Bacterial Exacerbations Of Chronic Bronchitis Research Articles

Simple Determination of Gemifloxacin Levels in Human Plasma using High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Gemifloxacin, a broad-spectrum antibacterial agent of the fluoroquinolone class, is used to treat bacterial infections, including acute bacterial exacerbation of chronic bronchitis and community-acquired pneumonia. This study aimed to develop a simple and robust analysis of gemifloxacin in human plasma by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The sample was prepared using simple protein precipitation procedures with acetonitrile and separated using the Gemini C18 column with a mobile phase (0.1% formic acid: 0.1% formic acid in acetonitrile = 78: 22 (V/V)). Moxifloxacin was used as an internal standard. The mass spectrometer was operated in the positive ion mode using multiple reaction monitoring. Each precursor ion of gemifloxacin and moxifloxacin was monitored at m/z 390.1/402.1, and their product ions were monitored at m/z 372.3/384.4. The calibration curve showed linearity in 0.005–5 μg/mL with an appropriate correlation coefficient (≥0.99). The variation coefficient of intra- and interprecision values of gemifloxacin was <15%. The intra- and interaccuracy values ranged from 85% to 115%, except for the lower limit of quantification (accuracy range: 80%–120%). The proposed method was performed with a simple preparation step, and moxifloxacin, which is easily accessible, was used as the internal standard. These results suggest that the present assay is a practical analytical method and, therefore, can be readily applied for analysis, including in pharmacokinetic studies and therapeutic drug monitoring of gemifloxacin.

Comparative neurological safety of fluoroquinolones versus therapeutic alternatives.

Fluoroquinolones, one of the most commonly prescribed antibiotic classes, have been implicated in cases of central nervous system (CNS) and peripheral nervous system (PNS) adverse events, which highlights the need for epidemiologic studies of the neurological safety of fluoroquinolones. To evaluate the safety of fluoroquinolones with regard to risk of diagnosed neurological dysfunction. We conducted a propensity score-matched inception cohort study using claims data from a commercially insured population. Our study included adults prescribed an oral fluoroquinolone or comparator antibiotic between January 2000 and September 2015 for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, uncomplicated urinary tract infection, or acute bronchitis. Our outcomes were CNS dysfunction, and four separate but complementary PNS dysfunction outcomes. Cox proportional hazards models were estimated after matching on propensity scores fitted using the variables age, sex, epilepsy, hereditary peripheral neuropathy, renal dysfunction, diabetes, gabapentinoid use, statin use, isoniazid use, and chemotherapy use. Our cohort contained 976 568 individuals exposed to a fluoroquinolone antibiotic matched 1:1 with a comparator. Matching produced balance (standardized mean difference <0.1) on all variables included in the propensity score. The hazard ratio associated with fluoroquinolone exposure was 1.08 (95% confidence interval 1.05-1.11) for CNS dysfunction, and 1.09 (95% CI 1.07-1.11) for the most commonly occurring PNS dysfunction outcome. Fluoroquinolone antibiotic use was associated with the development of neurological dysfunction versus comparator antibiotic use in the adult population.

Evaluation of Fluoroquinolone Use in Hospice Patients (GP783)

• Recall risks associated with fluoroquinolone use in hospice patients• Identify a process for balancing risk vs benefit of fluoroquinolones in hospice patients. Since 2004, the Food and Drug Administration (FDA) has released eight safety communications regarding serious adverse effects associated with fluoroquinolones, including peripheral neuropathy, tendonitis/tendon rupture, worsening of myasthenia gravis, central nervous system effects (confusion, hallucinations), hypoglycemia, QTc prolongation, and aortic tear/rupture. An FDA Boxed Warning was issued to reserve use of fluoroquinolones for patients with no alternative treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. Despite the warnings and risks, fluoroquinolone antibiotics are commonly prescribed. To evaluate risk factors for serious adverse effects in hospice patients taking fluoroquinolones. Retrospective chart review of a national hospice pharmacy provider was completed. Decedents with pharmacy claims for fluoroquinolones during January 2019 were reviewed. Demographics collected included hospice diagnoses, presence of cardiac disease or hypertension medications, concomitant corticosteroids, QTc prolonging medications, sex, and fluoroquinolone claims within 14 days of death. Nearly 15% (n=10,719) of decedents had at least one antibiotic claim during the review period, average age 80.1 years. Over 24% of patients filled the fluoroquinolone within 14 days of date of death. Fluoroquinolones comprised 24.4% of claims (n=4,651), the largest percentage of all antibiotic claims. Fluoroquinolone prescriptions were predominantly ciprofloxacin (51.4%) and levofloxacin (48.6%). The top 5 hospice diagnoses in the study population were cardiac (21.4%), dementia (21.3%), pulmonary (18.3%), cancer (15.6%), and stroke (8.7%). Known QTc prolongation risk factors included female patients (60.2%), age over 65 years (86.0%), and concomitant QTc risk medication use (51.5%). Additional FDA fluoroquinolone risk factors were present: hypertension (64.1%), concomitant corticosteroid use (22.9%). Our population review illustrates high utilization of fluoroquinolones in patients with multiple risk factors for serious adverse events. Increased awareness of patient risk factors identified by FDA warnings may help promote safer antibiotic prescribing for hospice patients.

