Gentamicin affects melanogenesis in normal human melanocytes

Background: Aminoglycoside antibiotics, including gentamicin, despite their ability to induce adverse effects on pigmented tissues, remain valuable and sometimes indispensable for the treatment of various infections. It is known that gentamicin binds to melanin biopolymers, but the relation between this drug affinity to melanin and its toxicity is not well documented. The aim of this work was to examine the impact of gentamicin on viability and melanogenesis in HEMa-LP (light pigmented) and HEMn-DP (dark pigmented) normal human melanocytes.

Methodology/principal findings: The effect of gentamicin on cell viability was determined by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay; melanin content and tyrosinase activity were measured spectrophotometrically. It has been demonstrated that gentamicin induces concentration-dependent loss in melanocytes viability. The application of antibiotic in concentration of 10?mM causes higher reduction in viability of the light pigmented melanocytes (by about 74%) when compared with the dark pigmented ones (by about 62%). The value of the concentration of a drug that produces loss in cell viability by 50% (EC₅₀) for both cell lines was found to be ～7.5?mM. It has been shown that gentamicin causes inhibition of tyrosinase activity and reduces melanin content in light pigmented melanocytes significantly more than in the dark pigmented cells.

Conclusion/significance: We have found that gentamicin modulates melanization process in melanocytes in vitro, what may explain the potential role of melanin biopolymer in the mechanisms of undesirable toxic effects of this drug in vivo, as a result of its accumulation in pigmented tissues. We have also stated that the melanogenesis process in light pigmented melanocytes is more sensitive to the inhibitory effect of gentamicin than in the dark pigmented cells.     

Cytotoxic effect of lomefloxacin in culture of human epidermal melanocytes

BackroundLomefloxacin is a potent bactericidal antibiotic. The use of this drug in treatment of various infections is accompanied by serious adverse effects on pigmented tissues. The exact mechanisms of lomefloxacin side effects have not been well established yet. The aim of this study was to characterize the interaction between lomefloxacin and ?, and to examine how this interaction affects the cell viability and melanization in melanocytes.MethodsNormal human epidermal melanocytes and the model DOPA-? were used. The binding parameters of lomefloxacin-? complexes as well as the antibiotic effect on cell viability and melanization in pigmented cells were investigated using a spectrophotometric method.ResultsOur results indicate that lomefloxacin forms stable complexes with ?. The analysis of drug binding to ? has shown that at least two classes of independent binding sites are involved in formation of these complexes. The WST-1 assay was used to detect the antibiotic cytotoxic effect. The value of ED₅₀ for lomefloxacin was about 0.75 mmol/l. It has been shown that lomefloxacin causes inhibition of tyrosinase activity, and reduces ? content in human skin melanocytes in a dose-dependent manner.ConclusionThe ability of the analyzed fluoroquinolone to form complexes with ?, and the demonstrated inhibitory effect on a melanization process in melanocytes in vitro may explain a potential role of ? biopolymer in the mechanisms of undesirable side effects of lomefloxacin in vivo resulting from its accumulation in pigmented tissues.     

Interaction between ciprofloxacin and melanin: the effect on proliferation and melanization in melanocytes

There have been described serious adverse events caused by ciprofloxacin in pigmented tissues. It is known that some fluoroquinolones bind well to melanin rich tissues, but the relation between their affinity to melanin and the skin or eye toxicity is not well documented. The aim of this study was to examine whether ciprofloxacin binds to melanin, and how this interaction affects the proliferation and melanization in melanocytes. We have demonstrated that complexes which ciprofloxacin forms with melanin possess at least two classes of independent binding sites. Their association constants are K(1)~10(5) M(-1) and K(2)~10(2) M(-1), respectively. Ciprofloxacin has induced evident concentration-dependent loss in melanocytes viability. The value of ED(50) was found to be ~0.5 mM. It has also been shown that ciprofloxacin reduces melanin content, and decreases tyrosinase activity in human skin melanocytes. The ability of ciprofloxacin to interact with melanin and its inhibitory effect on melanization in melanocytes in vitro may explain a potential role of melanin in the mechanisms of ciprofloxacin toxic effects in vivo.     

