pasado, presente y futuro.
1: Am Fam Physician 2002 Feb 1;65(3):455-64 [Texto
Quinolones: a comprehensive review.
Oliphant CM, Green GM.
University of Wyoming School of Pharmacy, Casper, USA. firstname.lastname@example.org
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, sexually 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 prolongation 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 important class of
antibiotics will likely worsen current problems with antibiotic resistance.
Applications of fluoroquinolones in biologic warfare are also discussed.
2: Curr Opin Investig Drugs 2001 Jun;2(6):745-51
Antibacterial agents (oxazolidinones, quinolones, macrolides and new agents):
patent highlights June to December 2000.
Phillips OA, Matowe WC.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University,
Several patent disclosures were made on oxazolidinone, quinolone, macrolide and
new antimicrobial agents between June and December 2000; 26 of these patents are
discussed in this review. The exciting report on new oxazolidinone derivatives
with potent activity against fastidious Gram-negative organisms is highlighted.
Most of the new quinolones are structurally dissimilar to the traditional fluoroquinolones and demonstrate activity against Helicobacter pylori (MIC=0.013
microg/ml). New 14-membered macrolides with broad-spectrum activity including
against Mycobacterium avium are also presented. A novel peptidic antibiotic with
potent antimicrobial activity against Streptococcus pneumoniae (MIC<0.0005
microg/ml) is also highlighted.
3: Semin Respir Infect 2001 Sep;16(3):215-24
Future of the quinolones.
School of Biomedical Sciences, University of St. Andrews, St. Andrews, Fife,
New fluoroquinolones and fluoronaphthyridones continue to provide the mainstay
of antibiotic development, despite recent events associated with unexpected or
uncharacteristically severe adverse drug reactions. These have included hepatotoxicity caused by trovafloxacin (suspended), cardiotoxicity associated
with grepafloxacin, and phototoxicity caused by clinafloxacin (both withdrawn).
Prolongation of the QT interval appears to be an emergent class effect, the
implications of which are not yet fully understood. However, the second-generation agents ciprofloxacin and, latterly, levofloxacin have
excellent safety profiles and provide standard optimal choices for therapy of a
wide range of gram-negative pathogens. They are also useful for many respiratory
infections, though the use of ciprofloxacin in pneumococcal pneumonia has been
questioned and continued use of levofloxacin may act as a selection pressure for
emergence of quinolone-resistant Streptococcus pneumoniae. Active
conservation measures may be required to protect the class from this problem because
alternatives, should high-level penicillin-resistance continue to spread, are
few. The new 8-methoxy quinolones (moxifloxacin and gatifloxacin) are more
highly potent against both penicillin-susceptible and multidrug-resistant S.
pneumoniae, while retaining activity against enterobacteria. Clinical Phase III
development has shown them to produce very satisfactory clinical and bacteriologic responses in respiratory infections and to be remarkably free of
clinically significant adverse effects. Postmarketing surveillance of moxifloxacin in Germany has revealed no additional concerns. These agents are
now licensed in many countries, including the United States, and add a further,
broad-based respiratory dimension to the future of the class. Copyright 2001 by
W.B. Saunders Company
4: Chemotherapy 2001;47 Suppl 3:9-14; discussion 44-8
Comparison of side effects of levofloxacin versus other fluoroquinolones.
Internal Medicine Unit, Bichat-Claude Bernard Hospital, Paris, France.
The side-effect profile of levofloxacin was compared with that of other fluoroquinolones based on European and international data from approximately 130
million prescriptions. Levofloxacin was found to be very safe with a low rate of
hepatic abnormalities (1/650,000). In contrast, 140 trovafloxacin-treated patients developed hepatic problems, 14 of which were severe, and 8 required
transplantation. The main CNS problems associated with fluoroquinolones include
dizziness, convulsions, psychosis, and insomnia. Levofloxacin, ofloxacin, and
moxifloxacin reportedly have the lowest potential of inducing central nervous
system (CNS) adverse events among the fluoroquinolones currently available.
Cardiovascular problems were seen in 1/15 million levofloxacin prescriptions
compared to 1-3% of sparfloxacin patients having QTc prolongation of greater
than 500 msec. Moxifloxacin was also associated with QTc prolongation when
compared to non-fluoroquinolone comparators. Nausea, vomiting, and diarrhoea
remain the main adverse drug reactions (ADRs) associated with levofloxacin.
