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Comparative antimycobacterial activities of difloxacin, temafloxacin, enoxacin, Pefloxacin, reference fluoroquinolones, and a new macrolide, clarithromycin
Antimicrobial Agents and Chemotherapy
Abstract
The activities of fluoroquinolones and a new macrolide against 30 clinical isolates of Mycobacterium tuberculosis were determined
in vitro by agar diffusion. In order of relative potencies against M. tuberculosis, temafloxacin (MIC for 90% of isolates
[MIC90], 2.3 micrograms/ml) was at least as active as the reference quinolones ofloxacin (MIC90, 2.4 micrograms/ml) and ciprofloxacin
(MIC90, 4.3 micrograms/ml). Less active were difloxacin (MIC90, 4.7 micrograms/ml), pefloxacin (MIC90, 6.7 micrograms/ml),
and enoxacin (MIC90, 8.3 micrograms/ml). The macrolide clarithromycin was more potent than erythromycin but less potent than
the fluoroquinolones. Our results suggest that the newer fluoroquinolones and clarithromycin should be included with ciprofloxacin
and ofloxacin in pharmacokinetic studies that may lead to trials in human subjects with mycobacterial infections.
... Other new agents also appear to have promising activity against TB. Macrolides, like clarithromycin, azithromycin [16,17] and Rifapentine, were less active in vitro against Mtb than the FQs. Generally, they are used in combination with at least one other drug to avoid resistance [18]. ...
... Compound 14 reduced the bacterial load in lung and spleen tissues [94], while compound 15 reduced the bacterial load by 30% and 42%, respectively, at a dose of 50 mg/kg body weight [91][92][93]. The 1-(cyclopropyl/2,4difluorophenyl/ tert-butyl)-1,4-dihydro-8-methyl-6-nitro-4-oxo-7-(substituted-secondary-amino) quinoline-3carboxylic acids, most active compound (16) was showed MIC of 0.42 µM and 0.09 µM against Mtb and MDR-TB [94] and 7-(3-(diethylcarbamoyl)piperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (17) was exhibited promising MIC of 0.09 µM against Mtb and MDR-TB. Compound 17 decreased the mycobacterial load in lung and spleen tissues respectively at a dose of 50 mg/kg body weight [94]. ...
The reappearance of tuberculosis (TB) and resistant of Mycobacterium strains is a crucial public health concern for the treatment of TB. Some findings on the fluoroquinolone (FQs) derivatives are being developed as effective anti-TB agents. Some FQs antibiotics like ofloxacin, moxifloxacin, gatifloxacin, sparfloxacin, ciprofloxacin, levofloxacin are act as bactericidal with exceptional activity against Mtb and are presently used as second-line anti-TB drugs. The FQs exert their antibacterial effects by trapping gyrase and topoisomerase-IV enzymes on deoxyribonucleic acid (DNA) and blocking the replication and transcriptions. Unlike most other bacteriums, Mtb lacks topoisomerase-IV, but contains the genes gyrA and gyrB encoding the A and B subunits of DNA gyrase. Various new-generation FQs are under clinical trials with the aim of reducing the time periods of TB treatment while others are considered to be capable candidates for future drug development.
... The fluoroquinolones, such as ciprofloxacin (184), ofloxacin (193), and its L-isomer, levofloxacin, are active in vitro and are being actively investigated (135,344) for their uses against mycobacteria. The usual dose of ofloxacin is 400 to 800 mg/day. ...
... The macrolides, including azithromycin and clarithromycin, which show excellent activity against many nontuberculous mycobacteria, are not active against M. tuberculosis (135). Amoxicillin-clavulanic acid was suggested in an early report to be active (225), although some experts do not recommend its use (173). ...
A resurgence of tuberculosis has occurred in recent years in the United States and abroad. Deteriorating public health services, increasing numbers of immigrants from countries of endemicity, and coinfection with the human immunodeficiency virus (HIV) have contributed to the rise in the number of cases diagnosed in the United States. Outbreaks of resistant tuberculosis, which responds poorly to therapy, have occurred in hospitals and other settings, affecting patients and health care workers. This review covers the pathogenesis, epidemiology, clinical presentation, laboratory diagnosis, and treatment of Mycobacterium tuberculosis infection and disease. In addition, public health and hospital infection control strategies are detailed. Newer approaches to epidemiologic investigation, including use of restriction fragment length polymorphism analysis, are discussed. Detailed consideration of the interaction between HIV infection and tuberculosis is given. We also review the latest techniques in laboratory evaluation, including the radiometric culture system, DNA probes, and PCR. Current recommendations for therapy of tuberculosis, including multidrug-resistant tuberculosis, are given. Finally, the special problem of prophylaxis of persons exposed to multidrug-resistant tuberculosis is considered.
... The second line class of drugs known as fluoroquinolones is characterized by structural similarity to nalidixic acid and by the antimicrobial mode of action (Gorzynski et al., 1989). Fluoroquinolones target the type II topoisomerases, DNA gyrase and topoisomerase IV, of bacteria (Piton et al., 2010). ...
Mycobacterium tuberculosis isolates from multiple drug resistant or extensively drug resistant patients show a particular set of mutations in drug targets conferring resistance. However, the selection of drug-resistant strains in vitro yields an alternative set of mutations, thought to result from the cost-benefit associated with drug resistance. Mutations allowing for survival under antibiotic may not be beneficial when presented with the host environment or with a drug-free environment. These fitness effects drive the natural evolution of this bacterium. Using recombineering a large cohort of mutations was generated within two drug targets, inhA and gyrA, to study in vitro the variability of mutations allowable under either isoniazid or ofloxacin, respectively. As a proof of concept this process was carried out in Mycobacterium smegmatis. Analysis of survivors allowed for identification of novel mutations and substitutions, as well as showing mutations previously found only in clinical isolates can be present in laboratory isolates.
... Another possible alternative preventive therapy regimen is PZA plus a fluoroquinolone with reported in vitro activity against M. tuberculosis. A recent report indicates that ofloxacin and cipro-floxacin have similar antimycobacterial potencies in vitro (24). Suggested doses for these agents include 400 mg twice a day of ofloxacin and 750 mg twice a day of ciprofloxacin. ...
Summary Recent outbreaks of multidrug-resistant tuberculosis (MDR-TB) have posed challenges for the management of exposed persons. This report offers suggestions for evaluating and managing persons (i.e., contacts) who have been exposed to patients with infectious MDR-TB (TB due to strains of Mycobacterium tuberculosis resistant to both isoniazid {INH} and rifampin {RIF}), provides background information on alternative preventive therapy regimens with drugs other than INH or RIF, and presents considerations relevant to making a decision to offer one of these alternative regimens.
... Fluoroquinolones, such as ciprofloxacin, ofloxacin, and especially sparfloxacin, have potent in vitro activities against M. tuberculosis (9,17,19,21), including the vast majority of multidrug-resistant clinical isolates (8). Fluoroquinolones have been demonstrated to have clinical efficacy against tuberculosis in combination with other antituberculosis agents (12,18,27). ...
To examine the mechanism of resistance to fluoroquinolones in Mycobacterium tuberculosis, we selected spontaneous fluoroquinolone-resistant mutants from a susceptible strain, H37Rv, and studied the susceptibilities of these mutants and two fluoroquinolone-resistant clinical isolates (A-382, A-564) to various fluoroquinolones and to isoniazid and rifampin. Furthermore, since mutations within the quinolone resistance-determining region of the structural gene encoding the A subunit of DNA gyrase are the most common mechanism of acquired resistance, we amplified this region by PCR and compared the nucleotide sequences of the fluoroquinolone-resistant strains with that of the susceptible strain. Fluoroquinolone-resistant mutants of H37Rv appeared at frequencies of 2 x 10(-6) to 1 x 10(-8). For three mutants selected on ciprofloxacin, ofloxacin, and sparfloxacin, respectively, and the two clinical isolates, MICs of ciprofloxacin and ofloxacin were as high as 16 micrograms/ml, and those of sparfloxacin were 4 to 8 micrograms/ml. They displayed cross-resistance to all fluoroquinolones tested but not to isoniazid or rifampin. Sparfloxacin and FQ-A (PD 127391-0002) were the most potent fluoroquinolones. All of the fluoroquinolone-resistant strains (MICs, > or = 4 micrograms/ml) had mutations in the quinolone resistance-determining region which led to substitution of the Asp residue at position 87 (Asp-87) by Asn or Ala or the substitution of Ala-83 by Val in the A subunit of DNA gyrase. Similar mutations have been noted in other bacterial species and recently in mycobacteria. The broad resistance to fluoroquinolones that arose readily by point mutation in the laboratory and apparently during inadequate therapy, as was the case in the clinical isolates, may ultimately lead to to serious restriction of the use of these drugs in the treatment of tuberculosis.
