rifampin and Cystic-Fibrosis

Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers. Meticillin-resistant Staphylococcus aureus (MRSA) has emerged not only as an important infection in people who are hospitalised, but also as a potentially harmful pathogen in cystic fibrosis. Chronic pulmonary infection with MRSA is thought to confer on people with cystic fibrosis a worse clinical outcome and result in an increased rate of lung function decline. Clear guidance for MRSA eradication in cystic fibrosis, supported by robust evidence, is urgently needed. This is an update of a previous review.. To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. To ascertain whether attempts at eradicating MRSA can lead to increased acquisition of other resistant organisms (including Pseudomonas aeruginosa), increased adverse effects from drugs, or both.. We identified randomised and quasi-randomised controlled trials by searching the Cochrane Cystic Fibrosis and Genetic Disorders (CFGD) Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE and three clinical trials registries; by handsearching article reference lists; and through contact with experts in the field. We last searched the CFGD Group's Cystic Fibrosis Trials Register on 4 October 2021, and the ongoing trials registries on 31 January 2022.. Randomised controlled trials (RCTs) or quasi-RCTs of any combinations of topical, inhaled, oral or intravenous antimicrobials primarily aimed at eradicating MRSA compared with placebo, standard treatment or no treatment.. We used standard methodological procedures expected by Cochrane and used the GRADE methodology to assess the certainty of the evidence.. The review includes three RCTs with 135 participants with MRSA infection. Two trials compared active treatment versus observation only and one trial compared active treatment with placebo.  Active treatment versus observation In both trials (106 participants), active treatment consisted of oral trimethoprim and sulfamethoxazole combined with rifampicin. One trial administered this combination for two weeks alongside nasal, skin and oral decontamination and a three-week environmental decontamination, while the second trial administered this drug combination for 21 days with five days intranasal mupirocin. Both trials reported successful eradication of MRSA in people with cystic fibrosis, but they used different definitions of eradication. One trial (45 participants) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures compared to control (odds ratio (OR) 12.6 (95% confidence interval (CI) 2.84 to 55.84; low-certainty evidence). However, by day 168 of follow-up, there was no difference between groups in the proportion of participants who remained MRSA-negative (OR 1.17, 95% CI 0.31 to 4.42; low-certainty evidence). The second trial defined successful eradication as the absence of MRSA following treatment in at least three cultures over a period of six months. We are uncertain if the intervention led to results favouring the treatment group as the certainty of the evidence was very low (OR 2.74, 95% CI 0.64 to 11.75). There were no differences between groups in the remaining outcomes for this comparison: quality of life, frequency of exacerbations or adverse effects (all low-certainty evidence) or the change from baseline in lung function or weight (both very low-certainty evidence). The time until next positive MRSA isolate was not reported. The included trials found no differences between groups in terms of nasal colonisation with MRSA. While not a specific outcome of this review, investigators from one study reported that the rate of hospitalisation from screening through day 168 was lower with oral trimethoprim and sulfamethoxazole combined with rifampicin compared to control (rate ratio 0.22, 95% CI 0.05 to 0.72; P = 0.01). Nebulised vancomycin with oral antibiotics versus nebulised placebo with oral antibiotics The third trial (29 participants) defined eradication as a negative respiratory sample fo

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Humans; Methicillin-Resistant Staphylococcus aureus; Pseudomonas aeruginosa; Rifampin