However, the ADR rate for levofloxacin is still one of the lowest of any fluoroquinolone at 2% (compared to 2-10% for other fluoroquinolones). Ofloxacin
and levofloxacin have a very low phototoxic potential, whereas this is a problem
for sparfloxacin, enoxacin, and pefloxacin. The tolerance profile of
levofloxacin can be considered to be very good, and better than most, if not all
of the fluoroquinolones available. Copyright 2001 S. Karger AG, Basel
5: Chemotherapy 2001;47 Suppl 3:3-8; discussion 44-8
History of quinolones and their side effects.
Department of Internal Medicine and Unit of Infectious Diseases, Tel Aviv University School of Medicine, Tel Aviv, Israel. email@example.com
Fluoroquinolone development from 1985 to the present was reviewed. Severe drug
adverse events were noted for enoxacin, pefloxacin and fleroxacin, which were
phototoxic. Temafloxacin was associated with severe hemolytic-uremic syndrome,
lomefloxacin caused phototoxicity and central nervous system (CNS) effects, and
sparfloxacin was associated with phototoxicity and QTc prolongation. Tosufloxacin caused severe thrombocytopenia and nephritis, and hepatotoxicity
was reported for trovafloxacin. Grepafloxacin was withdrawn due to cardiovascular effects, and clinafloxacin was associated with phototoxicity and
hypoglycaemia. The structure of the quinolones directly relates to both their
activity and side-effect profiles. The relationship among specific substituents
attached to the quinolone nucleus are clarified. The incidence of specific
adverse events associated with individual fluoroquinolones was reviewed in a
five-year post-marketing surveillance (PMS) study in Japan, in which a total
adverse drug reaction (ADR) rate of 1.3% was found for levofloxacin, compared to
total ADR rates of 3.3% for pazufloxacin, 3.6% for tosufloxacin, 4.5% for gatifloxacin and 5.4% for balofloxacin. Gastrointestinal effects were the most
common adverse events for all fluoroquinolones. Levofloxacin had the lowest rate
of CNS effects and skin adverse events among the agents listed. Copyright 2001
S. Karger AG, Basel
6: Drugs 2001;61(6):747-61
Fluoroquinolones: place in ocular therapy.
Smith A, Pennefather PM, Kaye SB, Hart CA.
St. Paul's Eye Unit, Royal Liverpool University Hospital, England.
The fluoroquinolones have become widely used antibacterial agents in the treatment of ocular infections, with topical, intravitreal and systemic routes
of administration being used. In general, fluoroquinolones (such as ciprofloxacin, ofloxacin, lomefloxacin and norfloxacin) have good activity
against gram-negative and gram-positive bacteria. Therapeutic concentrations are
achieved in the cornea after topical administration so that the fluoroqinolones
have largely replaced combination therapy for the treatment of bacterial keratitis. However, a second line agent is needed when resistance is likely,
such as in disease caused by streptococcal species. Reversal of resistance to
quinolones may not occur with withdrawal of the antibacterial. This stresses the
importance of prudent prescribing to reduce the occurrence of resistance to
quinolones. When used in therapeutic topical dosages, corneal toxicity does not
occur. Similarly, retinal toxicity is not seen when fluoroquinolones are used at
therapeutic dosages, systemically or topically. Corneal precipitation occurs,
particularly with ciprofloxacin and to a lesser extent norfloxacin, but does not
appear to interfere with healing. In the treatment of endophthalmitis there is
reasonable penetration of systemic fluoroquinolones into the vitreous but sufficiently high concentrations to reach the minimum inhibitory concentration
for 90% of isolates (MIC90) of all important micro-organisms may not be guaranteed. Systemic administration may be useful for prophylaxis after ocular
7: Clin Infect Dis 2001 Mar 15;32 Suppl 1:S9-S15
Mechanisms of action of antimicrobials: focus on fluoroquinolones.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA
02114-2696, USA. firstname.lastname@example.org
Five bacterial targets have been exploited in the development of antimicrobial
drugs: cell wall synthesis, protein synthesis, ribonucleic acid synthesis,
deoxyribonucleic acid (DNA) synthesis, and intermediary metabolism. Because
resistance to drugs that interact with these targets is widespread, new antimicrobials and an understanding of their mechanisms of action are vital. The
fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to
the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase
and topoisomerase IV. Ternary complexes of drug, enzyme, and DNA block progress
of the replication fork. Cytotoxicity of fluoroquinolones is likely a 2-step
process involving (1) conversion of the topoisomerase-quinolone-DNA complex to
an irreversible form and (2) generation of a double-strand break by denaturation
of the topoisomerase. The molecular factors necessary for the transition from
step 1 to step 2 remain unclear, but downstream pathways for cell death may
overlap with those used by other bactericidal antimicrobials. Studies of fluoroquinolone-resistant mutants and purified topoisomerases indicate that many
quinolones have differing activities against the two targets. Drugs with similar
activities against both targets may prove less likely to select de novo resistance.