FDA collaboration to improve safe use of fluoroquinolone antibiotics: an ex post facto matched control study of targeted short-form messaging and online education served to high prescribers.

Objective:This ex post facto matched control study was conducted to evaluate the effect of targeted short-form messages or continuing medical education (CME) on fluoroquinolone prescribing among high prescribers.Methods:A total of 11,774 Medscape healthcare provider (HCP) members prescribing high volumes of fluoroquinolones were randomized into three segments to receive one of three unique targeted short-form messages, each delivered via email, web alerts, and mobile alerts. Some HCPs receiving targeted short-form messages also participated in CME on fluoroquinolone prescribing. A fourth segment of HCPs participated in CME only. Test HCPs were matched to third-party-provider prescriber data to identify control HCPs. We used prescriber data to determine new prescription volume; percentage (%) of HCPs with reduced prescribing; new prescription volume for acute bacterial sinusitis (ABS), uncomplicated urinary tract infection (uUTI), and acute bacterial exacerbations of chronic bronchitis in those with chronic obstructive pulmonary disease (ABECB-COPD). Open rates for emailed targeted short-form messages were also measured.Results:Targeted short-form messages and CME each resulted in significant new prescription volume reduction versus control. Combining targeted short-form messages with CME yielded the greatest percentage of test HCPs with reduced prescribing (80.1%) versus controls (76.2%; p<0.0001). New prescription volume decreased significantly for uUTI and ABS following exposure to targeted short-form messages, CME, or both. Targeted short-form messages containing comparative prescribing information with or without clinical context were opened at slightly higher rates (10.8% and 10.6%, respectively) than targeted short-form messages containing clinical context alone (9.1%).Conclusions:Targeted short-form messages and CME, alone and in combination, are associated with reduced oral fluoroquinolone prescribing among high prescribers.

Explore the application of mixed solvency technique in the injection formulation of poorly soluble drugs

In the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are poorly water-soluble. The objective of present research is to explore the application of mixed solvency technique in the injection formulation of poorly soluble drugs and to reduce concentration of individual solubilizers (used for solubility enhancement) to minimize the toxic effects of solubilizers. In the present work poorly soluble drugs Ofloxacin are selected as model drugs. Ofloxacin is a synthetic fluoroquinolone broad spectrum anti-microbial agent used in the treatment of bacterial infections and it is presently available in the market only as tablet dosage form. It is preferred in the treatment of adults with community acquired pneumonia and acute bacterial exacerbations of chronic bronchitis caused by susceptible organism. The present study was undertaken with an intention to develop a stable and effective parenteral formulation, containing the drug Ofloxacin. Ofloxacin is a light sensitive and water soluble drug but unstable at higher temperature in water. So the effects of various co solvents in the solubility of Ofloxacin have been evaluated. Ofloxacin was tried with co solvents such as PEG-200, Span 20 and Glycerin. The drug was made into injection formulation. Various batches of Ofloxacin injection formulation were prepared evaluates for Color, Clarity Test, Leakage Test, Viscosity Determination, pH Determination, Drug content Determination, Stability Study. The formulations were also subjected to accelerated stability test. Out of all trials, formulation containing 45% of PEG- 200 was found to be more stable and passed all tests satisfactorily.

