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PubMed1984

Sisomicin, netilmicin and dibekacin. A review of their antibacterial activity and therapeutic use.

Sisomicin is a naturally occurring aminoglycoside antibiotic produced by Micromonospora inyoensis, while dibekacin and netilmicin are both semisynthetic aminoglycosides. Dibekacin is 3',4'-dideoxykanamycin B and netilmicin is 1-N-ethyl sisomicin. In both cases, these modifications render the agents insusceptible to some of the enzymes found in resistant strains of bacteria which inactivate the parent compounds. Antibacterial activity: All 3 drugs show bactericidal activity against a wide range of Gram-negative bacteria (including E. coli, Enterobacter, Klebsiella and Proteus spp. and Ps. aeruginosa) and also against staphylococci; however, in common with other amino-glycosides, streptococci are usually resistant (except when beta-lactam antibiotics are used in combination) and anaerobic organisms are not sensitive. Sisomicin is closely related structurally to gentamicin Cla, but in vitro studies have shown it to have superior activity to gentamicin against Ps. aeruginosa, closely paralleling the activity of tobramycin, while still possessing the high activity of gentamicin against Serratia and other Gram-negative rods. However, sisomicin is inactivated by virtually all bacterial enzymes which inactivate gentamicin and tobramycin. Nevertheless, it retains useful activity against a number of gentamicin-resistant strains of Ps. aeruginosa which are resistant by non-enzymatic (possibly permeability barrier) mechanisms; in this respect it closely resembles tobramycin. Dibekacin closely resembles tobramycin structurally and in vitro it seems to have a very similar antibacterial spectrum, including activity against some strains of Ps. aeruginosa resistant to gentamicin. Netilmicin has a generally broader antibacterial spectrum than gentamicin, tobramycin, sisomicin or debekacin and is resistant to inactivation by phosphorylating and adenylylating enzymes; however, it is inactivated by all acetylases, apart from acetylase 3-I. Its spectrum is therefore not as wide as that of amikacin against 'gentamicin-resistant' strains. Nonetheless, it is intrinsically more active than amikacin, weight-for-weight, against sensitive strains, apart possibly from Ps. aeruginosa. In fact, its activity against species of the Enterobacteriaceae and staphylococci sensitive to gentamicin is of the same order as the latter and possibly better for Klebsiella-Enterobacter species. All 3 agents show marked antibacterial synergy with a variety of beta-lactam antibiotics against a range of bacteria. Pharmacokinetically, sisomicin, netilmicin and dibekacin all behave like gentamicin. All 3 drugs are excreted in the urine unchanged and have beta-phase elimination half-lives of around 2 to

Aging↗
PubMed1985

Ceftazidime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Ceftazidime is a new 'third generation' cephalosporin administered intravenously or intramuscularly. Similarly to other third generation cephalosporins it has a broad spectrum of in vitro activity against Gram-positive and Gram-negative aerobic bacteria, is particularly active against Enterobacteriaceae (including beta-lactamase-positive strains) and is resistant to hydrolysis by most beta-lactamases. Importantly, in vitro ceftazidime is presently the most active cephalosporin available against Pseudomonas aeruginosa, but it is less active against Staphylococcus aureus than first and second generation cephalosporins. Only larger comparative trials are likely to discern any statistically significant differences in clinical efficacy which may exist between ceftazidime and other antibiotics, but ceftazidime appears to be similar in efficacy to 'standard' comparative drugs in lower respiratory tract infections and complicated and/or chronic urinary tract infections among debilitated or hospitalised patients. Thus, in patients having Gram-negative infections at these sites and in whom the potential toxicity of the aminoglycosides is a concern, ceftazidime may be a valuable alternative in that it apparently lacks serious side effects and does not require routine drug plasma concentration monitoring. In fibrocystic patients having acute respiratory tract infections, ceftazidime is highly effective at both reducing symptoms of infection and temporarily reducing the sputum counts of Pseudomonas species. However, in these patients resistance to ceftazidime may develop, as seen with other beta-lactam antibiotics. In the treatment of fever of unknown origin or documented infections in immunocompromised adults and children, ceftazidime appears to be similar in efficacy to various 2- or 3-drug combinations. Nevertheless, the coadministration of an antibiotic having greater efficacy against Gram-positive bacteria should be considered in immunocompromised patients. Results from a small number of comparative trials suggest that ceftazidime may be as effective as the aminoglycosides in intra-abdominal, obstetric and gynaecological, and skin and soft tissue infections. However, further clinical experience, particularly a few well designed comparative studies, is needed to clarify the comparative efficacy in these conditions as well as in septicaemia/bacteraemia, meningitis, and bone and joint infections.