8: Clin Infect Dis 2001 Mar 15;32 Suppl 1:S1-8
Mechanisms responsible for cross-resistance and dichotomous resistance among the
Center for Research in Anti-Infectives and Biotechnology, Department of Medical
Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE
68178, USA. email@example.com
Resistance to the quinolones almost always arises from the accumulation of
mutations in chromosomal genes responsible for the drug targets, permeability,
or active efflux. This resistance can be depicted as a stepwise process in which
each step, represented by separate mutations, diminishes susceptibility on
average 4- to 8-fold. The precise path followed in this stepwise process differs
with the quinolone that selects resistance as well as the organism involved. At
each step, the influence of each mutation on susceptibility to other quinolones
not used in the selection process varies greatly, and a pattern of either cross-resistance or dichotomous resistance may be seen. From an understanding of
the stepwise process by which resistance to the quinolones evolves, it is possible to use an 8-fold rule to predict which compounds may provide effective
therapy for a given infection and be least likely to select for resistance.
9: Rev Clin Esp 2000 Dec;200(12):682-4
Use of new quinolones in respiratory infections
Sanz Moreno J, Jimenez Rodriguez A.
Servicio de Medicina Interna, Hospital Universitario Principe de Asturias,
Universidad de Alcala de Henares, Madrid.
10: Med Clin North Am 2000 Nov;84(6):1447-69
Clinical use of the fluoroquinolones.
Owens RC Jr, Ambrose PG.
Department of Infectious Diseases, Maine Medical Center, Portland, Maine, USA.
The appetite for modification to the basic quinolone nucleus has grown logarithmically since the first quinolone was employed in clinical practice.
Important structural refinements have led to expanded microbiologic activity,
optimal pharmacokinetics, and increased safety profiles. The practicing clinician and researcher may glean considerable information from the quinolone
structure with regard to microbiologic spectra and safety before administering
these agents to patients. Although some toxicities can be ominously predictable,
such as with the so-called high-risk quinolones (e.g., double-halogenated and
trifluorinated quinolones), clinicians must rely on animal models of toxicity
and clinical trial data to discern other toxicities (e.g., Q-Tc interval prolongation). A few quinolones enjoy a relatively clean safety profile and are
well tolerated (e.g., gatifloxacin, levofloxacin, ciprofloxacin). Other quinolones may be associated with significant collateral system toxicity during
therapy; however, under certain conditions, albeit rare, their potential for
benefit may outweigh the existing risk. Clinafloxacin, for use in the management
of lung infections caused by multiply resistant B. cepacia in cystic fibrosis
patients, is an example of a risk that may be outweighed by its therapeutic
benefit. Because there are many treatment alternatives within the clinician's
armamentarium, the obligation is to select the safest, most therapeutically
effective, and most cost-effective agent that is available. In addition to
increasing mortality and morbidity, the development of toxicity or an adverse
event during therapy may compromise the immediate effectiveness of treatment as
well as affect the cost of the patient's care significantly. With the immediate
abundance of quinolones available for use, the safest, most effective, and
best-tolerated agents will likely emerge as the most appropriate therapeutic
choices when a quinolone is indicated.
11: Clin Infect Dis 2000 Aug;31 Suppl 2:S24-8
Mechanisms of action and resistance of older and newer fluoroquinolones.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical
School, Boston, MA 02114-2696, USA. firstname.lastname@example.org.
The fluoroquinolones interact with 2 bacterial targets, the related enzymes DNA
gyrase and topoisomerase IV, both of which are involved in DNA replication.
Quinolones form complexes of these enzymes with DNA, complexes that block movement of the DNA-replication fork and thereby inhibit DNA replication.