Indications for Systemic Fluoroquinolone Therapy in Europe and Prevalence of Primary-Care Prescribing in France, Germany and the UK: Descriptive Population-Based Study.

In the USA the benefit-risk profile of fluoroquinolones for treating patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections (uUTIs) is considered unfavorable. However, the number of fluoroquinolone products in the EU indicated and prescribed for these infections is uncertain. The objective of this study was to provide data on indications for fluoroquinolones in Europe and examine the prevalence of prescribing in France, Germany and the UK. Descriptive analysis of indications for systemic fluoroquinolone antibiotics across the European Economic Area (EEA) and descriptive analysis of systemic fluoroquinolone antibiotic prescribing in France, Germany and UK electronic health records (2000-2015). All EEA countries had fluoroquinolone products indicated for acute sinusitis, acute bronchitis, or uUTIs, with differences in the number of products between countries for: acute sinusitis (19.5-51.9%), acute bronchitis (22.2-73.4%), and uUTIs (52.0-89.1%). The prevalence of fluoroquinolone prescribing for the treatment of respiratory tract infections (RTIs) appeared to fall with time in all countries and for UTI in France and UK only. Changes were greatest in the UK. In France, Germany, and the UK, respectively: acute sinusitis accounted for 29.5, 20.6, and 40.7% of all oral fluoroquinolone prescriptions for upper RTIs; acute bronchitis accounted for 63.0, 83.0, and 89.9% of all fluoroquinolone prescriptions for lower RTIs; uUTIs accounted for 83.3, 89.9, and 32.2% of all fluoroquinolone prescriptions for UTIs. Large numbers of fluoroquinolone products in Europe are listed for the treatment of milder infections such as acute bronchitis, acute sinusitis and uUTIs. Among the countries assessed, fluoroquinolones were commonly prescribed for these conditions and potentially should lead to a review of therapeutic guidelines.

FDA and the safe and appropriate antibiotic use of fluoroquinolones

The thorny topic of fluoroquinolone use in so-called trivial infections was reviewed in respect of risks and benefits on Nov 4, 2015, when a joint meeting of two US Food and Drug Administration (FDA) advisory committees (antimicrobial drugs and drug safety) was convened to discuss the relative risks and benefits in three infections: acute bacterial sinusitis, acute bacterial exacerbations of chronic bronchitis, and uncomplicated urinary tract infections. 1 US Food and Drug AdministrationJoint Meeting of the Antimicrobial Drugs Advisory Committee Meeting (AMDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm470444.pdfDate: 2015 Google Scholar

Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data.

Community-acquired respiratory tract infections (CARTI) are commonly caused by Streptococcus pneumoniae (SPN) and empirically treated with azithromycin. This study assessed clinical cure rates in azithromycin-treated subjects with CARTI caused by azithromycin-susceptible (Azi-S) or azithromycin-resistant (Azi-R) SPN. 1127 subjects with CARTI (402 acute otitis media, 309 community-acquired pneumonia, 255 acute bacterial exacerbations of chronic bronchitis and 161 acute bacterial sinusitis) in 13 Phase 3 clinical trials (1993-2007) had a confirmed pathogen, received azithromycin and were assessed for clinical cure/failure. 34.4% of subjects (388/1127) had a positive culture for SPN; 33.4% (376/1127) had Azi-S or Azi-R SPN. 28.9% (112/388) of subjects with SPN had Azi-R SPN: 35.7% (40/112) were low-level Azi-R SPN (LLAR; MIC 2-8 mg/L), while 64.3% (72/112) were high-level Azi-R SPN (HLAR; MIC ≥16 mg/L). Among Azi-S and Azi-R SPN CARTI subjects, clinical cure rates were: 86.2% (324/376) overall; 89.4% (236/264) for subjects with Azi-S SPN; 78.6% (88/112) for subjects with Azi-R SPN (P = 0.003, versus Azi-S); 77.5% (31/40) for subjects with LLAR SPN (P < 0.001); and 79.2% (57/72) for subjects with HLAR SPN (P = 0.122). Clinical cure rates in CARTI subjects treated with azithromycin were higher for Azi-S SPN (89.4%) versus Azi-R SPN (78.6%; P = 0.003). However, cure rates were not different for subjects infected with LLAR-SPN versus HLAR-SPN. At the observed prevalence of Azi-R SPN of 28.9%, an additional 3.1 clinical failures would be predicted, as a consequence of azithromycin resistance (LLAR and HLAR), per 100 subjects treated empirically with azithromycin.