Intrinsic cytotoxic effects of fluoroquinolones on human corneal keratocytes and endothelial cells

ABSTRACT

Objective: To determine the intrinsic cytotoxicity of five fluoroquinolones (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin) on human corneal keratocytes (HCK) and human corneal endothelial cells (HCE).

Research design and methods: Cultures of replicating HCK and HCE were exposed to ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, or ofloxacin concentrations of 1?mg/mL, 100?μg/mL, 10?μg/mL, 1?μg/mL, 100?ng/mL, or 10?ng/mL for 15, 30, 60, or 240?min. Each of the 24 fluoroquinolone concentration–time exposures was tested against its own serum-free minimal essential medium (MEM) control. Cell number was quantified with a fluorescence bioassay.

Main outcome measure: Cytotoxicity was defined as a significant (?p < 0.05) difference in cell number measured as mean calcein fluorescence product versus control for each fluoroquinolone concentration–time exposure.

Results: Fluoroquinolone-induced cytotoxicity was concentration- and time-dependent in HCK and HCE cultures. The number of cytotoxic concentration–time exposures was highest with ciprofloxacin (23 of 24 exposures in HCK and 24 of 24 exposures in HCE) and lowest with levofloxacin (10 of 24 exposures in both HCK and HCE).

Conclusions: In vitro cell cultures are useful for evaluating cell response to potentially toxic insults, although cell cultures may lack tissue components that may prevent or ameliorate damage in vivo. In this assay, fluoroquinolones displayed the potential to be cytotoxic to human corneal keratocytes and endothelial cells, depending on drug concentration and duration of exposure. The potential for cytotoxicity may differ among fluoroquinolones.     

Different mechanisms for the photoinduced production of oxidative DNA damage by fluoroquinolones differing in photostability.

Several fluoroquinolone antibacterial agents exhibit an adverse phototoxic effect in humans and are photo-cocarcinogenic in mice. The UV-induced production of reactive oxygen species plays a role in the toxicity and may be involved in carcinogenicity. Four fluoroquinolones were examined for the ability to photochemically produce oxidative damage in naked DNA. The major structural difference in the fluoroquinolones that would have an effect on their photostability is the functionality at the 8-position. At this position, 1-cyclopropyl-7-(2,8-diazbicyclo[4.3.0]non-8-yl)-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (BAY y3118) contains a chlorine atom, lomefloxacin a fluorine atom, ciprofloxacin a proton, and moxifloxacin a methoxy group. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in calf thymus DNA was assessed by HPLC with electrochemical detection, and strand breaks were measured in pBR322 with agarose gel electrophoresis. The relative photolability of the fluoroquinolones correlated to the extent of production of 8-oxodGuo and strand breaks, with both UVA and UVB irradiation, in the following order: BAY y3118 approximately lomefloxacin > ciprofloxacin > moxifloxacin. Experiments were performed to determine whether the mechanism of damage was due to a type I (radical) or type II (singlet oxygen) pathway. Nitrogen depletion of oxygen resulted in a decrease in the extent of formation of 8-oxodGuo, suggesting that oxygen was involved. The use of selective radical or singlet oxygen inhibitors was inconclusive with respect to which pathway was involved. The use of D(2)O as a solvent, which would extend the lifetime of singlet oxygen, suggested that this species is involved in the formation of 8-oxodGuo by moxifloxacin and ciprofloxacin, but not by lomefloxacin and BAY y3118. Similarly, it was found that singlet oxygen was not involved in strand break formation. Thus, the evidence suggests that fluoroquinolones can photochemically produce DNA damage by both type I and type II mechanisms.     

Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells

Background

Low effectiveness of anti-melanoma therapies makes it necessary to search for new drugs that could improve or replace the standard chemotherapy. Fluoroquinolones are a group of synthetic antibiotics, used in the treatment of wide range of bacterial infections. Moreover, this class of antibiotics has shown promising anti-tumor activity in several cancer cell lines. The aim of this study was to examine the effect of ciprofloxacin on cell viability, apoptosis and cell cycle distribution in COLO829 melanoma cells.

The safety profile of moxifloxacin and other fluoroquinolones in special patient populations

ABSTRACT

Background: Fluoroquinolones, including ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin, represent a major advance in the development of antimicrobial agents. They offer significant activity against Gram-negative pathogens, while more advanced generation fluoroquinolones including levofloxacin, gemifloxacin, and moxifloxacin are significantly active against Gram-positive (e.g., Streptococcus pneumoniae for some members of the class), typical, atypical, and anaerobic pathogens. Fluoroquinolones have a pharmacokinetic/pharmacodynamic profile that exhibits concentration-dependent killing and good oral absorption, allowing for once-daily dosing.

Objective: Review of data from fluoroquinolone studies, with an emphasis on the associated rare, but potentially clinically important, adverse events in specific patient populations. Review of clinical efficacy is included where relevant to the topic under discussion.

Methods: A literature search was conducted using terms including fluoroquinolones, moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, safety, adverse events, drug interactions, and pharmacokinetic parameters to identify literature providing information regarding the safety profile of specified fluoroquinolones in special patient populations (i.e., the elderly, patients with liver disease, kidney disease, glycemic disorder, those at risk for cardiovascular events). Although specific date criteria were not applied to the search, preference was given to more recent publications. Online databases searched include MEDLINE and EMBASE and relevant textbooks were utilized as well.

Findings: Fluoroquinolones, when used either as monotherapy or as combination therapy depending on their individual indications, attain adequate concentrations for treating infections in different target sites, including epithelial lining fluid, alveolar macrophages, skin, and gastrointestinal tissues. Overall, fluoroquinolones have predictable and mild-to-moderate adverse-event profiles and are generally well tolerated. Findings of this review are limited by the availability of publications and case reports.

Conclusions: Fluoroquinolones, are associated with rare, but clinically important, adverse events in special patient populations (including the elderly; those with hepatic, renal, or glycemic disorders; and those at risk for cardiovascular events). Recognition of differences in the clinical efficacy and safety profiles of fluoroquinolones in special patient populations should lead to better antimicrobial agent selection.     

In vitro method for prediction of the phototoxic potentials of fluoroquinolones

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.     

Modulation of melanogenesis and antioxidant defense system in melanocytes by amikacin

Amikacin is principally used to treat infections caused by microorganisms resistant to other aminoglycosides. Ototoxicity is one of the side effects of amikacin, but the causative mechanism of damage to the ear has not been fully established. Thus, the aim of this work was to examine the impact of amikacin on the melanogenesis and antioxidant defense system in cultured human normal melanocytes (HEMa-LP). Amikacin induced the concentration – dependent loss in melanocytes viability. The value of EC₅₀ was determined to be ～7.5 mM. The analyzed antibiotic inhibited melanin biosynthesis in concentration-dependent manner. Increasing the amikacin concentration also resulted in a decrease in cellular tyrosinase activity. To study the antioxidant defense system in melanocytes, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in cells exposed to amikacin were determined. Significant changes in cellular antioxidant enzymes activities were observed. Modulation of melanogenesis and the antioxidant status of melanocytes resulting from the use of amikacin in vitro may explain a potential role of melanin and melanocytes in the mechanisms of aminoglycosides ototoxic effects in vivo.     

Economic consequences of ACS-related rehospitalizations in the US

ABSTRACT

Background: Clostridium difficile associated diarrhea (CDAD) is an important cause of hospital-acquired diarrhea, and increasingly of community-acquired diarrhea. The occurrence of CDAD in the hospitalized patient is associated with increased length of stay, morbidity, mortality, and healthcare costs. Exposure to antimicrobials is the single most important predisposing factor for acquiring CDAD. The data suggesting that fluoro­quinolones are an important risk factor for CDAD is becoming stronger. Also, different fluoroquinolones may pose different risks for CDAD development.