Many older quinolones differ in their relative activities against gyrase and
topoisomerase IV in a bacterial cell, having greater potency against gyrase than
against topoisomerase IV in many gram-negative bacteria and greater potency
against topoisomerase IV than against gyrase in many gram-positive bacteria.
Several newer quinolones appear to have more closely balanced activity against
these enzymes. Resistance to fluoroquinolones occurs as a result of mutational
amino acid substitutions in the subunits of the more sensitive (or primary-target) enzyme within the cell. If, however, both enzymes are similarly
susceptible to a fluoroquinolone, then the level of resistance caused by a
primary-target mutation may be low and may be limited by the sensitivity of the
secondary target. Fluoroquinolones also differ in the extent to which common
bacterial multidrug efflux pumps affect their activity, with some compounds
being unaffected by resistance mechanisms because of overexpression of such
pumps. Newer fluoroquinolone interaction with dual targets and avoidance of
efflux-resistance mechanisms may each contribute to the lower frequencies of
selection of resistant mutants in the laboratory.
12: Curr Clin Top Infect Dis 2000;20:63-91
The fluoroquinolones after ciprofloxacin and ofloxacin.
Harvard Medical School, Division of Infectious Diseases, Massachusetts General
Hospital, Boston, USA.
13: Mayo Clin Proc 1999 Oct;74(10):1030-7
Division of Infectious Diseases and Internal Medicine, Mayo Clinic Rochester,
The quinolones are broad-spectrum antibacterial agents that have a novel mechanism of action. As synthetic compounds, these agents have been developed
extensively to optimize antimicrobial activity, pharmacokinetic properties, and
drug safety. Although earlier quinolones were effective only in the genitourinary and gastrointestinal tracts and only had activity against aerobic
gram-negative bacteria, newer quinolones have wider potential applications and a
broader spectrum of activity. Some of the newer quinolones will have a role in
the treatment of community-acquired pneumonia and intra-abdominal infections.
Ciprofloxacin remains the most potent quinolone against Pseudomonas aeruginosa.
Among the quinolones, important differences exist in renal and hepatic elimination and dose-adjustment regimens. Although there are many Food and
Drug Administration-approved indications for some of the newer quinolones, the
quinolones are the drug of choice for only a few infections. Quinolone-resistant
bacteria are being increasingly identified and emerge under selective pressure
created by extensive use.
14: Clin Infect Dis 2000 Feb;30(2):243-54
New uses for new and old quinolones and the challenge of resistance.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical
School, Boston, MA 02114-2696, USA. email@example.com
15: Drugs 1999;58 Suppl 2:99-102
Newer quinolones in the long term prophylaxis of recurrent urinary tract infections (UTI).
Krcmery S, Hromec J, Tvrdikova M, Hassan M, Gulla D.
Department of Geriatric Medicine, Comenius University School of Medicine, Bratislava, Slovak Republic.
Up to 10% of premenopausal women experience recurrent symptomatic urinary tract
infection (UTI), mainly due to reinfection from the faecal flora. The recently
introduced fluoroquinolones possess a wide spectrum of activity against most
uropathogens and achieve high urinary concentrations for extended time periods.
Our initial study, conducted between 1993 and 1995, was designed to compare the
efficacy and safety of oral pefloxacin 800mg once weekly with oral ciprofloxacin
125mg once daily, over a 12-month prophylactic course in women with recurrent
UTI. A 12-month reinfection-free period was achieved in 83.3% of pefloxacin
patients and in 78.9% of ciprofloxacin patients. The present study, which commenced in 1996, was designed to compare pefloxacin 400mg with oral fleroxacin
400mg once weekly. Prophylaxis was maintained for 12 months. There are no statistically significant differences between the 2 regimens in terms of
efficacy and safety. The most frequently isolated pathogens causing breakthrough
reinfections were Escherichia coli and Enterococcus spp. Adverse effects observed were mostly neuropsychic (insomnia) and gastrointestinal. In both
studies, there was no evidence of emergence of quinolone-resistant organisms in
the urine or rectal flora, even after 12 months of chemoprophylaxis.
16: Drugs 1999;58 Suppl 2:96-8
The quinolones and renal infection.
Section of Infectious Diseases, St Boniface General Hospital/University of
Manitoba, Winnipeg, Canada.