Acute pulmonary exacerbations (APE) are a complication of cystic fibrosis (CF) and are associated with morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) is one of many organisms that has been detected in the airways of patients with CF. This review provides an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-MRSA antibiotics (ie, ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim (SMZ/TMP), and tetracycline derivatives (doxycycline, minocycline, tigecycline) in the treatment of APE and identifies areas where further study is warranted. A recent utilization study of antimicrobials for anti-MRSA has shown some CF Foundation accredited care centers and affiliate programs are using doses higher than the FDA-approved doses. Further studies are needed to determine the PK/PD properties in CF patients with clindamycin, minocycline, rifampin, SMZ/TMP, telavancin, and tigecycline; as well as, efficacy and tolerability studies with ciprofloxacin, clindamycin, doxycycline, levofloxacin, minocycline, rifampin, SMZ/TMP, in CF patients with MRSA.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Ciprofloxacin; Clindamycin; Cystic Fibrosis; Humans; Linezolid; Lipoglycopeptides; Methicillin; Methicillin-Resistant Staphylococcus aureus; Rifampin; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as, not only an important infection in people who are hospitalised, but also as a potentially harmful pathogen in cystic fibrosis. Chronic pulmonary infection with MRSA is thought to confer people with cystic fibrosis with a worse clinical outcome and result in an increased rate of lung function decline. Clear guidance for MRSA eradication in cystic fibrosis, supported by robust evidence, is urgently needed. This is an update of a previous review.. To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. To ascertain whether attempts at eradicating MRSA can lead to increased acquisition of other resistant organisms (including P aeruginosa) or increased adverse effects from drugs, or both.. Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE, clinical trial registries (Clinicaltrials.gov, WHO ICTRP, ISRCTN Registry), handsearching article reference lists and through contact with experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 27 July 2017.Ongoing trials registries were last searched: 07 August 2017.. Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment.. The authors independently assessed all search results for eligibility. They used the GRADE methodology to assess the quality of the evidence.. The review includes two trials with a total of 106 participants with MRSA infection. In both trials the active treatment was oral trimethoprim and sulfamethoxazole combined with rifampicin; however, one trial administered this combination for two weeks alongside nasal, skin and oral decontamination and a three-week environmental decontamination, while the second trial administered this drug combination for 21 days with five days intranasal mupirocin. In both trials the control arm was observation only.Both trials reported successful eradication of MRSA in people with CF as an outcome; however, the definition used for MRSA eradication differed. The first trial (n = 45) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that, when compared to control, oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures, odds ratio (OR) 12.6 (95% confidence interval (CI) 2.84 to 55.84; low-certainty evidence); however, by day 168 of follow-up there was no difference in the proportion of participants who remained MRSA-negative in either treatment arm, OR 1.17 (95% CI 0.31 to 4.42) (low-quality evidence). In the second trial, successful eradication was defined as the absence of MRSA following treatment (oral co-trimoxazole and rifampicin with intranasal mupirocin or observation) in at least three cultures over a period of six months. At the time of reporting, 40 out of 61 participants had completed follow-up, but results showed no difference between groups. Eradication was achieved in 12 out 29 participants (41%) receiving active treatment, and in 9 out of 32 participants (28%) on the observation arm, OR 1.80 (95% CI 0.62 to 5.25) (very low-quality evidence).With regards to this review's secondary outcomes, these were reported in the first trial only. The trial reports that no differences were observed between the two arms in terms of pulmonary exacerbations (from screening to day 28), nasal colonisation, lung function, weight or participant-reported outcomes. While not a specific outcome of this review, investigators reported that the rate of hospitalisation from screening through day 168 was lower with oral trimethoprim and sulfamethoxazole combined with rifampicin compared to control, rate ratio 0.22 (95% CI 0.05 to 0.72) (P = 0.0102).. Early eradication of MRSA is possible in people with cystic fibrosis, with one trial demonstrating superiority of active MRSA treatment compared with observation only in terms of the proportion of MRSA-negative respiratory cultures at day 28. However, by six months, the proportion of participants who remained MRSA-negative did not differ between treatment arms in either trial. Moreover, the longer-term clinical consequences in terms of lung function, mortality and cost of care, remain unclear.Using GRADE methodology, we judged the quality of the evidence provided by this review to be very low to low, due to potential biases from the open-label design and unclear detail reported in one trial. Based on the available evidence, it is the opinion of the authors that whilst early eradication of respiratory MRSA in people with cystic fibrosis is possible, there is not currently enough evidence regarding the clinical outcomes of eradication to support the use of the interventions studied.

