Pharmacokinetics Many of the fluoroquinolones are available in both parenteral and oral forms e.g., ciprofloxacin, oflox-acin, levofloxoflox-acin, and trovafloxacin.. Most fluoroquinolon
Trang 1Vol 10, No 1, January/February 2002 1
The fluoroquinolones are a group of synthetic
antimi-crobial agents that are derived from nalidixic acid
The early generations of these broad-spectrum
antibi-otics 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
pneu-monia 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
distur-bance 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
fluoro-quinolones, such as trovafloxacin, gatifloxacin, and
moxifloxacin, the six-member piperazine ring at
posi-tion 7 has been changed to a pyrrolidine group
The mechanism of action of these bactericidal
agents is that they selectively target bacterial
topoisom-erases 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 fluoro-quinolones 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 fluo-roquinolones 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 occur-rence 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 bacte-ria is by targeting topoisomerase II
Mutations of the genes that code for the two topoisom-erases 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, oflox-acin, levofloxoflox-acin, and trovafloxacin) Absorption is excellent with oral administration, yielding blood con-centrations 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
Trang 2minum, 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
cipro-floxacin, 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
com-pared 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
metabo-lism and transintestinal secretion; therefore, the
phar-macokinetics 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 MIC90(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%,2which 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%, com-pared 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 fluoro-quinolones has been used to treat arthroplasty-related
infections Patients with S aureus infections develop
resistance to rifampin early, but the addition of a fluo-roquinolone seems to prevent the emergence of ri-fampin 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)
Trang 3patients 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
suc-cess 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
fluoro-quinolones, including the following6: (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)
pa-tients with multidrug-resistant tuberculosis or
infec-tion with atypical mycobacteria for whom a
fluoro-quinolone 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
in-fected 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,
gati-floxacin, 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
pur-pose 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 admin-istered 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 inci-dence 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 ob-served 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, chon-drotoxicity, effects on growth, and tendinopathy In animal studies of the quinolones, immature joint carti-lage, 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 chela-tion 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 fibro-sis.8 The potential for cartilage damage and growth disturbance with these compounds has led to the restricted use of these antimicrobials in children, preg-nant women, and nursing mothers, although its use in children with cystic fibrosis and in other study popula-tions11 has not been associated with any particular problems
Alan M Levine, MD, and John R DiBona, PharmD
Trang 4More 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 posiaddi-tions 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
nurs-ing 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 resis-tant 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
Levofloxacin
Ciprofloxacin
Dicloxacillin
Doxycycline
Rifampin
Clindamycin
* 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
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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
infec-tions: 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;
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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
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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.