The fluoroquinolones are excellent drugs for the treatment of most patients with
renal infection. Ciprofloxacin has proved its value in good clinical trials for
uncomplicated acute pyelonephritis and has been used widely for complicated
urinary tract infections with presumed renal infection.
17: Drugs 1999;58 Suppl 2:92-5
Quinolones in sexually transmitted diseases: state of the art.
Department of Clinical Microbiology, University College London Hospitals, England.
Progress in the development of fluoroquinolones for the treatment of sexually
transmitted diseases has been slow. New compounds have appeared with good in
vitro activity against the gonococcus, Chlamydia trachomatis and the genital
mycoplasmas. However, there have been increasing reports of clinically relevant
resistance by the gonococcus, and chlamydial and mycoplasmal resistance in vitro
has been described. Formally reported treatment studies have not been forthcoming, despite an emerging role for the newer fluoroquinolones in the
ambulatory treatment of pelvic inflammatory disease.
18: Drugs 1999;58 Suppl 2:85-91
Use of quinolones in osteomyelitis and infected orthopaedic prosthesis.
Lew DP, Waldvogel FA.
Department of Medicine, Geneva University Hospital, Switzerland. Daniel.Lew@hcuge.ch
The present review provides an updated critical analysis of the use of quinolones in osteomyelitis and orthopaedic prosthetic infections. Only papers
published in peer-reviewed journals and related to the following areas were
selected: experimental osteomyelitis, penetration of quinolones into human bone,
and clinical use in comparative and noncomparative studies. Local drug carriers
impregnated with quinolones allow high local antibiotic concentrations to be
achieved in experimental systems. Considerable clinical experience has been
gained mostly with ciprofloxacin and ofloxacin. Cumulated results in clinical
trials show clinical success rates of more than 90% in osteomyelitis caused by
Enterobacteriaceae. The combination of quinolones and rifampicin for the treatment of staphylococcal osteomyelitis as well as orthopaedic prosthetic
infections appears very promising in clinical studies with a small number of
patients. However, further comparative studies using quinolones as single agents
or in combination (versus standard parenteral therapy) remain necessary in
osteomyelitis due to Staphylococcus aureus or Pseudomonas aeruginosa. In particular, studies with the newer quinolones should be strongly encouraged in
acute or chronic osteomyelitis and in more complicated situations such as diabetic osteomyelitis or foreign-body infection.
19: Drugs 1999;58 Suppl 2:78-81
Activity of quinolones against Chlamydia pneumoniae.
Department of Pediatrics, SUNY Health Science Center at Brooklyn, USA. firstname.lastname@example.org
Quinolones are currently being used as empirical therapy for the treatment of
community-acquired pneumonia and other respiratory infections as they cover a
broad range of conventional bacterial and 'atypical' pathogens, including Chlamydia pneumoniae. C. pneumoniae has been associated with 10 to 20% of
community-acquired pneumonia in adults and recently has been implicated as being
associated with several nonrespiratory conditions, including atherosclerosis.
However, data on the treatment of even respiratory infection due to C. pneumoniae are limited. Although currently available quinolones have good
activity against C. pneumoniae in vitro, all published treatment studies have
relied on serological diagnosis, thus microbiological efficacy has not been
assessed. Anecdotal experience suggests that in vitro activity may not always
correlate with efficacy in vivo.
20: Drugs 1999;58 Suppl 2:71-7
Cost effectiveness of quinolones in hospitals and the community.
Department of Clinical Pharmacology, Ninewells Hospital, Dundee, Scotland.
In hospitals, oral quinolone therapy has lower daily associated costs (acquisition and administration) than most intravenous regimens. In addition,
oral switch therapy shortens the duration of hospital stay for most patients.
However, randomised trials are required to measure the economic impact of the
switch to oral therapy in terms of hospital care costs and the burden imposed on
community health services, on relatives or carers and on the patient. Evidence
about the reliability of absorption of quinolones in hospitalised patients is
more likely to be obtained from large population kinetic studies than randomised
effectiveness trials. The existing literature on cost effectiveness of quinolones in the community is disappointing. The principal problems are poor
definition of diagnostic criteria, inclusion of irrelevant comparator drugs and
a failure to include infections caused by bacteria that are resistant to the
comparator. Consequently, there is little evidence to support the use of economic models to determine the consequences of antibiotic resistance in the
21: Drugs 1999;58 Suppl 2:65-70
Effect of quinolones on intestinal ecology.
