereceiving antiarrhythmic drugs or other med-ications that might prolong the QTc.11,24-27,33,34

Drug InteractionsClinically significant drug interactions are

known to occur with all quinolones (Table3).6,7,11,24-32 When products containing multi-valent cations (calcium, aluminum, magne-sium, iron, zinc), including sucralfate (Cara-fate), antacids, nutritional supplements, andmultivitamin and mineral supplements, aretaken within two to four hours of an orallyadministered quinolone, the maximum

Quinolones


TABLE 2

Adverse Effects of Quinolones*

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain

CNS: headache, dizziness, drowsiness, confusion,insomnia, fatigue, malaise, depression, somnolence, seizures, vertigo, lightheadedness, restlessness, tremor

Dermatologic: rash, photosensitivity reactions, pruritus

Other: QTc prolongation, hepatotoxicity, abnormal or bitter taste, tendon rupture

CNS = central nervous system; QTc = corrected QTinterval.

*—Because quinolones have been associated witharthropathy and chondrotoxicity in immature ani-mals, they are not recommended for use in childrenand adolescents younger than 18 years of age, or inpregnant or breastfeeding women.

Information from references 5, 6, 11, and 24through 35.

Gastrointestinal and central nervous system effects (e.g., headaches, dizziness, drowsiness) are the mostfrequent adverse events with quinolone therapy.

serum concentration of the quinolone maybe reduced by 25 percent to approximately90 percent.1,36

Applications of Fluoroquinolones in Biologic Warfare

Bacillus anthracis (anthrax) spores haverecently been deployed as a biologic weapon

in the United States. Fluoroquinolones have arole in postexposure prophylaxis andchemotherapy for specific agents that couldbe used in biologic warfare (Table 4).37 Spe-cific fluoroquinolones are indicated for pro-phylaxis or treatment of anthrax, cholera,plague, brucellosis, and tularemia. Cipro-floxacin is the drug of choice for postexpo-


TABLE 3

Potential Interactions Between Quinolones and Other Drugs

Any quinolone*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

cisapride (Propulsid)||May increase risk of CNS stimulation and convulsions if used concomitantly with nonsteroidal

anti-inflammatory drugsMay lead to hypoglycemia and/or hyperglycemia if used concomitantly with antidiabetic agents

(oral hypoglycemics or insulin)¶

Gatifloxacin (Tequin)Increased serum digoxin (Lanoxin) levels#

Trovafloxacin (Trovan)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

morphine

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.

sure prophylaxis for anthrax until sensitivitiesare available. Although penicillin resistancehas only rarely occurred in the natural settingof anthrax, the former Soviet Union devel-oped a B. anthracis strain that was resistant toboth penicillin and tetracycline.37

The authors indicate that they do not have any con-flicts of interest. Sources of funding: none reported.

REFERENCES

1. Hooper D. Quinolones. In: Mandell GL, Bennett JE,Dolin R. Mandell, Douglas, and Bennett’s Principlesand practice of infectious diseases. 5th ed.Philadelphia: Churchill Livingstone, 2000:404-23.

2. Hooper DC, Wolfson JS. Mechanisms of quinoloneaction and bacterial killing. In: Quinolone antimi-crobial agents. 2d ed. Washington, D.C.: AmericanSociety for Microbiology, 1993:53-7.

3. Hooper DC. Mode of action of fluoroquinolones.Drugs 1999;58(suppl 2):6-10.

4. Turnidge J. Pharmacokinetics and pharmaco-dynamics of fluoroquinolones. Drugs 1999;58(suppl 2):29-36.

5. Hackbarth CJ, Chambers HF, Sande MA. Serumbactericidal activity of rifampin in combinationwith other antimicrobial agents against Staphylo-coccus aureus. Antimicrob Agents Chemother1986;29:611-3.

6. Walker RC. The fluoroquinolones. Mayo Clin Proc1999;74:1030-7.

7. Alghasham AA, Nahata M. Trovafloxacin: a newfluoroquinolone. Ann Pharmacother 1999;33:48-60.

8. Owens RC Jr, Ambrose PG. Clinical use of thefluoroquinolones. Med Clin North Am 2000;84:1447-69.

9. Hooper DC. New uses for new and old quinolonesand the challenge of resistance. Clin Infect Dis2000;30:243-54.

10. Ambrose PG, Owens RC Jr, Quintiliani R, Nightin-gale CH. New generations of quinolones: with par-ticular attention to levofloxacin. Conn Med 1997;61:269-72.

11. Gatifloxacin and moxifloxacin: two new fluoro-quinolones. Med Lett Drugs Ther 2000;42:15-7.

12. Eliopoulos GM. Activity of newer fluoroquinolonesin vitro against gram-positive bacteria. Drugs1999;58(suppl 2):23-8.

13. Applebaum PC. Quinolone activity against anaer-obes. Drugs 1999;58(suppl 2):60-4.

14. Wolfson JS, Hooper DC. Treatment of genitouri-

Quinolones


TABLE 4

Selected Potential Biologic Pathogens: Postexposure Prophylaxis and Treatment

Pathogen Postexposure prophylaxis Treatment

Bacillus anthracis Agent of choice: ciprofloxacin (Cipro)* Agents of choice: ciprofloxacin, doxycycline(anthrax) Alternative: doxycycline (Vibramycin) Alternative if organisms are penicillin

sensitive: penicillin G

Vibrio cholerae Not available Agents of choice: oral rehydration therapy, (cholera) tetracycline, doxycycline, ciprofloxacin,

norfloxacin (Noroxin)

Yersinia pestis Agents of choice: doxycycline, Agents of choice: streptomycin, gentamicin, (plague) ciprofloxacin ciprofloxacin

Alternative: tetracycline Alternative: doxycycline

Brucella melitensis Agents of choice: doxycycline plus Agents of choice: doxycycline plus rifampin(brucellosis) rifampin (Rifadin) Alternative: ofloxacin (Floxin) plus rifampin

Francisella tularensis Agent of choice: doxycycline Agent of choice: streptomycin(tularemia) 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.4th ed. Frederick, Md.: U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, 2001.Retrieved November 2001 from http://www.usamriid.army.mil//education/bluebook.html.

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37. Kortepeter M, et al., eds. USAMRIID’s Medicalmanagement of biological casualties handbook.4th ed. Frederick, Md.: U.S. Army Medical Re-search Institute of Infectious Diseases, Fort Detrick,2001. Retrieved November 2001 from http://www.usamriid.army.mil/education/bluebook.html.


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