Objectives: The aim of this commentary is to summarize the literature as it relates to the role that fluoroquinolones may have in CDAD.

Methods: PubMed and Ovid MEDLINE were searched using the terms fluoroquinolones, ciprofloxacin, levo­floxacin, gatifloxacin, and moxifloxacin in combination with C. difficile, CDAD, pseudomembranous colitis and antibiotic associated diarrhea.

Results: The evidence for an association between fluoroquinolone use and CDAD, especially CDAD due to the hypervirulent NAP1 strain or the polymerase chain reaction ribotype 027, is becoming stronger.

Conclusions: Fluoroquinolones appear to predispose patients to CDAD. The data are suggestive but not conclusive. More studies are needed to define the role that fluoroquinolones play in the development of CDAD. Meticulous and enhanced infection control practices at all times and the judicious use of antimicrobials will help contain the epidemic of CDAD.     

Binding characteristics of fluoroquinolones to synthetic levodopa melanin

To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (r(max)) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and r(max), suggesting that the binding lacked stereoselectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin-drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 M HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine-melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin-melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine approximately ciprofloxacin, sparfloxacin >/= lomefloxacin > timolol, levofloxacin approximately enoxacin, norfloxacin, and that the relative r(max) value was: norfloxacin, enoxacin >/= chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.     

The insulinotropic effect of fluoroquinolones

Antimicrobial fluoroquinolones induce, with strongly varying frequency, life-threatening hypoglycemias, which is explained by their ability to block K_ATP channels in pancreatic B-cells and thus to initiate insulin secretion. In apparent contradiction to this, we observed that none of the fluoroquinolones in this study (gatifloxacin, moxifloxacin, ciprofloxacin, and a number of fluorophenyl-substituted compounds) initiated insulin secretion of perifused mouse islets when the glucose concentration was basal (5 mM). Only when the glucose concentration was stimulatory by itself (10 mM), the fluoroquinolones enhanced secretion. The fluoroquinolones were ineffective on SUR1 Ko islets, which do not have functional K_ATP channels. All of these fluoroquinolones depolarized the membrane potential of mouse B-cells (patch-clamping in the whole-cell mode). Using metabolically intact B-cells (perforated-patch mode) however, 100 μM of gatifloxacin, ciprofloxacin or moxifloxacin were unable to depolarize when the glucose concentration was 5 mM, whereas other K_ATP channel blockers (tolbutamide and efaroxan) remained effective. Only at a very high concentration (500 μM) gatifloxacin and moxifloxacin, but not ciprofloxacin induced repetitive depolarizations which could be antagonized by diazoxide. In the presence of 10 mM glucose all fluoroquinolones which enhanced secretion markedly elevated cytosolic calcium concentration ([Ca²⁺]_i). In the presence of 5 mM glucose gatifloxacin and moxifloxacin at 500 μM but not at 100 μM elevated [Ca²⁺]_i. It is concluded that fluoroquinolones in the clinically relevant concentration range are not initiators, but rather enhancers of glucose-induced insulin secretion. The block of K_ATP channels appears necessary but not sufficient to explain the hypoglycemic effect of fluoroquinolones.     

Comparison of an in vitro cellular phototoxicity model against controlled clinical trials of fluoroquinolone skin phototoxicity.