Edlund C, Nord CE.
Department of Immunology, Microbiology, Pathology and Infectious Diseases,
Huddinge University Hospital, Stockholm, Sweden.
Quinolones have a selective effect on the normal human intestinal microflora.
Published data on 13 different quinolone agents [ciprofloxacin, enoxacin, norfloxacin, ofloxacin, pefloxacin, lomefloxacin, levofloxacin, sparfloxacin,
rufloxacin, sitafloxacin (DU-6859a), gatifloxacin, trovafloxacin and moxifloxacin] show that gram-negative aerobic bacteria, especially
Enterobacteriaceae, are strongly suppressed or eliminated during therapy. Gram-positive aerobic cocci are affected strongly by administration of
sitafloxacin and moxifloxacin and to minor degrees by the other quinolones.
Three new quinolones--gatifloxacin, trovafloxacin and moxifloxacin--are very
active against anaerobic bacteria in vitro but have minor effects on the anaerobic intestinal human microflora. Similar findings have been reported for
the other 10 quinolones. Thus, the quinolone antibacterials have an ecological
impact on the human intestinal microflora, mainly on the enterobacteria, that
should be taken into account when these agents are used for prophylaxis or
treatment of gastrointestinal bacterial infections.
22: Drugs 1999;58 Suppl 2:60-4
Quinolone activity against anaerobes.
Department of Pathology, Hershey Medical Center, Pennsylvania 17033, USA.
The first generation of fluoroquinolones such as ciprofloxacin and ofloxacin are
inactive against most anaerobic bacteria. However, some broad-spectrum quinolones, which have recently become clinically available or are under active
development, have significant antianaerobic activity. This review summarises the
in vitro activity of currently available, as well as experimental, quinolones
against clinically significant anaerobic bacteria. Quinolones with low activity
against anaerobes include ciprofloxacin, ofloxacin, levofloxacin, fleroxacin,
pefloxacin, enoxacin and lomefloxacin. Compounds with intermediate antianaerobic
activity include sparfloxacin and grepafloxacin. Trovafloxacin, gatifloxacin and
moxifloxacin yield low MICs against most groups of anaerobes. Quinolones with
the greatest in vitro activity against anaerobes include clinafloxacin and
23: Drugs 1999;58 Suppl 2:55-9
Quinolone use in the developing world: state of the art.
Tropical Disease Foundation, Makati Medical Center, Makati City, The Philippines.
The development of bacterial resistance to previously recommended standard
therapy for common childhood infections in developing countries, notably dysentery and invasive salmonellosis, has left treatment options limited to the
quinolones. A number of randomised controlled trials of the quinolones in shigellosis have demonstrated their efficacy and safety in children. Strategies
to make these drugs available in developing countries for specific indications
should be devised. Quinolones, however, should be limited to specific indications in order to prevent the emergence of bacterial resistance and thus
preserve their clinical efficacy for important childhood infectious diseases in
24: Drugs 1999;58 Suppl 2:52-4
Quinolones in the treatment of typhoid fever.
Pfizer Pharmaceutical Group, Ortakoy, Istanbul, Turkey. email@example.com
Typhoid fever is a severe systemic disease. Treatment with appropriate antibiotics is essential for enteric fever. Development and rapid dissemination
of resistance to chloramphenicol, ampicillin, and cotrimoxazole have complicated
the treatment of enteric fever. Therapeutic options for the treatment of multidrug-resistant strains are limited to third generation cephalosporins or
fluoroquinolone antibiotics. Recent clinical experiences have shown that quinolones are the drugs of choice for treatment of enteric fever. Studies have
shown that shorter courses may be sufficient to cure uncomplicated typhoid
25: Drugs 1999;58 Suppl 2:49-51
Quinolones in the aged.