The World Health Organization (WHO) estimates that there are 1.9 billion people infected with tuberculosis worldwide, 14 million infected with human immunodeficiency virus (HIV), and 5.6 million coinfected with tuberculosis and HIV. The overlap between at-risk populations especially in the developing world is increasing, which suggests that these figures will increase rather than improve. Alone, these two pathogens confer an enormous disease burden on mankind. In combined infection, both organisms have a synergistic effect, increasing morbidity and mortality.
Tuberculosis (TB) infections were chronicled by ancient Greek physicians as phthisis in describing the cough, fever and wasting character of this disease. TB did not become a major problem until the industrial revolution when urban overcrowding led to an increase in cases [1].
The treatment of tuberculosis in association with HIV is essentially not different from that of patients without HIV infection and follows well-established principles. The choice of chemotherapy regimen may be limited by cost or toxicity or be influenced by the likelihood of multiple drug resistance. Because patients with HIV are likely to be immunosuppressed and to become more so with time, there is some debate about whether one or more drugs should be continued after completing a course of treatment. As patients with HIV are more likely to relapse or acquire new infection, preventive therapy for life may be desirable. In areas of high prevalence of HIV and tuberculosis (as in Sub-Saharan Africa), tuberculosis remains the major cause of death in AIDS (Kassim et al., 1995). Strategies for chemoprophylaxis in these high risk groups must be considered.
Mycobacteria show a high degree of intrinsic resistance to most antibiotics and chemotherapeutic agents. The low permeability of the mycobacterial cell wall, with its unusual structure, is now known to be a major factor in this resistance. Thus hydrophilic agents cross the cell wall slowly because the mycobacterial porin is inefficient in allowing the permeation of solutes and exists in low concentration. Lipophilic agents are presumably slowed down by the lipid bilayer which is of unusually low fluidity and abnormal thickness. Nevertheless, the cell wall barrier alone cannot produce significant levels of drug resistance, which requires synergistic contribution from a second factor, such as the enzymatic inactivation of drugs.
Synopsis
Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of ery-thromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneu-moniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies — chelonae and — abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the micro-biologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated.
The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including β-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections.
Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithro-mycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater toler-ability, principally by inducing fewer gastrointestinal disturbances.
In conclusion, at this stage of its development clarithromycin appears to have a clinical profile which will make it a useful alternative to erythromycin, other macrolides and β-lactam antibiotics, for the treatment of community-acquired infections. Its activity against Mycobacteria including M. avium complex infection in AIDS patients may make it a first line option in this difficult to treat disease. Future comparative trials will help to further define its overall role in antimicrobial chemotherapy.
Antimicrobial Activity
Clarithromycin has an in vitro spectrum of activity broadly similar to that of erythromycin, although some significant differences in activity have been observed. Staphylococcus aureus and S. epidermidis strains susceptible to penicillin and/or erythromycin are also susceptible to clarithromycin. However, where these organisms show resistance to erythromycin, clarithromycin is inactive. Clarithromycin is active against streptococcus groups A, B, C (particularly) and G, and against S. bovis. It is more active than roxithromycin against group A streptococci and is more active than erythromycin and azithromycin against S. bovis and group G streptococci. S. pneu-moniae strains are also particularly susceptible to clarithromycin, except where these strains are resistant to erythromycin. Enterococci (streptococcus group D) are usually resistant to clarithromycin. Clarithromycin is the most potent macrolide tested against Bacillus species, and it is more active than azithromycin and clindamycin against Listeria monocytogenes. Clarithromycin shows poor overall activity against Corynebacterium species, although this finding is considered to reflect resistance by a subpopulation of isolates.
Overall, clarithromycin is either active or moderately active against Campylobacter species, but is notably more active than erythromycin, azithromycin and roxithromycin against Helico-bacter pylori. Haemophilus infiuenzae is either susceptible or resistant to clarithromycin and erythromycin but is susceptible or moderately susceptible to its primary metabolite, 14-hydroxy clarithromycin, in vitro. Indeed, 14-hydroxy clarithromycin is almost 3-fold more active than the parent compound against this organism. In contrast H. parainfluenzae is resistant to clarithromycin and erythromycin, although the activity of 14-hydroxy clarithromycin against this organism was not determined. Furthermore, despite the implications of these findings there are indications that Haemophilus species are susceptible to clarithromycin in the clinical setting. Combined laboratory data indicate that Neisseria gonorrhoeae strains (including those producing β-lacta-mase) are susceptible to clarithromycin and other macrolides although less so than to azithromycin and clindamycin. Overall, N. meningitidis is moderately susceptible to clarithromycin and erythromycin. Clarithromycin is particularly active against Bordetella pertussis, Bordetella par-apertussis and Borrelia burgdorferi, and is more active than erythromycin against the latter organism. Moraxella (Branhamella) catarrhalis (including β-lactamase producing strains) and strains of the Legionella genus (principally L. pneumophila) are susceptible to clarithromycin, which was the most active of the macrolides tested against L. pneumophila. Pasteurella multocida is more susceptible to clarithromycin than to erythromycin.
Clinical isolates of Bacteroides species were generally resistant to clarithromycin and erythromycin, although B. melaninogenicus is particularly susceptible to clarithromycin as is Pro-pionibacterium acnes. Clarithromycin was moderately active against Clostridium species and it was the most active macrolide tested against Eubacterium species. Peptococcus species show varying sensitivities to clarithromycin, although against combined isolates of the Peptococcus/Pep-tostreptococcus genera clarithromycin was moderately active.
Clarithromycin was the most potent of the macrolides tested against Chlamydia trachomatis and C. pneumoniae (TWAR), and produced potent inhibition of Mycoplasma pneumoniae. Isolates of Ureaplasma urealyticum were generally susceptible to clarithromycin, although other strains are resistant. Mycoplasma hominis is resistant to clarithromycin and erythromycin.
Clarithromycin is active against Mycobacterium chelonae subspecies -chelonae and -abscessus and is generally moderately active against M. fortuitum-fortitum and Mycobacterium avium complex (MAC), consistently showing greater activity than other macrolides. Clarithromycin also shows activity against other mycobacterium species including Mycobacterium marinum, Myco bacterium kansaii and Mycobacterium fortuitum-peregrinum. The metabolic function of M leprae was similarly inhibited by clarithromycin and standard antileprotic drugs. Clarithromycin is inactive against M. tuberculosis and, like azithromycin, appears to have parasitostatic activity against Toxoplasma gondii.
In general, bacterial strains resistant to erythromycin are also resistant to clarithromycin, although bacterial strains resistant to penicillin class drugs are susceptible to clarithromycin where macrolide resistance is absent. The combination of clarithromycin plus its 14-hydroxy metabolite demonstrates additive or synergistic activity against H. influenzae, M. catarrhalis, Legionella species, and some streptococci and staphylococci.
Clarithromycin is bactericidal against a variety of organisms including H. influenzae, L. pneu-
mophila, S. pneumoniae and M. avium complex, and demonstrated a postantibiotic effect against H. influenzae, S. aureus, S. pyogenes and β-haemolytic Streptococci.
Clarithromycin produces its antimicrobial effect by inhibition of intracellular protein synthesis. It is widely distributed throughout the body, is highly concentrated in tissues, organs (particularly the lung) and leucocytes, and enhances phagocytosis. Clarithromycin causes significant morphological changes in the cell wall of M. avium complex leading to cytoplasmic vacuolation.
Clarithromycin produces good antimicrobial activity in experimental models of infection induced by a variety of Gram-positive and Gram-negative bacteria (including L. pneumophila and H. influenzae) and other organisms including M. avium complex and M. leprae.
Pharmacokinetic Properties
Clarithromycin is well absorbed from the gastrointestinal tract, although it undergoes substantial first pass metabolism reducing systemic bioavailability to 55% after a 250mg dose in healthy volunteers. Maximum clarithromycin plasma concentrations (Cmax) in healthy ‘Western’ volunteers were 0.62 to 0.84 mg/L and 1.77 to 1.89 mg/L following single dose administration of clarithromycin 250 and 500mg, respectively. Marginally higher values were recorded in Japanese volunteers administered clarithromycin 200 or 400mg. In these studies the time to reach Cmax(tmax) was about 3 hours, irrespective of ethnic origin. The areas under the plasma concentration-time curves (AUC) were about 4 and 11 mg/L · h for doses of 250 and 500mg in ‘Western’ volunteers, but were approximately doubled in Japanese volunteers givęn 200 or 400mg.
