LA CONSULTA SEMANAL

CONSULTA

1: Am Fam Physician 2002 Feb 1;65(3):455-64 [Texto completo]
Quinolones: a comprehensive review.
Oliphant CM, Green GM.
University of Wyoming School of Pharmacy, Casper, USA. coliphant@wmcnet.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.
Publication Types:
Review
Review, Tutorial

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,
Safat. dphillips@hsc.kuniv.edu.kw
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.
Publication Types:
Review

3: Semin Respir Infect 2001 Sep;16(3):215-24 
Future of the quinolones.
Ball P.
School of Biomedical Sciences, University of St. Andrews, St. Andrews, Fife, Scotland. Peterball1@aol.com
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
Publication Types:
Review

4: Chemotherapy 2001;47 Suppl 3:9-14; discussion 44-8 
Comparison of side effects of levofloxacin versus other fluoroquinolones.
Carbon C.
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
Publication Types:
Review

5: Chemotherapy 2001;47 Suppl 3:3-8; discussion 44-8 
History of quinolones and their side effects.
Rubinstein E.
Department of Internal Medicine and Unit of Infectious Diseases, Tel Aviv University School of Medicine, Tel Aviv, Israel. unit@netvision.net.il
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
Publication Types:
Review

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 trauma.
Publication Types:
Review

7: Clin Infect Dis 2001 Mar 15;32 Suppl 1:S9-S15 
Mechanisms of action of antimicrobials: focus on fluoroquinolones.
Hooper DC.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114-2696, USA. dhooper@partners.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.
Publication Types:
Review

8: Clin Infect Dis 2001 Mar 15;32 Suppl 1:S1-8 
Mechanisms responsible for cross-resistance and dichotomous resistance among the quinolones.
Sanders CC.
Center for Research in Anti-Infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA. ecsanders@earthlink.net
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.
Publication Types:
Review

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.
Publication Types:
Review

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.
Publication Types:
Review

11: Clin Infect Dis 2000 Aug;31 Suppl 2:S24-8 
Mechanisms of action and resistance of older and newer fluoroquinolones.
Hooper DC.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114-2696, USA. dhooper@partners.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.
Publication Types:
Review

12: Curr Clin Top Infect Dis 2000;20:63-91 
The fluoroquinolones after ciprofloxacin and ofloxacin.
Hooper DC.
Harvard Medical School, Division of Infectious Diseases, Massachusetts General Hospital, Boston, USA.
Publication Types:
Review

13: Mayo Clin Proc 1999 Oct;74(10):1030-7 
The fluoroquinolones.
Walker RC.
Division of Infectious Diseases and Internal Medicine, Mayo Clinic Rochester, Minnesota, USA.
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.
Publication Types:
Review

14: Clin Infect Dis 2000 Feb;30(2):243-54 
New uses for new and old quinolones and the challenge of resistance.
Hooper DC.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114-2696, USA. dhooper@partners.org
Publication Types:
Review

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.
Publication Types:
Review

16: Drugs 1999;58 Suppl 2:96-8 
The quinolones and renal infection.
Ronald A.
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.
Publication Types:
Review

17: Drugs 1999;58 Suppl 2:92-5 
Quinolones in sexually transmitted diseases: state of the art.
Ridgway GL.
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.
Publication Types:
Review

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.
Publication Types:
Review

19: Drugs 1999;58 Suppl 2:78-81 
Activity of quinolones against Chlamydia pneumoniae.
Hammerschlag MR.
Department of Pediatrics, SUNY Health Science Center at Brooklyn, USA. mhammerschlag@pol.net
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.
Publication Types:
Review

20: Drugs 1999;58 Suppl 2:71-7 
Cost effectiveness of quinolones in hospitals and the community.
Davey P.
Department of Clinical Pharmacology, Ninewells Hospital, Dundee, Scotland. peter@memo.dundee.ac.uk
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 community.
Publication Types:
Review

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.
Publication Types:
Review

22: Drugs 1999;58 Suppl 2:60-4 
Quinolone activity against anaerobes.
Appelbaum PC.
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 sitafloxacin (DU-6859a).
Publication Types:
Review

23: Drugs 1999;58 Suppl 2:55-9 
Quinolone use in the developing world: state of the art.
Tupasi TE.
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 developing countries.
Publication Types:
Review

24: Drugs 1999;58 Suppl 2:52-4 
Quinolones in the treatment of typhoid fever.
Akalin HE.
Pfizer Pharmaceutical Group, Ortakoy, Istanbul, Turkey. akalie@pfizer.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 fever.
Publication Types:
Review

25: Drugs 1999;58 Suppl 2:49-51 
Quinolones in the aged.
Nicolle LE.
University of Manitoba, Winnipeg, Canada. lnicolle@hsc.mb.ca
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 mechanisms 
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 reported.
Publication Types:
Review

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.
Publication Types:
Review

27: Drugs 1999;58 Suppl 2:19-22 
Activity of quinolones against mycobacteria.
Jacobs MR.
Department of Pathology, Case Western Reserve University, University Hospitals of Cleveland, Ohio 44106, USA. mrj6@po.cwru.edu
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 antimycobacterial agents.
Publication Types:
Review

28: Drugs 1999;58 Suppl 2:11-8 
Mechanisms of fluoroquinolone resistance: an update 1994-1998.
Piddock LJ.
Division of Immunity and Infection, Medical School, University of Birmingham, Edgbaston, England. l.j.v.piddock@bham.ac.uk
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.
Publication Types:
Review

29: Drugs 1999;58 Suppl 2:6-10 
Mode of action of fluoroquinolones.
Hooper DC.
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston 02114-2696, USA. dhooper@partners.org
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.
Publication Types:
Review

30: Drugs 1999;58 Suppl 2:1-5 
The future of the quinolones.
Andriole VT.
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 clinical use.
Publication Types:
Review