University of Manitoba, Winnipeg, Canada. firstname.lastname@example.org
Pharmacokinetic studies of fluoroquinolone antibacterials generally demonstrate
some quantitative alterations in elderly compared with younger populations. The
most common observations are an increased maximal plasma drug concentration and
area under the concentration-time curve, which are primarily attributable to the
10 to 15% decrease in lean body mass in the elderly. For quinolones excreted
primarily by the renal route, there is a prolongation in elimination half-life
correlated with the aging-associated decline in creatinine clearance. Quinolones
with major routes of nonrenal clearance will not usually show a prolongation in
half-life because of compensatory relative increases in nonrenal
Alterations directly attributable to aging alone, however, are minor, and vary
between different quinolones. They do not justify a consistent need for dosage
alterations on the basis of age alone. Agents with primarily renal excretion,
such as ofloxacin or levofloxacin, may require dosage adjustment in the very
elderly or the frail elderly, if significant decreases in creatinine clearance
are present. No age-related differences in adverse effects of fluoroquinolones
have been reported. Studies in both community-dwelling and institutionalised
elderly populations have consistently shown quinolones to be as effective as
comparative parenteral or oral therapy. While elderly populations may be at
greater risk of adverse effects because of comorbidities and concurrent
therapies, an increased occurrence of adverse events in elderly populations
receiving quinolone antimicrobials relative to younger populations has not been
26: Drugs 1999;58 Suppl 2:37-42
Toxicity of quinolones.
Stahlmann R, Lode H.
Institute of Clinical Pharmacology and Toxicology, Department of Toxicology,
University Medical Center Benjamin Franklin, Freie Universitat Berlin, Germany.
Reactions of the gastrointestinal tract, the CNS and the skin are the most often
observed adverse effects during therapy with fluoroquinolones. At least for some
of the newer fluoroquinolones a steep dose-response relationship of adverse
effects seems to exist. Pathogenesis of the neurotoxic effects of
fluoroquinolones is still unknown. Among the newer drugs, trovafloxacin caused
mild CNS reactions such as dizziness and lightheadedness in a considerable
proportion of patients. Young females seem to be especially sensitive to this
effect, which diminishes during treatment or if taken together with food.
Cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those
of other fluoroquinolones, but during therapy no clearcut drug-related serious
reactions have been reported, apart from a slight prolongation of the QT
interval. However, to avoid risks these drugs should not be prescribed to
patients with known prolongation of the QT interval (e.g. patients on
antiarrhythmics). Phototoxicity has been described for all quinolones, but
derivatives with a halogen atom at position 8 show the highest potential for
such reactions. Fleroxacin, sparfloxacin, clinafloxacin and lomefloxacin belong
to this group of fluoroquinolones. The phototoxic potential of the other new
fluoroquinolones is considerably lower, but extensive exposure to UV light
should generally be avoided during therapy with all quinolones. Chondrotoxicity
of quinolones, as observed in immature animals, can affect articular cartilage
and/or the epiphyseal growth plate, depending on the developmental stage.
Pathogenesis of chondrotoxicity can probably be explained by the
magnesium-chelating properties of these drugs. As juveniles are especially
sensitive, use of these drugs in paediatrics should be restricted to carefully
selected indications (such as the use of ciprofloxacin in cystic fibrosis)
Another manifestation of the toxic effects of quinolones on connective tissue
structures are tendopathies. Tendinitis and tendon ruptures have occurred as
late as several months after quinolone treatment. Overall, quinolones are well
tolerated drugs. Their specific toxic potentials have to be considered when they
are chosen for treatment of bacterial infections.
27: Drugs 1999;58 Suppl 2:19-22
Activity of quinolones against mycobacteria.
Department of Pathology, Case Western Reserve University, University Hospitals
of Cleveland, Ohio 44106, USA. email@example.com
The fluoroquinolones have been shown to be active in vitro against many
mycobacterial species, including most strains of Mycobacterium tuberculosis
complex and M. fortuitum, and some strains of M. kansasii, M.
avium-intracellulare (MAI) complex and M. leprae. Ciprofloxacin, ofloxacin and
sparfloxacin are the best studied of these agents to date, and are among the
most active of this group against M. tuberculosis and other mycobacteria.
Treatment of patients with multidrug-resistant pulmonary tuberculosis using
ofloxacin has resulted in the selection of quinolone-resistant mutants in a few
patients. Many strains of MAI, however, are resistant to fluoroquinolones, and
structure-activity relationships and DNA gyrase studies have been undertaken to
identify the moieties associated with activity and the lack thereof. The genetic
and molecular basis of quinolone resistance in mycobacteria has revealed both
the recent progress made in these areas and the limitations of the quinolones
against this genus. Considerable progress will need to be made in resolving
these issues in order for the quinolones to become clinically useful
28: Drugs 1999;58 Suppl 2:11-8
Mechanisms of fluoroquinolone resistance: an update 1994-1998.