Comparative Pharmacokinetics and Bioavailability of Gemifloxacin Administered as an Intravenous 200 mg Formulation or an Oral 320 mg Tablet

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent, which has potent activity against most Gram-negative and Gram-positive organisms. It is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The aim of this study was to assess the clinical potential of a new gemifloxacin 200 mg intravenous formulation by comparing its pharmacokinetic characteristics with those of the branded Factive(®) gemifloxacin tablet. A single-dose, open-label, randomized-sequence, two-period crossover study was performed with 17 healthy male volunteers. The two treatment periods were separated by a 1-week washout period. Blood samples were taken for up to 48 h post-dose. Plasma gemifloxacin concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. To calculate the pharmacokinetic parameters, noncompartmental analysis was performed. The two formulations were considered to be pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (intravenous/oral formulations) of the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and the AUC from time zero to infinity (AUC∞) were within the standard bioequivalence range (0.8-1.25). Safety and tolerability were evaluated on the basis of physical examinations, vital signs, electrocardiograms, clinical laboratory tests and adverse event monitoring. Seventeen subjects were enrolled, and 15 subjects completed the study. Sixteen subjects received intravenous 200 mg gemifloxacin and 15 received oral 320 mg gemifloxacin. The 15 subjects in the pharmacokinetic analysis set had a mean (standard deviation [SD]) age, height and weight of 27.2 (5.3) years, 173.5 (4.4) cm and 67.3 (7.4) kg, respectively. Both formulations had similar pharmacokinetic profiles. For the intravenous formulation, the mean (SD) AUClast, AUC∞ and maximum plasma concentration (C max) values were 9.12 (4.03) μg·h/mL, 9.26 (4.07) μg·h/mL and 2.90 (1.65) μg/mL, respectively, while these values for the oral formulation were 9.44 (3.34) μg·h/mL, 9.60 (3.49) μg·h/mL and 2.03 (0.95) μg/mL, respectively. For the intravenous and oral formulations, the median (range) time to reach C max (t max) values were 0.9 (0.7-1.0) and 1.0 (0.5-2.0) h, respectively. The mean relative bioavailability was 68.99 %. The 90 % CI of the ratios of the log-transformed values of AUClast and AUC∞ was 0.82-1.07. There were no serious adverse events. The intravenous and oral formulations were associated with treatment-emergent adverse event incidences of 63 % (10/16) and 13 % (2/15), respectively. After the intravenous formulation was administered, application site pain and paraesthesia were the most frequently reported adverse events (31 and 25 %, respectively). All adverse events resolved spontaneously without treatment. Intravenous 200 mg and oral 320 mg formulations of gemifloxacin are equivalent in terms of AUC following a single dose in healthy male subjects.

UV Spectrophotometric Method for Estimation of Ofloxacin in Tablet Dosage Form and Comparative Study of its Two Brands

Ofloxacin is used to treat a bacterial infection. It is indicated for the treatment of adults with mild to moderate infections triggered by susceptible strains of the nominated microorganisms in the infections likes acute bacterial exacerbations of chronic bronchitis, community acquired pneumonia, uncomplicated skin and skin structure infections, acute, uncomplicated urethral and cervical gonorrhea, nongonococcal urethiritis and cervicitis, mixed infections of the urethra and cervix, acute pelvic inflammatory disease (including severe infection), uncomplicated cystitis, complicated urinary tract infections and prostatitis. The most common side-effects are feeling sick, diarrhea, feeling dizzy and headache. Spectrophotometry is regarded as by its speed and simplicity, accuracy and inexpensive instrument needed, and hence it is a significant substitute to further analytical methods, through clear advantages in terms of cost of analysis. Assay of Ofloxacin tablets is carried out by a rapid, simple, accurate, and economical least time consuming spectrophotometric method and then compares it with the assay of two different brands available in Karachi, Pakistan. Results of assay reveal that both trademarks of Ofloxacin are bioequivalent and are within the endorsed range. Brand A shows a percent assay of 100% while Brand B shows low value for percentage assay that is 96.31%.