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Randomized Controlled Trials as Topic; Rifampin; Staphylococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Bacterial Agents; Comorbidity; Cystic Fibrosis; Drug Therapy, Combination; Ethambutol; Female; Humans; Macrolides; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Prognosis; Respiratory Function Tests; Rifampin; Risk Assessment; Severity of Illness Index; Treatment Outcome

Patients with cystic fibrosis are particularly at risk of infection with non-tuberculous mycobacteria (NTM). Prevalence of these infections increases with age to around 15 %. The main species involved are M. abscessus and M. avium, the latter not found in children under 15. Diagnosis relies on clinical, radiological and above all bacteriological criteria defined by the ATS. Identification of the causal species of NTM is essential and requires genetic techniques, some of which are currently evaluated. Treatment depends on the mycobacterial species. For M. avium, combined therapy with rifampicin, clarithromycin and ethambutol must be extended 12 months after negativation. M. abscessus infection is particularly resistant to therapy. Usual treatment is a one month course of intravenous imipenem or cefoxitin plus amikacin followed by oral clarithromycin plus ethambutol for at least 12 months after negativation. In case of local lesions, surgery is an option.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Child; Clarithromycin; Cystic Fibrosis; Drug Therapy, Combination; Ethambutol; Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Rifampin

Few studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication.. In a randomized multicenter trial conducted on patients with new-onset MRSA infection we evaluated the efficacy of an early eradication treatment (arm A) compared with an observational group (B). Arm A received oral rifampicin and trimethoprim/sulfamethoxazole (21 days). Patients' microbiological status, FEV1, BMI, pulmonary exacerbations and use of antibiotics were assessed.. Sixty-one patients were randomized. Twenty-nine (47.5%) patients were assigned to active arm A and 32 (52.5%) patients to observational arm B. Twenty-nine (47.5%) patients, 10 patients in arm A and 19 in arm B, dropped out of the study. At 6 months MRSA was eradicated in 12 (63.2%) out of 19 patients in arm A while spontaneous clearance was observed in 5 (38.5%) out of 13 patients in arm B. A per-protocol analysis showed a 24.7% difference in the proportion of MRSA clearance between the two groups (z = 1.37, P(Z>z) = 0.08). Twenty-seven patients, 15 (78.9%) out of 19 in arm A and 12 (92.3%) out of 13 in arm B, were able to perform spirometry. The mean (±SD) FEV1 change from baseline was 7.13% (±14.92) in arm A and -1.16% (±5.25) in arm B (p = 0.08). In the same period the BMI change (mean ±SD) from baseline was 0.54 (±1.33) kg/m2 in arm A and -0.38 (±1.56) kg/m2 in arm B (p = 0.08). At 6 months no statistically significant differences regarding the number of pulmonary exacerbations, days spent in hospital and use of antibiotics were observed between the two arms.. Although the statistical power of the study is limited, we found a 24.7% higher clearance of MRSA in the active arm than in the observational arm at 6 months. Patients in the active arm A also had favorable FEV1 and BMI tendencies.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Rifampin; Staphylococcal Infections; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.. A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.. Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28.. The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Topics: Adult; Aldehyde Oxidoreductases; Aminophenols; Aminopyridines; Benzodioxoles; Biological Availability; Biphenyl Compounds; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P-450 CYP3A Inducers; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Monitoring; Female; Humans; Male; Membrane Transport Modulators; Mutation; Pharmacogenetics; Quinolones; Rifampin; Treatment Outcome

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) respiratory infection in cystic fibrosis (CF) has increased dramatically over the last decade, and is now affecting approximately 25% of patients. Epidemiologic evidence suggests that persistent infection with MRSA results in an increased rate of decline in FEV1 and shortened survival. Currently, there are no conclusive studies demonstrating an effective and safe treatment protocol for persistent MRSA respiratory infection in CF.. The primary objective of this study is to evaluate the safety and efficacy of a 28-day course of vancomycin for inhalation in combination with oral antibiotics in eliminating MRSA from the respiratory tract of individuals with CF and persistent MRSA infection. This is a two-center, randomized, double-blind, comparator-controlled, parallel-group study with 1:1 assignment to either vancomycin for inhalation (250 mg twice a day) or taste-matched placebo for 28 days in individuals with cystic fibrosis. In addition, both groups will receive oral rifampin, a second oral antibiotic - trimethoprim/sulfamethoxazole (TMP/SMX) or doxycycline, protocol determined - mupirocin intranasal cream, and chlorhexidine body washes. Forty patients with persistent respiratory tract MRSA infection will be enrolled: 20 will be randomized to vancomycin for inhalation and 20 to a taste-matched placebo. The primary outcome will be the presence of MRSA in sputum respiratory tract cultures 1 month after the conclusion of treatment. Secondary outcomes include the efficacy of the intervention on: FEV1% predicted, patient reported outcomes, pulmonary exacerbations, and MRSA colony-forming units found in respiratory tract sample culture.. Results of this study will provide guidance to clinicians regarding the safety and effectiveness of a targeted eradication strategy for persistent MRSA infection in CF.. This trial is registered at ClinicalTrials.gov (NCT01594827, received 05/07/2012) and is funded by the Cystic Fibrosis Foundation (Grants: PMEP10K1 and PMEP11K1).