Clarithromycin undergoes rapid biotransformation to produce the microbiologically active 14-hydroxy (R) metabolite, which achieves peak plasma concentrations of 0.4 and 0.8 mg/L within 3 hours of administering clarithromycin 250 or 500mg. In ‘Western’ volunteers AUC values for the 14-hydroxy metabolite were 3.1 to 4.9 and 6.1 to 6.9 mg/L·h following administration of clarithromycin 250 or 500mg, respectively. The presence of food does not appear to have a clinically significant effect on the pharmacokinetic parameters of clarithromycin. With continued administration of clarithromycin 250mg twice daily, steady-state is usually attained after 5 doses with Cmax for the parent and 14-hydroxy metabolite of 1 and 0.6 mg/L, respectively. Steady-state maximum plasma concentrations of 2.4 to 3.5 mg/L for clarithromycin and 0.7 to 0.8 mg/ L for the metabolite are achieved with a 500mg dose. Oral administration of clarithromycin 200mg resulted in a Cmax 3-fold greater, and an AUC 5-fold greater than those for erythromycin 200mg.
Clarithromycin appears to be widely distributed throughout the body, generally achieving higher concentrations in tissues and organs (including the lung and tonsils) than in blood. Indeed, reported values for volume of distribution have been large — 226 to 266L in ‘Western’ volunteers and 115 to 138L in Japanese volunteers. At concentrations representative of those achieved clinically, clarithromycin was 42 to 70% bound to human plasma protein.
The primary metabolic pathways for clarithromycin are oxidative N-demethylation and hy-droxylation, which are saturable resulting in nonlinear kinetics. The principal metabolite of clarithromycin is the 14-hydroxy derivative, which is mainly excreted with the parent drug via urinary mechanisms. The elimination half-life (t1/2β) for clarithromycin ranged from 2.6 to 4.4 hours and the plasma clearance from 42 to 64 L/h when administered in doses of 250 to 500mg to ‘Western’ volunteers. Values for t1/2β were very similar in Japanese volunteers, but total body clearance was much lower’(22 to 24 L/h). In ‘Western’ children, the pharmacokinetic profile of clarithromycin is consistent with that seen in adults. Limited data in Japanese children reveal AUC and t1/2β values to be about half those in Japanese adults receiving similar doses. A reduction in urinary clearance in the elderly and patients with severe renal insufficiency is associated with an increase in AUC, Cmax and/or t1/2β. Mild-to-severe hepatic impairment does not significantly affect the pharmacokinetics of clarithromycin, although reduced metabolite formation may occur with severe liver impairment.
Therapeutic Efficacy
Clarithromycin is effective in the treatment of several types of infection when administered as a 250 or 500mg dose twice daily in ‘Western’ adult patients, or in lower divided doses in Japanese adults. In noncomparative studies, the clinical success rate for clarithromycin in ‘Western’ patients with lower respiratory tract infections was 94 to 99%, whereas the clinical efficacy (excellent plus good responses) derived from Japanese studies ranged from 86 to 91%, except in bronchiectasis (58%). Bacterial eradication rates in Japanese studies ranged from 70 to 94% for the most commonly isolated pathogens. In comparative studies of ‘Western’ patients with pneumonia, acute bronchitis or acute exacerbations of chronic bronchitis, clarithromycin produced clinical cure rates of 47 to 96%, clinical success rates of 76 to 100% and bacteriological eradication rates of 57 to 100%. In these studies, the clinical efficacy of clarithromycin was at least comparable with that of erythromycin, josamycin, roxithromycin, ampicillin, cefaclor, cefuroxime and/or ce-fixime. The clinical efficacy of clarithromycin in Japanese patients with pneumonia, bronchitis or bronchiectasis, was also equivalent to that of cefaclor (77 vs 67%) but greater than that of midecamycin acetate (90 vs 74%), bacteriological eradication rates in these studies showing similar trends for the various drugs.
Upper respiratory tract infections (including those of the middle ear), also responded well to clarithromycin. Thus, in noncomparative ‘Western’ studies (employing dosages of 250 or 500mg twice daily), clinical success rates of 84 to 97% were recorded. In noncomparative Japanese trials, clinical efficacy rates of 62 to 87% were recorded, whilst bacteriological eradication rates of 75 to 94% were noted for the most commonly isolated organisms (S. aureus, S. pyogenes and S. pneumoniae). In comparative studies in ‘Western’ patients with streptococcal pharyngitis, clarithromycin therapy produced clinical cure in 80 to 96% of patients, clinical success in 95 to 100% of patients and bacteriological eradication rates of 88 to 100%. Patients with acute maxillary sinusitis also responded well to treatment with clarithromycin as evidenced by clinical cure rates of 58 to 69%, clinical success rates of 85 to 95% and bacteriological eradication rates of 89 to 92%. Clarithromycin was considered equally effective as erythromycin or phenoxymethyl penicillin in treating pharyngitis and as effective as amoxicillin (with or without clavulanic acid) in treating acute maxillary sinusitis. Clarithromycin also demonstrated efficacy equivalent to that of josamycin in the treatment of acute tonsillitis and acute suppurative otitis media in Japanese patients. In the treatment of tonsillitis, clinical efficacy and bacteriological eradication rates of 87 and 99% were noted for clarithromycin. Clarithromycin was less effective in the treatment of suppurative otitis media, as evidenced by clinical efficacy and bacteriological eradication rates of 63%.
In the treatment of skin and soft tissue infections, clarithromycin was associated with an overall efficacy rate of 74% and bacteriological eradication rates of ⩾86% in Japanese noncomparative studies. Furthermore, in a Japanese comparative study, clarithromycin and erythromycin were similarly effective (clinical response rates 83 vs 79% and bacteriological eradication rates 92 vs 93%). Clarithromycin was also shown to be equally effective as erythromycin or cefadroxil in ‘Western’ patients with skin and soft tissue infections. Clinical success rates of 95 and 96% were noted for clarithromycin and comparator drugs, respectively, while bacteriological eradication rates were identical for the two groups (92%).
In Japanese noncomparative studies, the clinical efficacy of clarithromycin in the treatment of infections of the urogenital tract ranged from 48 to 92% (depending on the causative pathogen), with the greatest responses elicited in those with chlamydial (92%) or ureaplasmic infections (85%). Oromaxillofacial and ophthalmic infections responded with efficacy rates of 74 to 89%.
In preliminary studies of Mycobacterium avium complex infection in AIDS patients, clarithromycin, either alone or in combination with other antimicrobial drugs, has been shown to reduce or eradicate the pathogen from blood samples, and this has been associated with clinical improvement. Clarithromycin has also shown promising activity in immunocompromised patients with disseminated Mycobacterium
chelonae — chelonae infection or toxoplasma encephalitis.
Clarithromycin has a proven efficacy in the treatment of paediatric infections in Japanese and ‘Western’ patients. Thus, in Japanese noncomparative studies where clarithromycin suspension was usually given at a dosage of 10 to 15 mg/kg bodyweight twice or 3 times daily, excellent plus good clinical response rates of 80 to 97% were recorded for Japanese children with impetigo, infections of the respiratory tract or gastrointestinal tract. In ‘Western’ comparative studies, clarithromycin 7.5 mg/kg twice daily (maximum 250mg twice daily) in suspension was considered as effective as phenoxymethylpenicillin for streptococcal pharyngitis, amoxicillin (with or without clavulanic acid) for acute otitis media, cefadroxil or erythromycin for skin or skin structure infections and amoxicillin for lower respiratory tract infections.
Preliminary studies have shown clarithromycin to be effective in the treatment of infection with Helicobacter pylori and in the treatment of leprosy.
Tolerability
Analysis of 4291 ‘Western’ patients revealed an adverse event rate of 19.6% for clarithromycin, the most common occurrences being nausea, diarrhoea, abdominal pain, dyspepsia and headache. In excess of 90% of these adverse events were either mild or moderate in severity. The adverse event rate for clarithromycin was similar to that of common β-lactam antimicrobials, although in comparison with pooled data for other macrolides (erythromycin, josamycin and roxithro-mycin), clarithromycin caused substantially fewer gastrointestinal effects, particularly when compared with erythromycin alone. Premature discontinuation of therapy due to adverse events for clarithromycin (3 to 3.5%) was similar to that with β-lactam antimicrobials (2.7 to 3.5%) but was significantly less than that with other macrolides considered together (5.9%). Increased trans-aminase levels were recorded for patients treated with clarithromycin or other macrolides. However, the incidence of elevated aspartate aminotransferase and alanine aminotransferase was significantly lower (about 2-fold) for clarithromycin compared with other macrolides, especially josamycin.