Electrochemical Study of the Interaction Between the Antibacterial Drug Gemifloxacin and dsDNA Using Pencil Graphite Electrode

Gemifloxacin (GMF) is a broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. The investigation of the GMF - double-stranded DNA (dsDNA) interaction using an electrochemical DNA-biosensor, showed for the first time clear evidence of interaction with dsDNA. The interaction between GMF and dsDNA onto pencil graphite electrode (PGE) was assessed at pH 4.80 acetate buffer using differential pulse voltammetry (DPV). The interaction mechanism was disclosed with the decrease of the guanine oxidation peak current. The changes in the experimental parameters such as the accumulation time and the concentration of GMF were studied. Linearity of the guanine oxidation signals was obtained in response to the range of 0.5 – 8.0 μg/mL GMF. Detection and quantification limits in the range of μg/mL were determined. Keywords: Biosensor, dsDNA, Voltammetry, Guanine, Gemifloxacin.

Non-inferiority clinical trials: Practical issues and current regulatory perspective.

Non-inferiority clinical trials are being performed with an increasing frequency now-a-days, because it helps in finding a new treatment that have approximately the same efficacy, but may offer other benefits such as better safety profile. Non-inferiority clinical trials aim to demonstrate that the test product is no worse than the comparator by more than a pre-specified small amount. There are several fundamental differences between non-inferiority and superiority trials. Some practical issues concerning the non-inferiority trials are assay sensitivity, choice of the non-inferiority margin, sample size estimation, choice of active-control, and analysis of non-inferiority clinical trials. For serious infections such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, community-acquired bacterial pneumonia, and acute bacterial skin and skin structure infections, the United States Food and Drug Administration (US FDA) has recently recommended that it is possible to define a reliable and consistent estimate of the efficacy of active treatment relative to placebo from available data, which can serve as the basis for defining a new inferiority margin for an active-controlled, non-inferiority trial. But for some indications with a high rate of resolution without antibacterial drug therapy such as acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and acute bacterial otitis media (ABOM), the US FDA has recommended that the available data will not support the use of a non-inferiority design and other trial designs (i.e., superiority designs) should be used to provide the evidence of effectiveness in these three indications.

Role of the Oral Beta-Lactams in the Treatment of Exacerbations of Chronic Bronchitis: Critical Analysis and Therapeutic Recommendations

The GIARIR study group has made a critical analysis of the most recent scientific literature on acute bacterial exacerbations of chronic bronchitis (ABECB) with the aim of proposing therapeutic recommendations applicable to the current epidemiological situation in Italy. The international literature has indicated the scarcity of studies on the treatment of ABECB compared to an abundance of information regarding chronic obstructive pulmonary disease (COPD), of which ABECB is often considered the initial ore predisposing stage, even though a precise evolutionary correlation between these pathologies has not yet been demonstrated.ABECB is the principle cause of doctor visits, hospitalization and death in COPD patients. The natural course of the disease is characterized by the appearance of exacerbation episodes (a mean of two yearly). For this reason it is indispensable to prevent exacerbations, to treat them as quickly as possible, in order to minimize their negative effects on the respiratory tract and the patient's general health.The routine use of antibiotic therapy is controversial because at least 20% of exacerbations do not have an infectious origin and about 30% are viral. In most cases the choice of antibiotic is empiric, in both ABECB patients without risk factors (mild form) and in those with risk factors such as cigarette smoking or constant exposure to air pollutants (moderate form). For these reasons it is necessary to keep up to date on the local and regional bacteria etiological situation and to be aware of antibiotic resistance patterns for the most commonly involved pathogens.An analysis of the most recent information in italy has confirmed the involvement of the terrible three bacterial species—Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae—as the cause of 85-95% of ABECB cases, as well as an increase in resistance to various classes of molecules by all the respiratory pathogens. On the basis of the known resistance patterns in italy, some antibiotics are no longer considered first choice for empiric therapy such as the unprotected betalactams, tetracycline, trimethoprim/sulfamethoxazole and the macrolides) which should be used only after antibiotic susceptibility testing indicates they are still active against the pathogens. The epidemiological picture of bacterial resistance in italy has greatly restricted the choice of antibiotics which can be used for this type of infection, justifying interest in the oral beta-lactams which have the highest therapeutic index and are first choice therapy against bacterial exacerbations of chronic bronchitis. Included in this group are amoxicillin-clavulanate and the new cephem molecule, cefditoren, which has been available in italy since 2008. Thanks to its good pharmacokinetics and pharmacodynamics as well as clinical performance, cefditoren may be considered a drug of choice against exacerbations of chronic bronchitis.