Division of Immunity and Infection, Medical School, University of Birmingham,
Edgbaston, England. firstname.lastname@example.org
Fluoroquinolone resistance is mediated by target changes (DNA gyrase and/or
topoisomerase IV) and/or decreased intracellular accumulation. The genes
(gyrA/gyrB/parC/parE) and proteins of DNA topoisomerase IV show great
similarity, both at the nucleotide and amino acid sequence level to those of DNA
gyrase. It has been shown that there are hotspots, called the quinolone
resistance determining region (QRDR), for mutations within gyrA and parC. Based
on the Escherichia coli co-ordinates, the hotspots most favoured for giving rise
to decreased susceptibility and/or full resistance to quinolones are at serine
83 and aspartate 87 of gyrA, and at serine 79 and aspartate 83 for parC. Few
mutations in gyrB or parE/grlB of any bacteria have been described. Efflux of
fluoroquinolones is the major cause of decreased accumulation of these agents;
for Staphylococcus aureus, the efflux pump involved in norfloxacin resistance is
NorA, and for Streptococcus pneumoniae, PmrA. By analysis of minimum inhibitory
concentration (MIC) data derived in the presence and absence of the efflux
inhibitor reserpine, it has been shown that up to 50% of ciprofloxacin-resistant
clinical isolates of S. pneumoniae may possess enhanced efflux. This suggests
that efflux may be an important mechanism of clinical resistance in this
species. In Pseudomonas aeruginosa, several efflux operons have been
demonstrated genetically and biochemically. These operons are encoded by mex
(Multiple EffluX) genes: mexAmexB-oprM, mexCD-OprJ system and mexEF-oprN system.
The E. coli efflux pump is the acrAB-tolC system. Both the mar operon and the
sox operon can give rise to multiple antibiotic resistance. It has been shown
that mutations giving rise to increased expression of the transcriptional
activators marA and soxS affect the expression of a variety of different genes,
including ompF and acrAB. The net result is that expression of OmpF is reduced
and much less drug is able to enter the cell; expression of acrAB is increased,
enhancing efflux from the cell.
29: Drugs 1999;58 Suppl 2:6-10
Mode of action of fluoroquinolones.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical
School, Boston 02114-2696, USA. email@example.com
The mode of action of quinolones involves interactions with both DNA gyrase, the
originally recognised drug target, and topoisomerase IV, a related type II
topoisomerase. In a given bacterium these 2 enzymes often differ in their
relative sensitivities to many quinolones, and commonly DNA gyrase is more
sensitive in gram-negative bacteria and topoisomerase IV more sensitive in
gram-positive bacteria. Usually the more sensitive enzyme represents the primary
drug target determined by genetic tests, but poorly understood exceptions have
been documented. The formation of the ternary complex of quinolone, DNA, and
either DNA gyrase or topoisomerase IV occurs through interactions in which
quinolone binding appears to induce changes in both DNA and the topoisomerase
that occur separately from the DNA cleavage that is the hallmark of quinolone
action. X-ray crystallographic studies of a fragment of the gyrase A subunit, as
well as of yeast topoisomerase IV, which has homology to the subunits of both
DNA gyrase and topoisomerase IV, have revealed domains that are likely to
constitute quinolone binding sites, but no topoisomerase crystal structures that
include DNA and quinolone have been reported to date. Inhibition of DNA
synthesis by quinolones requires the targeted topoisomerase to have DNA cleavage
capability, and collisions of the replication fork with reversible
quinolone-DNA-topoisomerase complexes convert them to an irreversible form.
However, the molecular factors that subsequently generate DNA double-strand
breaks from the irreversible complexes and that probably initiate cell death
have yet to be defined.
30: Drugs 1999;58 Suppl 2:1-5
The future of the quinolones.
Yale University School of Medicine, New Haven, Connecticut 06520-8022, USA.
This review emphasises the advances in the development of newer quinolones:
their broader antimicrobial activity particularly their increased activity
against Pneumococcus and anaerobes; their longer half-life and tissue
penetration including activity in cerebrospinal fluid; and their excellent
efficacy in respiratory, intra-abdominal, pelvic, and skin and soft tissue
infections. Also, considerable progress has been made in our understanding of
the development of bacterial resistance to the newer quinolones. Additional
advances in quinolone development are likely to provide better compounds for