Many therapeutic drugs induce phototoxic skin responses following exposure to solar or artificial ultraviolet radiation sources. Several in vitro model systems have been developed to predict drug phototoxicity but none have been conducted in parallel with controlled clinical phototoxicity studies on systemically administered pharmaceuticals. The in vitro phototoxicity of eight fluoroquinolone (FQ) antibiotics (ciprofloxacin, grepafloxacin, lomefloxacin, norfloxacin, ofloxacin, trovafloxacin, BAYy3118, moxifloxacin) was determined by exposing Chinese hamster fibroblasts to UVA radiation. Cell damage was quantified with standard MTT or neutral red assays and an in vitro phototoxic index calculated (PI(vit)=% cell viability with UVA alone /% cell viability with UVA+FQ) for each endpoint. Clinical photosensitizing ability of the eight systemically administered FQ was investigated using double-blind, placebo and positive controlled, clinical skin phototesting of normal subjects. Minimal erythema doses at 365+/-30nm were determined before and after 6-7 days of FQ ingestion and PI(clin) (minimal erythema dose without FQ/minimal erythema dose with FQ) calculated. Linear regression analysis of PI(vit) vs PI(clin) gave correlations of up to 0.893. Principal components analysis of PI(vit), daily dose, plasma levels and photophysical (absorption) properties of the eight FQ showed that phototoxic (arbitrarily defined as PI(clin)> or =2) and non-phototoxic (PI(clin)<2) FQ could be completely discriminated using these parameters, and that the in vitro models were able to rank the relative phototoxic potential of the eight FQ.     

Moxifloxacin: new preparation. A me-too with more cardiac risks

(1) Moxifloxacin is the fourth fluoroquinolone to be licensed in France with indications covering ENT and respiratory tract infections. (2) In community-acquired pneumonia, acute bacterial sinusitis and acute exacerbations of chronic bronchitis, moxifloxacin seems no more effective than other fluoroquinolones available in France (with which it has not been compared) or the other antibiotics with which it has been compared. (3) Moxifloxacin has the usual adverse effects of fluoroquinolones, but carries a greater risk of QT prolongation than ciprofloxacin, levofloxacin and ofloxacin.     

Moxifloxacin

Moxilloxacin is a new fluoroquinolone antibacterial agent with a broad spectrum of activity, encompassing gram-negative and gram-positive bacteria. It has improved activity against gram-positive species (including staphylococci, streptococci, enterococci) and anaerobes compared with ciprofloxacin. This is offset by slightly lower activity against pseudomonal species and Enterobacteriaceae. In common with other fluoroquinolones, moxifloxacin attains good penetration into respiratory tissues and fluids and its bioavailability is substantially reduced by coadministration with an antacid or iron preparation. However, moxifloxacin does not interact with theophylline or warfarin. In clinical trials in patients with community-acquired pneumococcal pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) or acute sinusitis, moxifloxacin 400 mg once daily achieved bacteriological and/or clinical success rates of approximately 90% or higher. Moxifloxacin was as effective as amoxicillin 1 g 3 times daily and clarithromycin 500 mg twice daily in CAP and as effective as clarithromycin in AECB. In patients with sinusitis, a 7-day course of moxifloxacin 400mg once daily was as effective as a 10-day course of cefuroxime axetil 250mg twice daily. In contrast to some other fluoroquinolones, moxifloxacin appears to have a low propensity for causing phototoxic and CNS excitatory effects. The most common adverse events are gastrointestinal disturbances.     

Ciprofloxacin 0.3% + dexamethasone 0.1% for the treatment for otitis media

Introduction: Ciprofloxacin 0.3% with dexamethasone 0.1% (ciprofloxacin/dexamethasone) is an ototopical preparation for acute otitis externa, otorrhea with tympanostomy tubes, and is frequently used to treat chronic suppurative otitis media (CSOM). The advantage of topical therapy is the ability to deliver higher concentration of antibiotics to the treatment site when compared with oral or parenteral antibiotics. The delivery of a high concentration of antibiotics significantly decreases treatment failure and makes the development of resistant organisms unlikely. Previous ototopical preparations contained antibiotics such as aminoglycosides that are known to be ototoxic making treatment of otic infections without an intact tympanic membrane difficulty.

Areas covered: A literature search of PubMed was performed as the basis for a literature-based discussion on the clinical efficacy of ciprofloxacin/dexamethasone compared to oral antibiotics and ototopical therapy without a steroid component. The potential ototoxicity of ototopical therapies is discussed, including evidence demonstrating the lack of ototoxicity of fluoroquinolone and dexamethasone containing drops.