Aging↗
PubMed1988

Fluoroquinolone antibiotics. Microbiology, pharmacokinetics and clinical use.

The newer fluoroquinolones are a major advance in antimicrobial chemotherapy. They inhibit the supercoiling activity of the DNA gyrase enzyme, thus exerting their antibacterial action on DNA and RNA synthesis, resulting in a biphasic response and killing of susceptible organisms. The newer fluoroquinolones have an extended antimicrobial spectrum compared to their older congeners, and are highly active against most Gram-negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa. While Staphylococcus aureus and coagulase-negative staphylococci are usually susceptible to the fluoroquinolones, streptococci are generally more resistant and enterococci are resistant. All of the newer fluoroquinolones may be administered orally and most of them have been administered parenterally. They are widely distributed in the body, attaining therapeutic concentrations in most tissues. All of the fluoroquinolones have long half-lives and may be administered once or twice daily. The fluoroquinolones have proved effective in many infections, including uncomplicated or complicated urinary tract infections, respiratory tract infections, gonorrhoea, bacterial gastroenteritis, and soft tissue infections due to Gram-negative organisms. In general, success has been notable in the management of Gram-negative infections but less so with Gram-positive infections. Resistance has occurred and is proving a problem with P. aeruginosa in some cystic fibrosis patients, but as yet no plasmid-mediated resistance has developed. Cross-resistance occurs between the quinolones but only rarely with other classes of antibacterial drugs. The fluoroquinolones have an excellent safety record and their adverse effects, which include hypersensitivity reactions, dizziness, headache, gastrointestinal disturbance and minor haematological abnormalities are usually mild and transient. However, the fluoroquinolones have been found to damage juvenile weight-bearing joints in animals and are therefore only to be used with caution in children; transient arthralgia has been reported in a cystic fibrotic teenager on long term ciprofloxacin therapy. All of the fluoroquinolones except ofloxacin are associated with a variable increase in the serum concentration of theophylline, warfarin and caffeine. Thus, the fluoroquinolones are an attractive option in the management of many infections. Cost and possible resistance, however, should counsel caution in their use, and may limit them to situations where a cheaper antimicrobial of equivalent efficacy is not available.

4-Quinolones↗
PubMed1991

Ofloxacin. A reappraisal of its antimicrobial activity, pharmacology and therapeutic use.

Ofloxacin is a fluoroquinolone whose primary mechanism of action is inhibition of bacterial DNA gyrase. In vitro it has a broad spectrum of activity against aerobic Gram-negative and Gram-positive bacteria, although it is poorly active against anaerobes. Ofloxacin, unlike most other broad spectrum antibacterial drugs, can be administered orally as well as intravenously. Penetration into body tissues and fluids is highly efficient. Clinical trials with orally and intravenously administered ofloxacin have confirmed its potential for use in a wide range of infections, where it has generally proved as effective as standard treatments. Ofloxacin in well tolerated, and in comparison with other available fluoroquinolones is less likely to cause clinically relevant drug interactions. Ofloxacin thus offers a valuable oral treatment (with an option for intravenous administration if necessary) for use in a wide range of clinical infections, but with a particular advantage in more severe or chronic infections when recourse to parenteral broad spectrum agents would normally be required, thereby providing cost savings and additionally allowing outpatient treatment.