10 years’ experience with the pneumococcal quinolone moxifloxacin

Moxifloxacin (MXF) is the latest broad-spectrum fluoroquinolone marketed worldwide. It has in vitro activity against a wide range of Gram-positive and Gram-negative pathogens including anaerobes and intracellular organisms, as well as strains resistant to β-lactam or macrolide antibiotics. For relevant respiratory pathogens, MXF attains the threshold values of pharmacodynamic indices predictive of clinical efficacy and minimization of resistance development. On the other hand, due to its limited activity against Pseudomonas aeruginosa, it is less suitable for ‘late-onset’ nosocomial infections. In clinical trials, it has been found to be at least as effective and safe as comparators, while often showing higher bacteriological success rates. In some randomized studies MXF has shown superiority over comparator regimens in the treatment of patients with community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis. A consistent observation in many clinical trials of respiratory tract infections is the early onset of effect and a faster resolution of symptoms compared with standard therapy, possibly resulting from its fast distribution into tissue and high bactericidal activity leading to more rapid bacterial eradication. Although originally developed for respiratory tract infections, MXF over the years as been shown to be effective, and consequently received approval for additional indications.

Gemifloxacin use in the treatment of acute bacterial exacerbation of chronic bronchitis.

The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB). Gemifloxacin, as one of the quinolones in this class, exhibits many of the pharmacokinetic and pharmacodynamic characteristics of the class with a few notable differences. Against Streptococccus pneumoniae it has a lower minimal inhibitory concentration (MIC) than the other respiratory fluoroquinolones and it has activity against both bacterial DNA gyrase and topoisomerase IV. The increased activity of gemifloxacin against both enzymes may be associated with decreased rates of resistance. Clinically, gemifloxacin has been shown to have positive effects on length of hospitalization and increased success at long-term follow-up in AECB patients. These associations were observed in noninferiority comparison studies. Although an advantage with the use of gemifloxacin in AECB is suggested, there are no comparison data is available to conclude that gemifloxacin is superior to the other respiratory fluoroquinolones. Gemifloxacin is generally well tolerated, but is associated with a characteristic rash and gastrointestinal upset as its most common observed side effects.

Treatment of acute bacterial exacerbations of chronic bronchitis

Background: Controversies persist regarding the optimal management of patients with acute exacerbations of chronic bronchitis (AECB). Objective: To evaluate the available evidence on relevant issues, namely the need for administering antimicrobials in patients with AECB, the identification of the subgroup of patients with AECB needing antibiotics, the antimicrobial regimen of choice and its optimal duration, the existence of new agents, and the value of non-antimicrobial regimens for AECB. Methods: Data from various sources of evidence, including recent relevant meta-analyses, were appraised. Conclusion: Administration of antimicrobial agents, combined with bronchodilators and systemic corticosteroids, is warranted in approximately half of AECBs (i.e., in bacterial exacerbations) to achieve a survival benefit. Simple clinical parameters, mainly sputum purulence, and biomarkers, such as procalcitonin, are useful in identifying patients requiring antibiotics. Advanced antibiotics (quinolones, macrolides, or amoxicillin/clavulanic acid) are more effective than ‘old’ antibiotics in AECB; regimens of short duration (for 5 days) are preferred. There is no difference between several classes of advanced antibiotics regarding their short-term effectiveness; however, quinolones are associated with better long-term outcomes than macrolides. Newer quinolones and new formulations of macrolides enrich clinicians' armamentarium against AECB.