Dosage and Administration
The recommended oral dosage of clarithromycin in adult ‘Western’ patients with various community-acquired infections (excluding M. avium complex) is 250 to 500mg twice daily for 7 to 14 days. Preliminary data suggest that clarithromycin 1 to 2 g/day is suitable for the treatment of AIDS patients with M. avium complex. ‘Western’ paediatric clinical studies employed a clarithromycin dosage of 7.5 mg/kg bodyweight twice daily (maximum 250mg twice daily) for 5 to 10 days. In adult Japanese patients the recommended dosage for clarithromycin is 400mg twice daily, whereas in Japanese children it is 10 to 15 mg/kg bodyweight in 2 or 3 divided daily doses. It is recommended that the duration of treatment be adjusted depending on the nature and severity of the infection, however, the duration in most Japanese clinical studies has been 7 to 14 days.
Pharmacokinetic studies indicate that dosage adjustment is appropriate in the presence of severe renal impairment. However, in the absence of this condition, dosage adjustment is not necessary in mild to severe hepatic impairment or for the elderly.
The fluoroquinolones are key components of current multidrug-resistant tuberculosis (MDR-TB) treatment regimens and are being evaluated in shortened treatment regimens as well as in the prevention of drug-resistant TB. The objective of this review was to identify existing evidence for the use of the fluoroquinolones ofloxacin, levofloxacin and moxifloxacin in the treatment of TB in children. Existing data from in vitro, animal and human studies consistently demonstrate the efficacy of the fluoroquinolones against Mycobacteriumtuberculosis, with superiority of levofloxacin and moxifloxacin compared to ofloxacin. In vitro and murine studies demonstrated the potential of moxifloxacin to shorten drug-susceptible TB treatment, but in multiple randomized controlled trials shortened fluoroquinolone-containing regimens have not been non-inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration, with newer more potent fluoroquinolones less likely to develop resistance. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-infected children; existing studies show substantially lower serum concentrations in children compared to adults at currently recommended doses, probably due to faster elimination. This has implications for optimizing paediatric treatment and for the development of resistance. Fluoroquinolone use has been restricted in children due to concerns about drug-induced arthropathy. The available data does not demonstrate any serious arthropathy or other severe toxicity in children. Although there is limited paediatric safety data for the prolonged treatment of MDR-TB, extended administration of fluoroquinolones in adults with MDR-TB does not show serious adverse effects and there is no evidence suggesting less tolerability of fluoroquinolones in children. Additional study of moxifloxacin and levofloxacin for TB treatment and prevention in children is an urgent priority.
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Graphical Abstract
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Quinolones, such as ciprofloxacin and ofloxacin, have gained wide acceptance for the treatment of bacterial infections of the respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Good pharmacokinetic profiles and potent activities against a wide range of Gram-negative and Gram-positive pathogens result in the use of these antibacterials in both hospital and community settings. Although recently developed clinical quinolones dominate in the chemotherapy of various bacterial infections, their use is restricted by limited activities against a number of clinically-important Gram-positive bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and enterococci. Ciprofloxacin, the market leader, also has low potency against anaerobes. Bacterial resistance (such as in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesised to address these drawbacks. The new quinolones currently under development are characterised by enhanced activities against streptococci, staphylococci, enterococci and anaerobes. Although the treatment of traditional bacterial infections is at present the focus of quinolone research, the future role of quinolones will extend current applications to include new indications of bacterial infections and other non-bacterial diseases. This review will concentrate on the more recently developed quinolones which possess significantly more therapeutic value than existing quinolones, and will provide information on those compounds under commercial development with major therapeutic potential. Recent developments in research into the identification of quinolones for the treatment of tuberculous, cancer, viral, fungal infections and parasitic diseases will also be discussed.
Macrolide antibiotics are well-established antimicrobial agents in both clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram-positive organisms, Mycoplasma species, and certain susceptible gram-negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12-, 14-, or 16-membered. Naturally occurring 14-membered macrolides include erythromycin A (C37H67NO13), erythromycin B (C37H67NO12), erythromycin C (C36H65NO13), erythromycin D (C36H65NO12), erythromycin F (C37H67NO14), and erythromycin E (C37H65NO14), as well as others. Erythromycin has been the principal subject of modification of 14-membered macrolides; some of the derivatives of erythromycin and oleandomycin include 2′-O-acetylerythromycin (C39H69NO14), 2′-O-propionylerythromycin (C40H71NO14), erythromycin ethyl carbonate (C40H71NO15), and others. 16-Membered macrolides are divided into leucomycin- and tylosin-related groups, which differ in the substitution pattern of their aglycones. Natural products include leucomycin A1 (C40H67NO14), leucomycin A5 (C39H65NO14), leucomycin A7 (C38H63NO14), midecamycin A2 (C42H69NO15), and others. A second large group of 16-membered macrolides differs from the leucomycins in the substitution pattern of the aglycone. One difference is a methyl or hydroxymethyl group at C-14. The most prominent member of this group is tylosin, an important veterinary antibiotic produced by S. fradiae. Tylosin and related products include tylosin (C46H77NO17), relomycin (20-dihydrotylosin) (C46H79NO17), macrocin (C45H75NO17), O-demethylmacrocin (C44H73NO17), and others. Other macrolides have been made by chemical, bioconversion, or genetic manipulations which represent hybrids of structures within the 14-membered family, within the 16-membered family, or between the two families. The advent of molecular biology has opened new possibilities for producing hybrid macrolides. Genetic manipulations of biosynthetic pathways in macrolide-producing microorganisms complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram-positive bacteria, Mycoplasma species, and certain gram-negative and anaerobic bacteria. Susceptible gram-positive bacteria include many species of Staphylococcus and Streptococcus; susceptible gram-negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis (formerly Branhamella), and Haemophilus ducreyi. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and streptogramin B antibiotics (MLS-resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolides are obtained by controlled submerged aerobic fermentations of soil microorganisms. Although species of Streptomyces have dominated, species of Saccharopolyspora, Micromonospora, and Streptoverticillium are also well represented. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. Relatively few macrolides are used in veterinary medicine. The most important is tylosin (Tylan, Elanco Products), which is used to control chronic respiratory disease caused by Mycoplasma gallisepticum in poultry.
From a U.S. perspective, the problem of MDRTB has been greatly ameliorated through the use of standardized four-drug regimens
in the initial phase of treatment, rapid DST, directly observed therapy, and improved infection control practices. The importation
of MDRTB cases from countries with high levels of drug resistance, however, will continue to challenge TB control efforts
in the United States. In other areas of the world, the rapid emergence of MDRTB represents an even greater challenge to such
efforts, and will require the influx of significant resources and expertise to meet this challenge. Given that the best treatment
of MDRTB is its prevention, the expansion of DOTS to prevent the production of MDRTB and the careful expansion of DOTS-Plus
to treat existing cases and prevent further transmission of MDR M. tuberculosis are critical. In addition, as the HIV epidemic reaches areas in which the prevalence of TB and antituberculosis drug resistance
are high, a concerted effort to treat these coexisting diseases will be essential to mitigate the convergence of factors that
led to the large outbreaks of MDRTB that occurred in the United States in the early 1990s.
In this article, I have thoroughly reviewed the status of development of new antimycobacterial drugs, particularly fluoroquinolones
(ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, and moxifloxacin), new macrolides (clarithromycin,
azithromycin, and roxithromycin), rifamycin derivatives (rifabutin, rifapentine, and KRM-1648), and others. The main purpose
of this review was to describe the in-vitro and in-vivo activities of these drugs against Mycobacterium tuberculosis and Mycobacterium avium complex. In addition, the therapeutic efficacy of these drugs in the clinical treatment of mycobacterial infections has also
been briefly mentioned.
Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.
Previously, pefloxacin and ofloxacin were found to be active against Mycobacterium leprae in vitro, in experimental animals,
and in clinical trials of lepromatous leprosy patients. In this study, we compared certain more recently developed fluoroquinolones
(lomefloxacin, PD 124816, WIN 57273, temafloxacin, and sparfloxacin) with pefloxacin and ofloxacin in M. leprae-infected mice
at doses of 50, 150, and 300 mg/kg given five times weekly. All seven of the fluoroquinolones studies were active against
M. leprae; temafloxacin and sparfloxacin were the most active, being fully bactericidal at all three dosage schedules. Additionally,
sparfloxacin was found to be fully bactericidal at 15 and 30 mg/kg given five times weekly.
The activity of clarithromycin alone and in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J
bgj/bgj) mouse model of disseminated Mycobacterium avium complex (MAC) infection. A dose-response experiment was performed
with clarithromycin at 50, 100, 200, or 300 mg/kg of body weight administered daily by gavage to mice infected with approximately
10(7) viable MAC. A dose-related reduction in spleen and liver cell counts was noted with treatment at 50, 100, and 200 mg/kg.