Bacterial Infections↗
PubMed1991

Lomefloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

The antibacterial efficacy of oral lomefloxacin has been investigated in a wide variety of infections, including respiratory and uncomplicated and complicated urinary tract infections, obstetric, gynaecological, joint, skin, oral, ear, nose, throat and eye infections. It has also been used as an otic solution in patients with otitis media and as an ophthalmic solution in the treatment of eye infections. In clinical trials its efficacy is equivalent to that of other quinolones and it is at least as effective as other antibacterial drugs ordinarily used in these infections. Lomefloxacin offers certain advantages compared with other quinolone antibacterial drugs in that it may be conveniently administered once daily and theophylline dosage adjustment does not appear to be necessary in patients receiving this bronchodilator concomitantly. Thus, orally administered lomefloxacin should prove a useful broad spectrum antibacterial drug for a wide variety of clinical infections.

Animals↗
PubMed1994

Quinolone antibacterials. An update of their pharmacology and therapeutic use.

Quinolones are a class of antibiotics structurally related to nalidixic acid. They exhibit bactericidal activity primarily by inhibiting bacterial DNA gyrase. The early quinolones had a limited spectrum of activity, low potency, high frequency of spontaneous bacterial resistance, low serum drug concentrations and short half-lives, which virtually restricted their use to urinary tract infection. The new fluorinated quinolones differ from their predecessors in their broad antibacterial spectrum, including both Gram-negative and Gram-positive aerobic, and facultative anaerobic bacteria as well as many Mycobacterium spp., Chlamydia spp., Legionella spp. and Mycoplasma spp., in addition to many strains of bacteria that are multiresistant to beta-lactam antibiotics and aminoglycosides. They also exhibit high potency, a low incidence of resistance, high oral bioavailability, extensive tissue penetration, low protein binding and long elimination half-lives. They are generally well tolerated apart from some gastrointestinal disturbance and rashes, including photosensitive eruptions and a propensity to cause central nervous system excitation. Clinically important interactions include those with antacids, theophylline, fenbufen and warfarin. Potential toxic effects include cartilage damage, ocular toxicity, teratogenicity and impairment of spermatogenesis. The role of fluoroquinolones continues to widen, encompassing infections of the urinary tract, respiratory tract, skin and soft tissues, bone and joints, infections in immunocompromised patients, sexually transmitted diseases, infectious diarrhoea, gynaecological infections and surgical prophylaxis. The convenience of oral therapy is an added advantage of the new fluoroquinolones.

4-Quinolones↗
PubMed1994

Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections.

The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells. Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir. Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet. Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.

AIDS-Related Opportunistic Infections↗
PubMed1995

Fleroxacin. A review of its pharmacology and therapeutic efficacy in various infections.