Topics: Adolescent; Anti-Bacterial Agents; Antibiotics, Antitubercular; Child; Cystic Fibrosis; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Nebulizers and Vaporizers; Remission Induction; Research Design; Rifampin; Staphylococcal Infections; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as a bacterial pathogen in patients with cystic fibrosis (CF) although its clinical effects can be variable. The aim of this study was to evaluate the efficacy of a three-step decolonization protocol for MRSA (Belfast CF MRSA decolonization protocol). Of the 17 paediatric patients treated during the five years of the study, eight (47%) were successfully decolonized following one five-day course of oral rifampicin and fusidic acid. The success rate increased to 12 (71%) patients after a second five-day oral treatment course in the 11 patients who remained culture positive at the end of the first treatment cycle. In a further four patients, clearance was achieved with a course of intravenous teicoplanin, increasing the decolonization rate to 16 of 17 patients (94%). These results compare favourably with other published studies and show that MRSA decolonization can be successful in a high proportion of paediatric CF patients.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Drug Therapy, Combination; Female; Fusidic Acid; Humans; Infant; Male; Methicillin Resistance; Pneumonia; Rifampin; Severity of Illness Index; Sputum; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin

Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.

Topics: Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Proline; Structure-Activity Relationship

Prevalence of MRSA in patients with CF has risen over the past decades, and chronic infection with MRSA is associated with worse outcome in this patient group.. This retrospective observational study investigated long-term eradication rate in pediatric and adult CF patients with chronic MRSA infection, using a 6-month eradication regimen containing 2 oral antibiotics, combined with topical decolonisation measures. Respiratory tract cultures were performed at least every three months, from the first MRSA-positive culture onwards.. A total of 24 patients with chronic MRSA infection were identified from our CF patient registry, of which 13 patients underwent an eradication attempt. The regimen consisted of 2 oral antibiotics: a combination of rifampicin, fusidic acid, clindamycin and co-trimoxazol, based on the sensitivity pattern of the MRSA strain. At the end of the study period (median 8.2 years), 12 out of 13 patients (92%) were MRSA negative. None of the patients interrupted treatment due to side-effects.. Eradication of chronic MRSA infection is feasible, well-tolerated and highly successful, and can offer a long-lasting MRSA-negative status, obviating the need for patient segregation.

Topics: Adult; Anti-Bacterial Agents; Child; Clindamycin; Cystic Fibrosis; Fusidic Acid; Humans; Methicillin-Resistant Staphylococcus aureus; Rifampin; Staphylococcal Infections

Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations.. Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites.. Azithromycin maximum concentration (C. PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin C. ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Azithromycin; Cross-Over Studies; Cystic Fibrosis; Ethambutol; Humans; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Prospective Studies; Rifampin

Methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients have greatly increased in prevalence in the past two decades and may lead to a more rapid rate of lung function decline. The objective of this study was to determine the impact of a MRSA eradication protocol on long-term culture results and clinical outcomes of pediatric CF patients in a real-world setting.. This was a single-center, retrospective study of children age 30 days to 17 years. Eradication followed the STAR-too study protocol. The primary outcome was the percent of patients with MRSA-negative cultures at 12 months. Secondary outcomes were the percent of patients with negative cultures at 3, 6, and greater than 12 months and changes in clinical outcomes compared to individual baseline.. Of the 55 patients who met inclusion criteria, 10 received protocol eradication. Baseline characteristics were similar between eradication and control groups except more eradication patients were on ivacaftor (30% vs 4%; P = .037). Two eradication patients did not receive rifampin due to ivacaftor use. Eradication did not significantly increase the percent of MRSA-negative cultures at 3 months (P = .122), 6 months (P = .058), or 12 months (P = .108); however, did increase culture negativity at greater than 12 months (P = .008). Eradication resulted in no significant differences in clinical outcomes compared to control.. An extensive eradication protocol may lead to an increased clearance rate of long-term CF respiratory cultures but does not appear to affect clinical outcomes. Eradication may be reasonable to attempt; however, more data is needed before routine recommendation in all patients.