Assessment of the bioequivalence of two formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions: A single-dose, randomized, open-label, two-period, two-way crossover study in healthy Jordanian male volunteers

Background: Clarithromycin extended-release tablets are indicated for the treatment of adults with acute maxillary sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae; acute bacterial exacerbation of chronic bronchitis due to H influenzae, Haemophilus parainfluenzae, M catarrhalis, or S pneumoniae; or community acquired pneumonia due to H influenzae, H parainfluenzae, M catarrhalis, S pneumoniae, Chlamydia pneumoniae, or Mycoplasma pneumoniae.Objective: This study was conducted to assess the bioequivalence of test and reference formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions.Methods: This was a single-dose, randomized, openlabel, 2-period, 2-way crossover study with a 1-week washout period between doses. Separate bioequivalence studies (fasting and fed) were performed in 2 groups of healthy male Jordanian volunteers. Eighteen blood samples were obtained from each volunteer over 38 hours after drug administration. Clarithromycin concentrations were determined in plasma using a validated high-performance liquid chromatography method with electrochemical detection. Pharmacokinetic parameters of clarithromycin (Cmax, Tmax, AUC0-t, AUC0-∞, λz [firstorder elimination rate constant], and t½) were calculated and analyzed statistically. Tolerability was assessed based on changes in vital signs and laboratory tests, and by questioning subjects about adverse events.Results: Thirty-eight volunteers each participated in the fasting and fed studies. The mean ages of participants in the fasting and fed studies were 26.7 and 27.6 years, respectively; their mean weight was 71.2 and 70.9 kg and mean height was 171.3 and 179.0 cm. Under fasting conditions, the arithmetic mean (SD) Cmax was 569.4 (189.3) ng/mL for the test formulation and 641.2 (202.0) ng/mL for the reference formulation, with a geometric mean ratio of 0.88. The arithmetic mean AUC0-t was 8602.9 (4105.1) and 8245.3 (4122.4) ng · h/mL in the respective formulations, with a geometric mean ratio of 1.06. The arithmetic mean Tmax was 8.0 (5.6) and 6.1 (3.8) hours. In the fed study, the Cmax and AUC of both formulations were significantly increased relative to the fasting study (P < 0.05). The arithmetic mean Cmax of the 2 formulations was 1183.0 (637.5) and 1199.6 (496.3) ng/mL, with a geometric mean ratio of 0.93. The arithmetic mean AUC0-t was 12,981.2 (7849.0) and 11,822.9 (5790.2) ng · h/mL, with a geometric mean ratio of 1.06. The arithmetic mean Tmax was 5.7 (2.8) and 6.7 (2.5) hours. The 90% CI for the ratio (test:reference) of log-transformed Cmax and AUC values was within the acceptance range of 0.80 to 1.25. The 2 formulations were both well tolerated, and no adverse events were reported during the study.Conclusions: In these fasting and fed studies in healthy male Jordanian volunteers, the 2 formulations of clarithromycin extended-release 500-mg tablets were found to be bioequivalent according to the US Food and Drug Administration regulatory definition. Administration with food significantly increased the rate and extent of absorption of both products, with no significant effect on their bioequivalence.

Moxifloxacin: update and perspectives after 8 years of usage

Moxifloxacin has a broad spectrum of activity, including Gram-positive and Gram-negative organisms, atypical respiratory pathogens, anaerobes and penicillin- and macrolide-resistant Streptococcus pneumoniae. It achieves good tissue penetration and high concentrations in clinically relevant tissues and fluids. It is available in both an oral and intravenous formulation, has a once-daily administration and a good tolerance and safety profile. Moxifloxacin is used mainly for the treatment of acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, acute bacterial sinusitis, complicated skin and skin-structure infections and complicated intra-abdominal infections, as well as pulmonary TB, although it is not approved in this indication. The most recent studies covering these clinical indications are discussed.

Fluoroquinolone-Resistant Group B Streptococci in Acute Exacerbation of Chronic Bronchitis