The fluoroquinolone antibacterial agent fleroxacin has a broad spectrum of in vitro activity which encompasses most Gram-negative species (particularly Enterobacteriaceae) and a number of Gram-positive organisms, including methicillin-sensitive staphylococci. It is available as oral and intravenous formulations. In clinical trials, fleroxacin has been evaluated in the treatment of uncomplicated urinary tract infections (single or multiple once-daily oral doses of 200 or 400mg), gonorrhoea and chancroid (single oral doses of 200 or 400mg), complicated urinary tract, nonpneumococcal lower respiratory tract and skin and soft tissue infections and typhoid fever (multiple once-daily oral or intravenous regimens, usually 400 mg/day), bacterial enteritis, and traveller's diarrhoea (single or multiple once-daily oral doses of 400mg). Bacteriological cure rates were generally around 90% or higher in complicated and uncomplicated urinary tract infections, uncomplicated gonorrhoea (approximately 100%), pyelonephritis, bacterial enteritis and typhoid fever, and exceeded 80% in lower respiratory tract, and skin and soft tissue infections and chancroid. These cure rates were similar to, or better than, those achieved with standard comparator antibacterial agents such as penicillins, cephalosporins, cotrimoxazole, or other quinolones. Fleroxacin 400mg once daily also achieved bacteriological cure in approximately 80% of patients with bone and joint infections in preliminary studies. In Japanese studies using a lower dosage of 200 or 300 mg/day, fleroxacin was reported to be bacteriologically effective in a range of infections, including urinary tract and upper and lower respiratory tract infections. Fleroxacin has a relatively long elimination half-life, which allows once-daily administration, and it appears to have less propensity for interactions with other medications in comparison to many other fluoroquinolones. Its tolerability profile is typical of this class of compound, with adverse events mostly relating to the gastrointestinal tract, CNS, and skin and appendages (including phototoxicity). Recent pooled tolerability data from worldwide clinical trials indicate that adverse events are reported by approximately 27% of patients receiving 200 mg/day orally or 400 mg/day orally or intravenously, and 17% of those receiving a single oral dose of 400mg. These exceed incidences reported for established fluoroquinolones, possibly indicating recent trends towards increased rates of reported adverse effects with these agents. However, in direct comparative studies with twice-daily fluoroquinolones, fleroxacin 400mg once daily produced a similar incidence of adverse effects to ofloxacin 800 mg/day and a slightly higher incidence than ciprofloxacin 1000 mg/day, while fleroxacin 200mg once daily produced a similar incidence to norfloxacin 800 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Macrolide antibiotics in paediatric infectious diseases.

Erythromycin and other macrolides have enjoyed a renaissance in the 1970s, 1980s and 1990s secondary to the discovery of "new' pathogens such as Chlamydia, Legionella, Campylobacter and Mycoplasma spp. Erythromycin is an important therapeutic agent in the paediatric age group for several reasons: (a) it exhibits proven efficacy for a wide range of infections (upper and lower respiratory tract infections, skin/skin structure infections, prophylaxis of endocarditis/acute rheumatic fever/ophthalmia neonatorum and pre-colonic surgery, campylobacteriosis, chlamydial and ureaplasmal infections, diphtheria, whooping cough, streptococcal pharyngitis) and gastrointestinal (GI) dysmotility states; (b) intravenous formulations are widely available; and (c) it is available in a number of formulations as a generic product, which is likely to result in significant cost savings. Nevertheless, erythromycin and similar earlier macrolides are characterised by a number of drawbacks including a narrow spectrum of antimicrobial activity, unfavourable pharmacokinetic properties and poor GI tolerability. Newer macrolides such as clarithromycin and azithromycin are useful in serving the needs of paediatric patients who are erythromycin-intolerant or who have infections caused by organisms that are intrinsically erythromycin-resistant, or for which a high percentage of strains are resistant (e.g. Haemophilus influenzae, Helicobacter pylori, Mycobacterium avium complex). In addition, these newer macrolides may be considered as alternatives to oral amoxicillin-clavulanic acid, second or third generation cephalosporins, or erythromycin plus sulphonamide in this patient population. Selection between specific macrolides and between macrolides and other antibiotics in the paediatric population is likely to depend, at least for the immediate future, on separate comparisons of product availability, cost, effectiveness and tolerability profiles.

Anti-Bacterial Agents↗
PubMed1996

Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection.