The difference in cell counts between treatment at 200 and 300 mg/kg was not significant. Clarithromycin at 200 mg/kg of body
weight was found to have activity against three additional MAC isolates (MICs for the isolates ranged from 1 to 4 micrograms/ml
by broth dilution). Clarithromycin at 200 mg/kg in combination with amikacin, ethambutol, temafloxacin, or rifampin did not
result in increased activity beyond that seen with clarithromycin alone. Clarithromycin in combination with clofazimine or
rifabutin resulted in an increase in activity beyond that seen with clarithromycin alone. The combination of clarithromycin
with clofazimine or rifabutin should be considered for evaluation in the treatment of human MAC infections.
Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of erythromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneumoniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies--chelonae and--abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the microbiologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated. The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including beta-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections. Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithromycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater tolerability, principally by inducing fewer gastrointestinal disturbances.(ABSTRACT TRUNCATED AT 400 WORDS)
The absolute bioavailability of clarithromycin, a new macrolide antimicrobial agent, was assessed in a three-way, randomized,
single-dose, crossover study conducted with 22 healthy volunteers, 19 of whom provided analyzable study data. The bioavailability
parameters of two 250-mg oral tablet formulations were calculated with reference to an identical dose administered by intravenous
infusion of the lactobionate salt. After adjustment for formulation potency, the mean absolute bioavailabilities of the two
oral formulations were 52 and 55%, on the basis of the appearance of parent compound in the systemic circulation. Metabolite
peak concentration and area under the plasma concentration-time curve data after oral dosing were generally greater than those
after intravenous infusion, suggesting that marked first-pass metabolism of clarithromycin occurs after oral administration.
Pharmacokinetic analysis of the parent drug and the active 14-hydroxy metabolite data suggests complete (or nearly complete)
absorption of the drug after oral administration.
The MICs of the macrolide clarithromycin for 31 clinical isolates of Mycobacterium kansasii were determined by three different
methods. The methods employed were the proportion resistance method on 7H10 agar, the radiometric (BACTEC) method, and the
T100 method of datum analysis. All methods gave similar results. The MICs were in a narrow range from 0.16 to 0.50 microgram/ml,
with the MICs for 90% of isolates tested of 0.50 microgram/ml for the agar dilution and radiometric methods and 0.37 microgram/ml
for the T100 method. The MBCs were determined for nine representative isolates by the radiometric broth method. The MBCs were
equal to the MICs for four isolates, and the MBCs were twofold higher than the MICs for five isolates. Killing of 99.9% of
the bacterial population was achieved at a clarithromycin concentration of 2.0 micrograms/ml for all nine isolates tested.
The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.
The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.
The in vitro and in vivo spectrum of antibacterial activity of clarithromycin is summarized and related to its human pharmacokinetics. In vitro studies by several investigators have documented clarithromycin's activity against bacterial agents of respiratory tract infections, skin and soft tissue infections, and sexually transmitted diseases. Clinical cure rates of 52%-83% (pneumonia), 79%-96% (bronchitis), 82%-96% (pharyngitis), 58% (sinusitis), and 78% (skin/skin-structure infections) have been reported in patients receiving clarithromycin in comparative trials. Respective bacteriologic eradication rates in clarithromycin recipients have been reported as 57%-89%, 79%-96%, 88%-100%, 89%, and 90%. In vitro and in vivo studies suggest that clarithromycin, when combined with its major human metabolite, 14-hydroxyclarithromycin, is also effective against Haemophilus influenzae. A New Drug Application claiming efficacy in the treatment of lower respiratory tract infection, sinusitis, pharyngitis, and skin and skin-structure infections caused by susceptible pathogens has been filed with the Food and Drug Administration (FDA). This review summarizes relevant pharmacokinetic, microbiological, and clinical data for clarithromycin.
To evaluate the effect of food on bioavailability, clarithromycin and 14-hydroxyclarithromycin (active metabolite) pharmacokinetics were assessed in 26 healthy adult volunteers after ingestion of a single oral 500-mg dose of clarithromycin in a fasting state (2 hours before breakfast after an overnight fast) and a nonfasting state (0.5 hours after the start of breakfast). Clarithromycin and 14-hydroxy metabolite plasma concentrations were measured using a high-performance liquid chromatographic technique. Food intake immediately before dosing increased the extent of absorption from the 500-mg tablet formulation by approximately 25%. The mean increase in metabolite area under the plasma concentration-time curve was approximately 9%. These results suggest that clarithromycin can be taken without regard to timing in relation to meals.
Most Enterobacteriaceae, enteropathogens, and fastidious gram-negative bacteria are highly susceptible to ofloxacin, a new
tricyclic fluoroquinolone. Aerobic gram-negative bacilli and gram-positive bacteria are generally not as susceptible to ofloxacin.
Obligate anaerobes are generally resistant to ofloxacin, while many mycobacteria, chlamydiae, legionellae, and mycoplasmas
are susceptible. Ofloxacin is generally less active than ciprofloxacin against gram-negative bacteria, is similarly active
against gram-positive bacteria, mycobacteria, legionellae, and mycoplasmas, and is more active against chlamydiae. However,
numerous animal studies have shown these two fluoroquinolones to be similar. Ofloxacin inhibits DNA synthesis, is rapidly
bactericidal, and is 1,000–2,400 times more potent against prokaryotic gyrase than against eukaryotic gyrase. The bactericidal
effect of ofloxacin is not completely neutralized by inhibitors of protein or RNA synthesis. Resistance to ofloxacin arises
from mutations within chromosomal genes involved with DNA gyrase and drug permeation. Selection of resistant mutants by ofloxacin
is not as frequent as that seen with nalidixic acid. However, due to the cross-resistance between ofloxacin and other fluoroquinolones,
all of these drugs should be used judiciously to preserve their clinical utility.
In vitro and animal investigations have demonstrated the antimycobacterial activity of some fluoroquinolones, including ciprofloxacin, but information regarding their clinical usefulness in mycobacterial infections is sparse. This article presents treatment results of 11 patients with tuberculosis and 4 with atypical mycobacterial infections. They were treated with combinations of ciprofloxacin and one or two other antituberculosis agents. Susceptibility of the infecting organisms to ciprofloxacin was determined in 14 of the 15 patients: in 12 of them, minimum inhibitory concentrations ranged between 0.31 and 1.25 micrograms/mL, suggesting a good level of activity. Serum concentrations of ciprofloxacin, sampled one hour after dosing and measured by a specific HPLC assay, revealed considerable variability (range 0.22-8.41 micrograms/mL). Serial plasma samples taken under controlled conditions suggested that a decreased rate of absorption was responsible for low one-hour concentrations in one of the subjects. Adverse reactions to ciprofloxacin were few and included nausea in four patients, crystalluria in one, and febrile reaction in another. A satisfactory response in terms of clinical and radiologic improvement, bacteriologic conversion, and absence of relapse was seen in 13 of the 14 patients who completed an adequate course of therapy. A controlled clinical trial of this promising antimycobacterial agent is needed.
The microbiologic activities of temafloxacin, ciprofloxacin, and ofloxacin against community-acquired respiratory tract pathogens are reviewed. The 90% minimal inhibitory concentrations (MIC90s) of these fluoroquinolones for gram-negative pathogens were generally comparable, that is, less than 0.06 micrograms/mL. Overall, the agents were less active against gram-positive pathogens, although temafloxacin was two- to fourfold more active than the other agents against staphylococci and streptococci. For strains of Mycoplasma pneumoniae and Chlamydia pneumoniae, temafloxacin was generally inhibitory at concentrations of 0.5-2 micrograms/mL. This microbiologic activity, combined with its pharmacokinetic profile, should make temafloxacin a useful antimicrobial agent for treating community-acquired respiratory tract infections.
Mycobacterium avium complex bacteria are opportunistic human pathogens, and their chemotherapy remains a challenge since these organisms are resistant to a majority of routine antituberculous drugs. Recently, a wide range of new macrolide antibiotics has been developed, among which the drug clarithromycin appears to have a selective action against M. avium bacteria. In the present study, we have investigated the action of clarithromycin alone (MIC and MBC determinations) and in association with the routine antimycobacterial drugs ethambutol and rifampin at sublethal concentrations (1 micrograms/ml; below concentrations obtainable in human serum) against M. avium. Our viable count data showed that clarithromycin was bactericidal against all 10 strains of M. avium studied and that its activity was enhanced by ethambutol (in 8 of 9 strains) and rifampin (in 3 of 9 strains). The use of all three drugs in association resulted in higher bactericidal effects than found with any of the drugs used alone or in two-drug combinations in seven of nine strains. The bactericidal effects of various drugs used alone and in combination at concentrations obtainable in human serum were investigated against the type strain ATCC 15769 by using 7H9 broth and BACTEC radiometry (extracellular action) and a J-774 macrophage cell line (intracellular action). A good agreement between the extracellular and intracellular activities was found. Electron microscopy using a ruthenium red cytochemical staining of the bacteria showed that clarithromycin disorganized the outer wall layer and the cytoplasmic membrane in the mycobacterial cell envelope and resulted in formation of large vacuoles inside the cytoplasm, with solubilization of ribosomal structures and consequent plasmolysis. Its association with ethambutol and rifampin resulted in more drastic alterations in the bacterial morphology than were seen with any of the drugs used alone, leading to the removal of the bacterial outer layer, homogenization of cytoplasm, complete cell lysis, and formation of ghosts.