Topics: Adolescent; Aminophenols; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Quinolones; Retrospective Studies; Rifampin; Staphylococcal Infections

Bacteria colonising the lungs of cystic fibrosis (CF) patients encounter high selective pressures. Hypermutation facilitates adaptation to fluctuating environments, and hypermutator strains are frequently isolated from CF patients. We investigated the prevalence of hypermutator isolates of Achromobacter spp. among patients affiliated with the CF Centre in Aarhus, Denmark. By exposure to rifampicin, the mutation frequency was determined for 90 isolates of Achromobacter spp. cultured from 42 CF patients; 20 infections were categorised as chronic, 22 as intermittent. The genetic mechanisms of hypermutation were examined by comparing DNA repair gene sequences from hypermutator and normomutator isolates. Achromobacter spp. cultured from 11 patients were categorised as hypermutators, and this phenotype was exclusively associated with chronic infections. Isolates of the Danish epidemic strain (DES) of Achromobacter ruhlandii cultured from patients from both Danish CF centres showed elevated mutation frequencies. The hypermutator state of Achromobacter spp. was most commonly associated with nonsynonymous mutations in the DNA mismatch repair gene mutS; a single clone had developed a substitution in the S-adenosyl-L-methionine-dependent methyltransferase putatively involved in DNA repair mechanisms, but not previously linked to the hypermutator phenotype. Hypermutation is prevalent among clinical isolates of Achromobacter spp. and could be a key determinant for the extraordinary adaptation and persistence of DES.

Topics: Achromobacter; Anti-Bacterial Agents; Chronic Disease; Cystic Fibrosis; Denmark; DNA Mismatch Repair; Humans; Mutation; Mutation Rate; MutS DNA Mismatch-Binding Protein; Phenotype; Prevalence; Rifampin

Hypermutable

Topics: Adult; Anti-Bacterial Agents; Australia; Bacterial Proteins; Cystic Fibrosis; Drug Resistance, Microbial; Humans; Mutation; Phylogeny; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin

In individuals with cystic fibrosis (CF), colonization with methicillin-resistant Staphylococcus aureus (MRSA) was reported to be associated with a deterioration of pulmonary disease as reflected by an accelerated decline in lung function. Thus, an early eradication of MRSA could be beneficial in these patients. Here, we report on an intensified MRSA eradication protocol.. Since 2012 a protocol for the eradication of newly acquired MRSA has been used in our CF Clinic, combining oral rifampicin and fusidic acid, inhaled vancomycin, nasal mupirocin, local antiseptic treatment and hygienic directives all of which are applied for only 7 days during an inpatient hospital stay.. Since 2012 seven patients (3 male, 4 female; age range 4 to 30 years) newly acquired MRSA. In 6 of the 7 patients (86%) successful eradication of MRSA was achieved upon first treatment using the protocol described above. In one patient a second course of treatment was performed which, however, also failed to eliminate the colonizing MRSA.. Our protocol led to an eradication rate of 86%. The impact of each individual component of the protocol remains to be determined.

Topics: Administration, Inhalation; Administration, Intranasal; Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents, Local; Baths; Child; Child, Preschool; Cystic Fibrosis; Drug Therapy, Combination; Female; Fusidic Acid; Hand Disinfection; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mupirocin; Retrospective Studies; Rifampin; Staphylococcal Infections; Treatment Outcome; Vancomycin; Young Adult

The CFTR potentiator ivacaftor is responsible for significant clinical improvements among a subset of patients with cystic fibrosis. Because it is a substrate of the cytochrome P450 system, specifically CYP3A4/5, ivacaftor is subject to significant drug-drug interactions, including due to commonly used antimicrobials such as rifampin. While the interaction of rifampin and ivacaftor has been examined in vitro, severe adverse events resulting from this interaction have not been reported in the literature. In this report, we describe the termination of steady, long-term improvement in a patient taking ivacaftor, resulting from the use of rifampin and precipitating a significant pulmonary exacerbation.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Chloride Channel Agonists; Cystic Fibrosis; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Medication Adherence; Methicillin-Resistant Staphylococcus aureus; Quinolones; Rifampin; Staphylococcal Infections; Treatment Outcome