Saquinavir is a peptide derivative which inhibits the HIV protease enzyme, preventing post-translational processing of viral polyproteins. It was the first agent of its class to become available for the treatment of HIV infection. Well controlled studies have assessed the effects of saquinavir, when used alone or in combination with reverse transcriptase inhibitors, in patients with advanced HIV infection. Analysis of CD4+ cell counts and measures of viral load in the ACTG 229 study suggest that triple therapy with saquinavir, zidovudine and zalcitabine is more effective than double therapy with saquinavir plus zidovudine or zidovudine plus zalcitabine in patients who have previously received long term treatment with zidovudine. Similar assessments from a small study in previously untreated patients suggest that double therapy with saquinavir plus zidovudine is more effective than monotherapy with either agent. Combination therapy with saquinavir and zalcitabine significantly reduced the time to the first AIDS-defining event or death, and the time to death, compared with zalcitabine alone, according to data from a large, long term study (NV 14256) in patients with advanced HIV infection who had previously received zidovudine. Saquinavir is generally well tolerated, either as monotherapy or in combination with reverse transcriptase inhibitors; no change in tolerability profile was reported when saquinavir was added to treatment with nucleoside analogues. In vitro and clinical studies have documented the emergence of saquinavir-resistant HIV strains. Although the possible impact of resistance on the clinical efficacy of saquinavir has yet to be fully characterised, genotypic and phenotypic resistance appear to develop slowly during treatment with saquinavir, and the drug does not appear to have a significant effect on the incidence of mutations associated with cross-resistance to other protease inhibitors. Thus, laboratory and clinical results suggest that saquinavir in combination with reverse transcriptase inhibitors is effective in the treatment of advanced HIV infection. Initial data on the effects of saquinavir on disease progression and mortality are promising, and the apparent absence of mutations conferring cross-resistance to other protease inhibitors is a potentially valuable clinical feature. Additional data on disease progression, mortality and viral resistance, together with information on relative efficacy (in comparison with other protease inhibitors), will need to be assessed before the clinical value of saquinavir can be fully determined. Nevertheless, saquinavir represents a valuable new pharmacological option for the treatment of HIV infection and is likely to be a useful component of combined therapy with reverse transcriptase inhibitors and/or other protease inhibitors.

Anti-Bacterial Agents↗
PubMed1997

Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection.

Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzyme reverse transcriptase and terminating elongation of the proviral DNA chain. The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.

Adult↗
PubMed1998

Nelfinavir. A review of its therapeutic efficacy in HIV infection.

UNLABELLED: Nelfinavir is a selective inhibitor of HIV protease, the enzyme responsible for post-translational processing of HIV propeptides. In the presence of the drug, immature, noninfectious virus particles are produced. Nelfinavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors profoundly suppresses viral replication. Plasma HIV RNA levels (viral loan) rapidly fall below the limit of detection (LOD; usually 400 or 500 copies/ml in the majority of patients. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. In an ongoing study > 70% of adults receiving a nelfinavir based combination regimen had plasma HIV RNA levels below the LOD (< 400 copies/ml) after 84 weeks. In addition, 73% of paediatric patients receiving nelfinavir plus at least 1 new NRTI had viral loads below the LOD (< 400 copies/ml) after 34 weeks. Furthermore, CD4+ cell counts generally increased in conjunction with reductions in viral load. Combination therapy with nelfinavir and saquinavir results in higher saquinavir plasma concentrations, make twice-daily administration of saquinavir feasible and may delay the emergence of resistant viral strains. A unique mutation at codon 30 (D30N) of the protease gene confers resistance to nelfinavir, but HIV with D30N mutation remains fully susceptible to indinavir, ritonavir and saquinavir in vitro. Nonetheless, in clinical use, significant cross-resistance is seen with all currently available protease inhibitors. Diarrhoea is the most frequently reported adverse event in patients receiving nelfinavir-based combination therapy and has been reported in up to 32% of nelfinavir recipients in randomised trials. Diarrhoea is generally of mild to moderate severity and does not result in weight loss. Rash, nausea, headache and asthenia were each reported in < or = 5% of patients. Approximately 5% of patients enrolled in an expanded access programme in the US discontinued nelfinavir because of adverse events. Nelfinavir is metabolised by the cytochrome P450 system. Several clinically significant pharmacokinetic drug interactions between nelfinavir and other drugs (i.e. ketoconazole, rifabutin, rifabutin, rifampicin), including other protease inhibitors (i.e. indinavir, ritonavir, saquinavir) have been documented. As with other available protease inhibitors, hyperglycaemia, hyperlipidaemia and abnormal fat distribution have been reported, albeit infrequently, in association with nelfinavir. CONCLUSION: Nelfinavir-based combination regimens are well tolerated and produce profound and prolonged suppression of HIV replication in adult and paediatric patients. Hence, nelfinavir is suitable for inclusion in antiretroviral regimens for initial therapy for HIV infection and, alternatively, in regimens for patients unable to tolerate other protease inhibitors.