The evolution of the fluoroquinolones is described, and structure-activity relationships outlined. The in-vitro antimicrobial activities of ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin against a wide range of organisms are critically reviewed. In-vitro factors influencing fluoroquinolone activity are discussed. Reports of the acquisition of resistance to the fluoroquinolones are evaluated. Finally, possible future directions for this group of antibiotics are discussed.
The in vitro activities of 20 fluoroquinolones against Mycobacterium leprae were evaluated by using the BACTEC 460 system.
M. leprae was incubated in BACTEC 12B medium at 33 degrees C under reduced oxygen for 2 to 3 weeks in the presence of fluoroquinolones
at 0.31 to 5 micrograms/ml. Activity was determined by a reduction in 14CO2 evolution compared with that of drug-free controls.
Of the commercially available agents, ofloxacin was most active, while enoxacin and norfloxacin were inactive. However, a
number of newer fluoroquinolones (AT-4140, OPC-17100, OPC-17066, PD-117596, PD-124816, PD-127391, and WIN-57273), all containing
a cyclopropyl group at R-1 and, with the exception of WIN-57273, either a halogen or methyl group at R-8, were more active
than ofloxacin in vitro. Further in vivo evaluations of these agents should help determine their potential for use against
leprosy.
The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.
The ofloxacin (OFLX) concentration in serum, saliva and pleural effusion was measured in 12 patients with pleural effusion after oral administration at a dose of 200 mg three times a day (600 mg daily). Three patients had non-small cell lung cancer and the others had pulmonary tuberculosis. The mean OFLX levels in the serum, saliva and pleural effusion at 2 hours after the first administration on day 3 was 3.15 +/- 1.52, 3.36 +/- 2.23 and 2.86 +/- 1.77 micrograms/ml respectively. There was a strong correlation among these concentrations. The OFLX concentration of pleural effusion was predictable from that of saliva. A 3-day oral administration is sufficient to achieve the OFLX level of pleural effusion similar to that of the serum. It is possible that OFLX is effective for pleuritis caused not only by common infectious pathogens but also by Mycobacterium tuberculosis.
A new fluoroquinolone, DU-6859a, was studied for its in vitro and in vivo antimycobacterial activities. MIC determination by the agar dilution method with 7H11 medium revealed that DU-6859a had MICs at which 90% of M. kansasii (0.78 microgram/ml), M. marinum (1.56 micrograms/ml), M. scrofulaceum (1.56 micrograms/ml), M. fortuitum (0.39 microgram/ml), M. chelonae subsp. abscessus (6.25 micrograms/ml), and M. chelonae subsp. chelonae (1.56 micrograms/ml) were inhibited were 4 to 32 times lower than those of ofloxacin and sparfloxacin. The MICs of DU-6859a at which 90% of M. tuberculosis (0.2 microgram/ml) and M. avium-M. intracellulare complex (12.5 micrograms/ml each) were inhibited were comparable to those of sparfloxacin but were four- to eightfold lower than those of ofloxacin. Thus, DU-6859a possessed more potent in vitro activity than sparfloxacin and ofloxacin against most mycobacterial species. DU-6859a exerted significant efficacy against infections caused by M. intracellulare and M. chelonae subsp. abscessus induced in mice when it was given at a dose of 1 mg per mouse (ca. 50 mg/kg of body weight) in terms of reducing the frequency of occurrence and the degree of gross pulmonary or renal lesions and bacterial loads in the lungs, spleens, or kidneys. The efficacy of DU-6859a was greater than that of ofloxacin and was more pronounced against M. chelonae infections than against M. intracellulare infections.
To evaluate the pharmacokinetics of topically applied clarithromycin, a new macrolide antibiotic, at various concentrations in a rabbit model.
Clarithromycin in dosages of 10, 20, and 40 mg/ml was administered topically every 2 hours for 48 hours to three groups of 16 New Zealand albino rabbits. Both corneas were treated. Right corneas were deepithelialized with n-heptanol. At 6, 12, 24, and 48 hours, tissue concentrations were determined in four animals from each group.
Tissue drug concentrations increased with drug dosage and duration of therapy. Drug concentrations were significantly higher at 48 hours than at 6 hours, 12 hours, and 24 hours for both epithelialized and deepithelialized eyes in the 20 mg/ml and 40 mg/ml treatment groups (all P < or = 0.0015). A steady state concentration was not achieved in any group. Tissue drug concentrations were higher in deepithelialized corneas for each dose after 6 hours, although differences were not significant (all P > 0.059). Highest mean drug concentration at 48 hours was 241 micrograms/g in animals receiving 40 mg/ml of clarithromycin. After 6 hours, tissue concentrations in some groups were above MIC90 for many Chlamydia sp., Streptococcus sp., and Staphylococcus sp., and by 12 hours, concentrations were greater than MIC90 in all groups for many nontuberculous mycobacteria.
Topical clarithromycin achieves therapeutic levels in corneal tissue in a rabbit model. Clarithromycin might be a useful broad-spectrum antibiotic for topical use in humans.
The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean +/- standard deviation) of ELF were 1.9 +/- 2.0 ml and 1.5 +/- 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 +/- 73.0 micrograms/ml at 8 h to 11.9 +/- 3.6 micrograms/ml at 24 h) and alveolar cells (range, 505.8 +/- 293.1 micrograms/ml at 4 h to 17.0 +/- 34.0 micrograms/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 +/- microgram/ml in ELF and 0 to 0.8 +/- 1.3 microgram/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments in unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.
The comparative activities of azithromycin (AZI) and clarithromycin (CLA) were evaluated against nontuberculous mycobacteria in a murine model of disseminated infection. Four-week-old beige mice (C57BL/6J bgj/bgj) were infected intravenously with approximately 10(7) viable Mycobacterium kansasii, M. xenopi, M. simiae, or M. malmoense. Treatment with AZI at 200 mg/kg, CLA at 200 mg/kg, ethambutol at 125 mg/kg, rifampin at 20 mg/kg, or clofazimine at 20 mg/kg of body weight was started 7 days postinfection, and the treatments were administered 5 days per week for 4 weeks. Control groups were sacrificed at the start and end of the treatments. Spleens and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto 7H10 agar. AZI and CLA had activities comparable to or better than that of rifampin, ethamutol, or clofazimine against these nontuberculous mycobacteria in the beige mouse test system. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against organisms in the spleens for M. xenopi and M. malmoense. The activities of AZI and CLA were comparable against organisms in the spleens for M. kansasii and M. simiae. The activities of these two agents were comparable against organisms in the lungs for all four nontuberculous mycobacterial species. AZI or CLA in combination with other agents may be useful for the therapy of nontuberculous mycobacterial infections in humans.
Mycobacteria show a high degree of intrinsic resistance to most antibiotics and chemotherapeutic agents. The low permeability of the mycobacterial cell wall, with its unusual structure, is now known to be a major factor in this resistance. Thus hydrophilic agents cross the cell wall slowly because the mycobacterial porin is inefficient in allowing the permeation of solutes and exists in low concentration. Lipophilic agents are presumably slowed down by the lipid bilayer which is of unusually low fluidity and abnormal thickness. Nevertheless, the cell wall barrier alone cannot produce significant levels of drug resistance, which requires synergistic contribution from a second factor, such as the enzymatic inactivation of drugs.
Mycobacterium avium strains susceptible to clarithromycin and azithromycin contain mutants resistant to these macrolides with
a frequency of 1.1 x 10(-10) to 1.2 x 10(-6). Cross-resistance between clarithromycin and azithromycin was demonstrated with
mutants selected in the laboratory as well as with resistant strains isolated from patients. The susceptibility-resistance
patterns of the macrolide-resistant strains with drugs other than macrolides were the same as those of the original susceptible
strains. The emergence of clarithromycin resistance in patients was a result of multiplication of the preexisting resistant
mutants that survived the elimination of bacteria during the initial period of treatment and was an exclusive cause of the
relapse of bacteremia.