To the Editor: Fluoroquinolones (FQs) that are active against streptococcal species (e.g., levofloxacin and moxifloxacin) have been recommended by numerous national health authorities and international organizations for treating acute exacerbations of chronic bronchitis and pneumonia in adults (1). However, use of these antimicrobial drugs for treating community-acquired infections has led to an increase in FQ-resistant strains in bacteria such as Streptococcus pneumoniae. Group B streptococci (GBS, e.g., S. agalactiae) are the leading cause of invasive infections (pneumonia, septicemia, and meningitis) in neonates. GBS are also associated with bacteremia, endocarditis, and arthritis, and are responsible for deaths and illness in nonpregnant women with underlying diseases and in elderly adults (2). We describe, to our knowledge, the first GBS clinical isolate in France resistant to FQ; the isolate was from a patient treated with levofloxacin. GBS CNR0717 strain was isolated as the predominant bacterium in a culture (>107 CFU/mL) from 2 purulent sputum samples from an 80-year-old man (leukocytes >25, epithelial cells 64 mg/L, and showed increased MICs for ciprofloxacin, sparfloxacin, levofloxacin, and moxifloxacin. No reduction of FQ MICs was observed with reserpine (10 mg/L), which indicated that resistance to FQ was not caused by an active efflux pump system. Table MICs of fluoroquinolones for strains of group B streptococci (GBS), France Three major mutations have been reported for FQ resistance in streptococci at codon positions 81 in gyrA and 79 or 83 in parC (4). DNA sequence analysis of these regions showed a mutation in parC (Ser 79 → Tyr) but not in the wild-type susceptible strain (NEM316). No mutation was detected in the gyrA gene. FQ resistance in streptococci is acquired through a stepwise process and has been extensively studied in S. pneumoniae. First-step mutants conferring low-level resistance generally result from mutations in either gyrA or parC. There is also a molecule-dependent target specificity: mutations in parC are generally selected by pefloxacin, ciprofloxacin, and levofloxacin, and those in gyrA are selected by sparfloxacin, gatifloxacin, moxifloxacin, gemifloxacin, and garenoxacin (5). In second-step mutants, mutations are present in both parC and gyrA and confer resistance to the antistreptococcal FQs levofloxacin, moxifloxacin, and gatifloxacin. FQ resistance in GBS has been reported in Japan, the United States, and Spain (6–8). Up to now, all FQ-resistant GBS strains described were highly resistant because of point mutations in gyrA and parC QRDR; a parC mutation at position 79 was present in all strains. These strains were isolated from elderly adults who, in some cases, had received quinolone therapy. Low-level resistance to FQ in GBS CNR0717 was associated with a Ser 79 → Tyr mutation in parC. Therefore, although the FQ sensitivity of this strain is unknown, a first-step mutant could have been selected in vivo as our patient was treated with levofloxacin for 2 weeks. GBS is an unusual cause of acute bacterial exacerbation of chronic bronchitis compared with other respiratory pathogens such as S. pneumoniae, but pathologies associated with this bacterium are changing. Clinical microbiologists should be aware of these changes and test isolates of Streptococcus spp. for susceptibility to FQs. This report indicates that FQ resistance among streptococci is a growing concern and that levofloxacin can select in vivo parC first-step mutants that will facilitate emergence of high-level FQ-resistant GBS strains, as demonstrated in vitro for S. pneumoniae (9). Finally, although FQ treatment is recommended for high-risk groups with acute exacerbations of chronic bronchitis, these antimicrobial drugs must be reserved for situations in which there are no effective alternative drugs to treat infections caused by multidrug-resistant bacteria. For susceptible strains, β-lactams, which still constitute the first-line recommended antimicrobial drugs, should be used for treatment of these patients (10).

Activity of moxifloxacin on biofilms produced in vitro by bacterial pathogens involved in acute exacerbations of chronic bronchitis

The aim of this study was to assess whether moxifloxacin is able to inhibit the synthesis of and to disrupt biofilms produced in vitro by bacterial pathogens involved in acute bacterial exacerbations of chronic bronchitis. Three strains each of Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus and Escherichia coli recently isolated from clinical respiratory specimens and capable of slime production were used. Biofilm formation on polystyrene plates was quantified spectrophotometrically by established methodologies. Moxifloxacin (0.5 mg/L) inhibited slime synthesis by >70% in S. aureus, H. influenzae and S. pneumoniae, 45–70% in E. coli and 35–70% in M. catarrhalis. Disruption of pre-formed structures was also promoted by moxifloxacin both for initial (5 h) and mature (48 h) biofilms. Drug concentrations reached during therapy (0.5–4 mg/L) resulted in a breakdown of initial biofilm of 60–80% in H. influenzae and S. pneumoniae, 48–86% in S. aureus, 37–69% in M. catarrhalis and 51–71% in E. coli. Mature biofilms were less susceptible to degradation. Moxifloxacin at concentrations that can be achieved in the bronchial mucosa during therapy therefore promotes a significant inhibition of biofilm synthesis and induces slime disruption, a feature that may be instrumental in reducing the exacerbations so frequently observed in this condition.