Adult↗
PubMed2001

The role of fluoroquinolones in tuberculosis today.

Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today. The fluoroquinolones are the most recent class of drugs offering hope in the fight against this disease. Ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin are currently the most commonly used agents used against Mycobacterium tuberculosis (TB), with in vitro minimum inhibitory concentrations (MICs) of 0.1 to 4 mcg/ml. Resistance in TB to fluoroquinolones may occur spontaneously or may be acquired, especially when these agents are used inappropriately. Cross-resistance among the fluoroquinolones has been shown in TB. The fluoroquinolones offer a favourable pharmacokinetic profile for the treatment of TB. Most demonstrate excellent oral bioavailability and achieve maximum (peak) serum concentrations well above the MIC. They are also distributed widely, including intracellularly. The fluoroquinolones are cleared renally and/or hepatically, with varying serum half-lives. Fluoroquinolones are most effective when the peak concentration (Cmax) to MIC ratio is maximised. Fluoroquinolones such as ciprofloxacin and ofloxacin have been used in regimens for the prevention of TB, but have been poorly tolerated when used in combination with pyrazinamide. Favourable responses with fluoroquinolones in regimens used in the treatment of clinical TB disease have been seen. They, however, are not to be considered as equal replacements for isoniazid or rifampicin (rifampin) and should be used with at least 2 other antituberculous agents. Therapeutic drug monitoring of fluoroquinolones is beneficial in assuring that maximum Cmax to MIC ratios are being achieved, especially in patients at risk for malabsorption, such as those infected with HIV. Higher, once-daily doses of most fluoroquinolones are becoming more common in treating TB. Fluoroquinolones are generally well tolerated with long term use in treating TB, but rare, serious adverse effects have been reported with general fluoroquinolone use. The most common drug interactions with fluoroquinolones in TB therapy include the malabsorption interactions associated with multivalent cations and cytochrome P450 interactions with ciprofloxacin. An increased risk of central nervous system effects with concomitant cycloserine has been reported and seen clinically. When using fluoroquinolones to treat TB, careful consideration of individual susceptibility patterns, pharmacokinetic and toxicity profiles should be taken. The aid of a TB expert may also be warranted. The exact role of the fluoroquinolones in treating TB remains to be determined.

Animals↗
PubMed2002

Gatifloxacin: a review of its use in the management of bacterial infections.

UNLABELLED: Gatifloxacin is an 8-methoxy fluoroquinolone antibacterial agent. The drug has a broader spectrum of antibacterial activity than the older fluoroquinolones (e.g. ciprofloxacin) and shows good activity against many Gram-positive and Gram-negative pathogens, atypical organisms and some anaerobes. Notably, gatifloxacin is highly active against both penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, a common causative pathogen in community-acquired pneumonia (CAP), acute sinusitis and acute bacterial exacerbations of bronchitis. Gatifloxacin is absorbed well from the gastrointestinal tract (oral bioavailability is almost 100%). Therefore, patients can be switched from intravenous to oral therapy without an adjustment in dosage. High concentrations of gatifloxacin are achieved in plasma and target tissues/fluids. Gatifloxacin has a long plasma elimination half-life, thus allowing once-daily administration. Few clinically significant interactions between gatifloxacin and other drugs have been reported. In patients with CAP, clinical response rates in recipients of intravenous/oral gatifloxacin 400 mg/day ranged from 86.8 to 98.0% and rates of bacterial eradication ranged from 83.1 to 100% (up to 28 days post-treatment). Gatifloxacin showed efficacy similar to that of amoxicillin/clavulanic acid, ceftriaxone (with or without erythromycin) with or without stepdown to clarithromycin, levofloxacin or clarithromycin. Gatifloxacin was as effective as clarithromycin or amoxicillin/clavulanic acid, and was significantly more effective (in terms of clinical response; p < 0.035) than 7 to 10 days' treatment with cefuroxime axetil in the treatment of acute exacerbations of chronic bronchitis. In acute sinusitis, gatifloxacin showed clinical efficacy similar to that of clarithromycin, trovafloxacin or amoxicillin/clavulanic acid. Genitourinary infections were also successfully treated with gatifloxacin. Gatifloxacin is generally well tolerated. Its tolerability profile was broadly similar to those of comparator agents in comparative trials. The most common adverse events are gastrointestinal symptoms (oral formulation) and injection site reactions. CONCLUSIONS: Gatifloxacin has an extended spectrum of antibacterial activity and provides better coverage of Gram-positive organisms (e.g. S. pneumoniae) than some older fluoroquinolones. The drug has favourable pharmacokinetic properties, is administered once daily and is at least as well tolerated as other fluoroquinolones. Gatifloxacin is a useful addition to the fluoroquinolones currently available for use in the clinical setting and has an important role in the management of adult patients with various bacterial infections. As with other fluoroquinolones, careful control of gatifloxacin usage in the community is important in order to prevent the emergence of bacterial resistance and thus preserve the clinical value of this agent.