Clarithromycin is a semisynthetic macrolide antibiotic, structurally related to erythromycin. It has a more favourable pharmacokinetic profile than erythromycin, thus allowing twice-daily administration and possibly increasing compliance among outpatients. Clarithromycin is well absorbed from the gastrointestinal tract and its systemic bioavailability (about 55%) is reduced because of first-pass metabolism. It undergoes rapid biodegradation to produce the microbiologically active 14-hydroxy-(R)-metabolite. The maximum serum concentrations of clarithromycin and its 14-hydroxy metabolite, following single oral doses, are dose proportional and appear within 3 hours. With multiple doses, steady-state concentrations are attained after 5 doses and the maximal serum concentrations of clarithromycin and of the 14-hydroxy derivative appear within 2 hours after the last dose. Clarithromycin is well distributed throughout the body and achieves higher concentrations in tissues than in the blood. Also, the 14-hydroxy metabolite exhibits high tissue concentrations, with values about one-third of the parent compound concentrations. The presence of food appears to have no clinically significant effect on clarithromycin pharmacokinetics. The main metabolic pathways are oxidative N-demethylation and hydroxylation, which are saturable and result in nonlinear pharmacokinetics. The primary metabolite (14-hydroxy derivative) is mainly excreted in the urine with the parent compound. A reduction in urinary clearance in the elderly and in patients with renal impairment is associated with an increase in area under the plasma concentration-time curve, peak plasma concentrations and elimination half-life. Mild hepatic impairment does not significantly modify clarithromycin pharmacokinetics. In conclusion, clarithromycin, because of its antibacterial activity and pharmacokinetic properties, appears to be a useful alternative to other macrolides in the treatment of community acquired infections.
Semi-synthetic derivatives of erythromycin have played an important role in antimicrobial chemotherapy. First generation derivatives such as 2'-esters and acid-addition salts significantly improved the chemical stability and oral bioavailability of erythromycin. A second generation of erythronolide-modified derivatives: roxithromycin, clarithromycin, azithromycin, dirithromycin and flurithromycin, have been synthesized and have exhibited significant improvements in pharmacokinetic and/or microbiological features. In addition, erythromycin itself has expanded its utility as an effective antibiotic against a variety of newly emerged pathogens. As a result of these developments, macrolide antibiotics have enjoyed a resurgence in clinical interest and use during the past half-dozen years, and semi-synthetic derivatives of erythromycin should continue to be important contributors to this macrolide renaissance. Despite these recent successes, other useful niches for macrolide antibiotics will remain unfilled. Consequently, the search for new semi-synthetic derivatives of erythromycin possessing even better antimicrobial properties should be pursued.
The in vitro activity of ciprofloxacin, ofloxacin, amifloxacin, and norfloxacin against 22 clinical isolates of Mycobacterium
tuberculosis was evaluated by agar dilution. The MICs for 90% of the isolates of ciprofloxacin and ofloxacin were 0.5 and
1 microgram/ml, respectively. Amifloxacin and norfloxacin were less active. The MICs for 90% of the isolates of ciprofloxacin
and ofloxacin against 20 clinical isolates of Mycobacterium intracellulare were determined by agar dilution to be 2 and 8
micrograms/ml, respectively.
The activities of ciprofloxacin and norfloxacin against 100 mycobacteria isolates were studied in vitro by the 1% standard
proportion method. Ciprofloxacin was more active against M. tuberculosis and M. fortuitum with MICs of 1.0 and 0.25 microgram/ml,
respectively, against 90% of isolates; norfloxacin had MICs of 8.0 and 2.0 micrograms/ml, respectively, against 90% of isolates.
Two hundred and seventy-six strains of mycobacteria were tested for susceptibility to ciprofloxacin (Bay 0 9867), a 4-quinolone antimicrobial agent. Most strains of Mycobacterium tuberculosis, Myco. fortuitum, Myco. kansasii, Myco. marinum and Myco. xenopi were sensitive to minimum inhibitory concentrations (MICs) of 0.78-1.56 mg/l, equivalent to resistance ratios of 1 or 2. Most strains of Myco. avium-intracellulare and Myco. chelonei required MICs of 12.5 mg/l or more, giving resistance ratios of 8.
The in vitro and in vivo antibacterial activity of A-56268 (TE-031), the 6-O-methyl derivative of erythromycin, was compared with those of erythromycin and other reference drugs. A-56268 had the same spectrum of antibacterial activity as erythromycin. A-56268 was generally 1 log2 dilution more potent or equal to erythromycin against all organisms except haemophilus influenzae and Propionibacterium acnes, for which A-56268 was 1 log2 dilution and 3 log2 dilutions, respectively, less potent. The MBC of A-56268 and erythromycin was not significantly different from the MIC against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus epidermidis, and H. influenzae but was more than 2 log2 dilutions higher than the MICs for some Staphylococcus aureus strains. Human serum at a concentration of 50% did not change the in vitro potency of A-56268 or erythromycin. A-56268 was similar to erythromycin in being more active at pH 8.0 than at the physiologic pH of 7.3. The activity of A-56268 was synergistic with sulfamethoxazole against 4 of 12 strains of H. influenzae. In mouse protection tests, when administered orally A-56268 was more potent than erythromycin against H. influenzae, S. pyogenes, S. pneumoniae, and S. aureus. After subcutaneous administration the potencies of A-56268 and erythromycin were not statistically different from each other. A-56268 was more potent than erythromycin against Legionella infection in guinea pigs. The concentration of A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In mice, the peak levels in serum of A-56268 and erythromycin were similar after subcutaneous administration and seven times higher for A-56268 after oral administration. The serum half-life of A-56268 was approximately twice that of erythromycin after administration by both routes.
Leprosy affects over 10 million people in the world. The disease is a model of graded cell-mediated immunity, in this case to the causative organism, Mycobacterium leprae. The clinical manifestations are due to (i) bacterial progression, (ii) immunologic responses of the host, (iii) peripheral nerve damage due to either or both bacterial progression and immunologic responses of the host, and (iv) preventable secondary deformities following nerve damage, which account for most of the stigma of the disease. Treatment modalities are now available to control or minimize the effects of bacterial progression, harmful immunologic responses of the host, peripheral nerve damage, and secondary deformities. Unique biochemical characteristics of M. leprae reside in the cell wall and associated macromolecules. Some of these molecules are potent immunogens in humans, while others constitute the structural integrity of the bacillus. Proteins of M. leprae are currently under intensive investigation as a result of deoxyribonucleic acid cloning of M. leprae genes. Structure-function and antigenic relationships of M. leprae proteins should become available by using recombinant deoxyribonucleic acid procedures coupled with T- and B-cell cloning to advance our understanding of the immunologic reactions encountered in Hansen's disease. Until recently, the study of the immunology of leprosy has been stymied by the lack of immunologically specific M. leprae antigens. The definition of specific antigens and production of recombinant and synthetic immunologic reagents have fostered state-of-the-art research efforts into new immunodiagnostic procedures and development of a leprosy vaccine. Also discussed is progress in understanding of the mechanism(s) underlying the M. leprae-specific immunodeficiency associated with lepromatous leprosy, including the role of suppressor T cells and defective macrophage function. Metabolic studies of M. leprae suggest intact catabolic pathways and energy generation with purine bases and catalase as possible growth factors. Special attention may also need to be given to biophysical parameters for eventual in vitro cultivation. Rapid in vitro systems, using quantitation of bacillary metabolic activity, may soon replace the lengthy mouse footpad test for determining the viability and drug susceptibility of the leprosy bacillus.
Various clinical isolates of mycobacteria were tested for susceptibility to ciprofloxacin by a standard macrobroth dilution
test and the radiometric BACTEC method. Agreement between the two test systems was species dependent: Mycobacterium tuberculosis (80%), M. kansasii with M. scrofulaceum (30%), M. avium-intracellulare (20%), and 0% for the rapidly growing mycobacteria. Most mycobacterial strains other than M. tuberculosis were susceptible to the breakpoint ciprofloxacin concentration of 2 mg/l as determined by BACTEC MICs, whereas none were
susceptible by macrobroth testing. Seven of nine M. tuberculosis isolates were susceptible by either method. Ciprofloxacin merits further study as a potential antimycobacterial agent.