Expert opinion: Because multiple studies have demonstrated that fluoroquinolones are not ototoxic, fluoroquinolone ototopical drops should be a first-line treatment for otorrhea without an intact membrane. The addition of dexamethasone 0.1% to ciprofloxacin 0.3% has been shown to decrease granulation tissue, improve clinical cure and achieve greater rates of bacterial eradication when compared to ciprofloxacin 0.3% alone.     

The Role of Fluoroquinolones in Sexually Transmitted Diseases

The management of sexually transmitted diseases (STDs) has reached a new level in the era of antibiotic resistance and human immunodeficiency virus infection. To date, no single antimicrobial is capable of eradicating the commonly encountered STD pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Among the marketed fluoroquinolones, ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin all provide excellent in vitro activity (MIC₉₀ < 0.06 μg/ml) and excellent in vivo efficacy against N. gonorrhoeae, including multiply resistant isolates (penicillinase-producing N. gonorrhoeae and chromosomally mediated resistant N. gonorrhoeae). Ofloxacin is the only fluoroquinolone approved by the Food and Drug Administration for chlamydial infection. All of the quinolones lack reliable in vitro activity against Ureaplasma urealyticum, a cause of nongonococcal urethritis. Although limited data suggest the usefulness of ciprofloxacin and ofloxacin in the treatment of pelvic inflammatory disease, these drugs cannot currently be recommended for single-agent therapy. Haemophilus ducreyi infections, however, can be managed effectively with the fluoroquinolones. Although their role continues to evolve, this class of drugs cannot be used equally to treat all STDs, and notably, no quinolone to date inhibits T. pallidum.     

莫西沙星合成方法

综述莫西沙星的有关合成反应。莫西沙星是新近上市的氟喹诺酮药物之一，其抗菌谱广，特别是喹诺酮环8位上甲氧基的存在，其抗革兰氏阳性菌活性比环丙沙星、诺氟沙星等明显增强，且无明显的光毒性。     

Moxifloxacin: a review of its clinical potential in the management of community-acquired respiratory tract infections

Moxifloxacin is an extended-spectrum fluoroquinolone which has improved coverage against gram-positive cocci and atypical pathogens compared with older fluoroquinolone agents, while retaining good activity against gram-negative bacteria. The antibacterial spectrum of moxifloxacin includes all major upper and lower respiratory tract pathogens; it is one of the most active fluoroquinolones against pneumococci, including penicillin- and macrolide-resistant strains. In in vitro studies, emergence of bacterial resistance was less common with moxifloxacin than with some other fluoroquinolones, but this requires confirmation in large-scale clinical studies. As with other fluoroquinolones, moxifloxacin achieves good penetration into respiratory tissues and fluids. It shows a low potential for drug interactions and dosage adjustment is not required for patients of advanced age or those with renal or mild hepatic impairment. The efficacy of oral moxifloxacin has been demonstrated in large, well-designed clinical trials in patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Moxifloxacin 400 mg once daily achieved bacteriological and clinical success rates of approximately 90% or higher. It was as effective as, or more effective than, comparators including clarithromycin, cefuroxime axetil and high dose amoxicillin in these trials. The most commonly reported adverse events in patients receiving moxifloxacin are gastrointestinal disturbances. Moxifloxacin is also associated with QTc prolongation in some patients; there are, as yet, no data concerning the possible clinical sequelae of this effect in high-risk patients. Moxifloxacin has a low propensity for causing phototoxic reactions relative to other fluoroquinolones, and animal data suggest that it has a low potential for causing excitatory CNS and hepatotoxic effects. Conclusions: As an extended-spectrum fluoroquinolone, moxifloxacin offers the benefits of excellent activity against pneumococci, once daily administration and a low propensity for drug interactions. Although studies are needed regarding its tolerability in at-risk patients with QT interval prolongation, available data suggest that moxifloxacin is likely to become a first-line therapy option for the treatment of community-acquired lower respiratory tract infections, particularly in areas where drug-resistant S. pneumoniae or H. influenzae are common.