Animals↗
PubMed1995

Formulary management of macrolide antibiotics.

Selection of macrolide antibiotics for formulary addition can be a difficult task, with the increasing availability of new agents as well as the numerous differences in pharmacokinetic and pharmacodynamic properties of available agents. Nonetheless, appropriate evaluation of the important characteristics of macrolide antibiotics should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in antimicrobial activity and efficacy, product formulation, tolerability and cost should be carefully considered when making formulary decisions. Notably, evidence from in vitro studies and clinical trials indicate differences between the macrolide antibiotics, especially in the management of a variety of opportunistic infections in immunocompromised patients. For selected clinical situations, it may be important to select an effective agent available in both oral and intravenous formulations, especially in severe pneumonia caused by Legionella spp. In addition, the availability of generic formulations should be considered for its potential to reduce cost. Comparative drug costs, as well as costs associated with noncompliance, should also be evaluated carefully. Dosage regimens should also be considered, as shorter durations of therapy and less frequent dose administration may lead to increased compliance and thereby improved effectiveness and economic efficiency.

Anti-Bacterial Agents↗
PubMed1984

Sensitivity of 523 blood culture isolates to 33 antibiotics.

523 blood culture isolates collected during 18 months (July 1980-December 1981) were analysed by the agar dilution method for sensitivity to 33 antibiotics. Breakpoints corresponding to the SIR system were used but for N-formimidoyl-thienamycin (N-f-thienamycin), azthreonam and fosfomycin serial dilutions were made. Aminoglycosides (netilmicin, gentamicin, amikacin and tobramycin) inhibited from 90 to 86% of the strains. This was comparable to the percentage inhibited by some cephalosporins (cefotaxime, cefoperazone, ceftazidime, ceftriaxone, cefuroxime, cephamandole and moxalactam) ranging from 95 to 89%. A very high number of strains (99%) were inhibited by N-f-thienamycin. By combination of certain antibiotics more than 99% of the strains could be inhibited.

Acinetobacter↗
PubMed1990

Fungal metabolism of 4-substituted amphetamines.

1. rac.-4-Ethoxyamphetamine was incubated with 14 different yeast and fungal microorganisms. 4-Hydroxyamphetamine was the major metabolite; traces of N-acetyl-4-ethoxyamphetamine were also detected. 2. The major fungal (Cunninghamella) metabolite of 4-propoxyamphetamine and 4-benzyloxyamphetamine was 4-hydroxyamphetamine. The major metabolites of 4-methoxyamphetamine were N-acetyl-4-methoxyamphetamine and 4-hydroxyamphetamine. 3. Acetoin derivatives were formed when alkoxyamphetamine substrates were incubated in the presence of various fungi and yeasts. 4. The findings indicate that Cunninghamella echinulata may be a useful microbial model for drug disposition and interaction studies.

Amphetamines↗