Sir, Ciprofloxacin, a new quinoline carboxylic acid derivative, has high in vitro activity against a wide range of pathogens including members of the family Enterobacteriaeeae and Pseudomonas aeruginosa (1). The pharmacokinetics after oral administration of the drug are characterized by rapid absorption, good diffusion into the extracellular space, and elimination by biliary excretion, hepatic metabolism, glomerular filtration and tubular secretion (2). In a study in fasting volunteers the absolute bioavailability ranged from 0.63 to 0.77, and the cumulative urinary excretion of unmetabolized drug in 24-hour-urine accounted for approximately 35 % of the initial oral dose (2). To assess the effect of antacids on intestinal absorption of oraily administered ciprofloxacin, we performed a randomized study in ten healthy volunteers (5 females, 5 males, mean age 30 years, mean body weight 67.5 kg) who were given 500 mg ciprofloxacin orally either in a fasting state or 24 h after administration of the antacid 10 600 mg Mg-OH + 900 mg A1-OH (Maalox). Serum and urine concentrations were determined by a bioassay and high performance liquid chromatography. The pharmacokinetic parameters were calculated using an open two-compartment model. Administration of the antacid led to a pronounced decrease of the peak serum concentration from a mean of 1.7 mg/l (range 1.3-2.6 mg/l) after ciprofloxacin alone to a mean of 0.1 mg/1 (range 0.06-0.2 mg/1) after ciprofloxacin plus antacid (p < 0.001). The time after which the serum concentration peaked was only slightly prolonged (73 -+ 13 min versus 87 + 21 min). The cumulative urinary excretion of unmetabolized ciprofloxacin in 24-hour-urine after ciprofloxacin administered alone accounted for 24% (range 1934 %) of the administered dose as against only 2.1% (range 0.9-4.7 %) after prior administration of the antacid. A possible explanation for the reduced absorption rate of ciprofloxacin administered after the antacid is that Mg +§ or AI +++ chelates form. In fact, chelate complexes of the drug with Mg +§ have been reported to reduce bactericidal concentrations of ciprofloxacin tested in nutrient broth against Escherichia coli KL16 (3). In addition, association constants for Mg** complexes of nalidixic and oxolinic acid, analogous substances, were reported to be 3.0 and 3.3 respectively. The diminished absorption of eiprofloxacin seen in our study could be explained by a reduced rate of absorption of the Mg ++ and AI ~* ciprofloxacin chelate complexes. To date it has been difficult to assess the significance of the chelates on absorption. Nevertheless, the pronounced effect of antacids on the bioavailability of ciprofloxacin should be considered if both these drugs are administered to a patient. Furthermore, all other new quinoline derivatives should be tested for such interaction with antacid drugs.
Nora from Dr. Merle A. Sande — The issues addressed in this AIDS Commentary are complex ones. Are organisms that constitute the Mycobacterium avium complex (MAC) significant pathogens in the patients infected with HIV? If they are, how should these infections in this population
of patients be treated? Dr. Lowell S. Young has done exactly what we hoped our guest commentators would do — he has given
his authoritative opinion in an area of AIDS about which there is very little solid data. Dr. Young is a highly visible infectious
diseases clinician-scientist who has recently focused his energies on developing new therapies for MAC infections. In this
commentary he addresses a number of key questions: What are the implications of isolating MAC organisms from patients with
AIDS? What are the best techniques for isolating these organisms? Under what circumstances is treatment of value? What drugs
appear to be most effective? Which ones look good for the future?
Ciprofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. The primary mechanism of action of ciprofloxacin is inhibition of bacterial DNA gyrase. It is a broad spectrum antibacterial drug to which most Gram-negative bacteria are highly susceptible in vitro and many Gram-positive bacteria are susceptible or moderately susceptible. Unlike most broad spectrum antibacterial drugs, ciprofloxacin is effective after oral or intravenous administration. Ciprofloxacin has been most extensively studied following oral administration. It attains concentrations in most tissues and body fluids which are at least equivalent to the minimum inhibitory concentration designated as the breakpoint for bacterial susceptibility in vitro. The results of clinical trials with orally and intravenously administered ciprofloxacin have confirmed the potential for its use in a wide range of infections, which was suggested by its in vitro antibacterial and pharmacokinetic profiles. It has proven an effective treatment for many types of systemic infections as well as for both acute and chronic infections of the urinary tract. Ciprofloxacin generally appeared to be at least as effective as alternative orally administered antibacterial drugs in the indications in which they were compared, and in some indications, to parenterally administered antibacterial therapy. However, further studies are needed to fully clarify the comparative efficacy of ciprofloxacin and standard antibacterial therapies. Bacterial resistance to ciprofloxacin develops infrequently, both in vitro and clinically, except in the setting of pseudomonal respiratory tract infections in cystic fibrosis patients. The drug is also well tolerated. Thus, as an orally active, broad spectrum and potent antibacterial drug, ciprofloxacin offers a valuable alternative to broad spectrum parenterally administered antibacterial drugs for use in a wide range of clinical infections, including difficult infections due to multiresistant pathogens.
Ofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. It is an orally administered broad spectrum antibacterial drug active against most Gram-negative bacteria, many Gram-positive bacteria and some anaerobes. Ciprofloxacin is the only other quinolone with superior in vitro antibacterial activity. However, the pharmacokinetic profile of ofloxacin is superior to that of ciprofloxacin, with more rapid absorption and a peak serum concentration several times higher. Moreover, ofloxacin achieves high concentrations in most tissues and body fluids. The results of clinical trials with ofloxacin have confirmed the potential for use in a wide range of infections, which was indicated by its in vitro antibacterial and pharmacokinetic profiles. It has proven effective against a high percentage of infections caused by Gram-negative organisms, slightly less effective against Gram-positive infections, and effective against some anaerobic infections. Clinical efficacy has also been confirmed in a variety of systemic infections as well as in acute and chronic urinary tract infections, and ofloxacin has generally appeared to be at least as effective as alternative orally administered antibacterial drugs. Ofloxacin is well tolerated and, although experience with the drug in clinical practice to date is limited, bacterial resistance does not appear to develop readily. Thus, ofloxacin is an orally active drug which offers a valuable alternative to other broad spectrum antibacterial drugs.
Cefmenoxime is an aminothiazolyl cephalosporin administered intravenously or intramuscularly. Like other 'third-generation' cephalosporins it is active in vitro against most common Gram-positive and Gram-negative pathogens, is a potent inhibitor of Enterobacteriaceae (including beta-lactamase-producing strains), and is resistant to hydrolysis by beta-lactamases. Cefmenoxime has a high rate of clinical efficacy in many types of infection and is at least equal in clinical and bacteriological efficacy to several other cephalosporins in urinary tract infections, respiratory tract infections, postoperative infections and gonorrhoea. Cefmenoxime, like latamoxef, cefoperazone and cefamandole, has an N-methyltetrazole side chain at the 3-position of the cephalosporin nucleus and thus possesses the potential for producing hypoprothrombinaemic bleeding and disulfiram-like reactions. However, these reactions have been reported very rarely and the antibacterial is generally well tolerated. It is likely that cefmenoxime will most closely resemble cefotaxime and ceftizoxime in therapeutic profile and usefulness.
The in vitro and in vivo properties of a new 1-difluorophenyl-6-fluoroquinolone, temafloxacin hydrochloride (A-62254), were compared with those of difloxacin and ciprofloxacin. Temafloxacin hydrochloride was as active as ciprofloxacin and difloxacin against staphylococci and as active as ciprofloxacin and 2 twofold dilutions more active than difloxacin against streptococci. Against gram-negative enteric bacteria and Pseudomonas aeruginosa, temafloxacin hydrochloride was 2 twofold dilutions more active than difloxacin but 2 to 4 twofold dilutions less active than ciprofloxacin. The MICs of temafloxacin hydrochloride and difloxacin were increased by 2 to 5 twofold dilutions in urine at pH 6.5 compared with 4 to 5 twofold-dilution increases in the MICs of ciprofloxacin. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were increased by 1 to 3 twofold dilutions in serum. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were the same or within 1 to 2 twofold dilutions at pHs 6.5, 7.2, and 8.0. When administered orally in mouse protection tests, temafloxacin hydrochloride was as active as difloxacin and 5 to 10 times more active than ciprofloxacin against infections with Staphylococcus aureus and streptococci. Against infections with gram-negative enteric bacteria and P. aeruginosa, temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin. Temafloxacin hydrochloride was three times less active than difloxacin but was five times more active than ciprofloxacin against infections with Salmonella typhimurium. Temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin against P. aeruginosa and Proteus mirabilis pyelonephritis in mice. The peak serum concentration and serum half-life of temafloxacin hydrochloride in mice were approximately one-half and one-sixth, respectively, that of difloxacin after oral administration. The peak serum concentration of temafloxacin hydrochloride in mice after oral administration was six times higher than that of ciprofloxacin, and the serum half-life was equal to that of ciprofloxacin.
Agent DL-8280 showed strong in vitro antimycobacterial activity on most pathogenic mycobacteria, including M. intracellulare and M. fortuitum, and it was also shown to be useful for differentiating among species of some related mycobacteria; for example, M. nonchromogenicum from M. terrae and M. trivale, and M. fortuitum from M. chelonei.
Procedures for the isolation and identification of mycobacteria. U.S. Department of Health Education and Welfare publication no. (CDC) 79-8230 p
- A L Vestal
Vestal, A. L. 1975. Procedures for the isolation and identification of mycobacteria. U.S. Department of Health, Education,
and Welfare publication no. (CDC) 79-8230, p. 97-115. Centers
for Disease Control, Atlanta.