Rifampicin potentiates the activity of aminoglycosides (AGs) versus Pseudomonas aeruginosa by targeting the AmgRS two-component system. In this study we examine the impact of rifampicin on the AG susceptibility of cystic fibrosis (CF) lung isolates of P. aeruginosa and the contribution of AmgRS to AG resistance in these isolates.. amgR deletion derivatives of clinical isolates were constructed using standard gene replacement technology. Susceptibility to AGs ± rifampicin (at ½ MIC) was assessed using a serial 2-fold dilution assay.. Rifampicin showed a variable ability to potentiate AG activity versus the CF isolates, enhancing AG susceptibility between 2- and 128-fold. Most strains showed potentiation for at least two AGs, with only a few strains showing no AG potentiation by rifampicin. Notably, loss of amgR increased AG susceptibility although rifampicin potentiation of AG activity was still observed in the ΔamgR derivatives.. AmgRS contributes to AG resistance in CF isolates of P. aeruginosa and rifampicin shows a variable ability to potentiate AG activity against these, highlighting the complexity of AG resistance in such isolates.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cystic Fibrosis; Drug Synergism; Gene Knockout Techniques; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin

Drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a rare and severe side-effect, mainly described after intake of anticonvulsants, allopurinol, or antibiotics. It usually begins within 2 months after drug introduction. Symptoms include cutaneous rash, hematologic abnormalities, and internal organ involvement and the diagnosis might be challenging. This case report illustrates for the first time this life-threatening complication in a patient with cystic fibrosis (CF). In this case, withdrawal of the offending drug was sufficient for full recovery. Clinicians involved in CF care should be aware of DRESS syndrome, as they commonly prescribe several potentially culprit drugs. Pediatr Pulmonol. 2017;52:E18-E21. © 2016 Wiley Periodicals, Inc.

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Diagnosis, Differential; Drug Hypersensitivity Syndrome; Eosinophilia; Humans; Male; Rifampin; Young Adult

People with cystic fibrosis (CF) may work in healthcare settings risking nosocomial pathogen acquisition. The aim of this study was to determine the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in adult healthcare workers with CF (HCWcf).. Data was collected in this observational study on MRSA acquisition from 405 CF patients attending an adult CF centre in Australia between 2001-2012. Demographic and clinical characteristics were compared between HCWcf and non-HCWcf. A sub-analysis was subsequently performed to compare demographic and clinical characteristics between those patients (HCWcf versus non-HCWcf) that acquired MRSA. We also investigated rates of chronic MRSA infection and the outcome of eradication treatment in HCWcf.. A higher proportion of HCWcf acquired MRSA [n = 10/21] compared to non-HCWcf [n = 40/255] (P <0.001). The odds of MRSA acquisition were 8.4 (95 % CI, 3.0 - 23.4) times greater in HCWcf than non-HCWcf. HCWcf with MRSA were older (P = 0.02) and had better lung function (P = 0.009), yet hospitalisation rates were similar compared to non-HCWcf with MRSA. Chronic MRSA infection developed in 36/50 CF patients (HCWcf, n = 6; non-HCWcf, n = 30), with eradication therapy achieved in 5/6 (83 %) HCWcf.. The rate of MRSA incidence was highest in HCWcf and the workplace is a possible source of acquisition. Vocational guidance should include the potential for MRSA acquisition for CF patients considering healthcare professions.

Topics: Adult; Anti-Bacterial Agents; Australia; Cross Infection; Cross-Sectional Studies; Cystic Fibrosis; Female; Fusidic Acid; Health Personnel; Humans; Incidence; Linezolid; Logistic Models; Male; Methicillin-Resistant Staphylococcus aureus; Multivariate Analysis; Retrospective Studies; Rifampin; Staphylococcal Infections; Treatment Outcome; Young Adult

Donor-derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid-resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required.

Topics: Adult; Allografts; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antitubercular Agents; Bacteremia; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Fluoroquinolones; Humans; Immunosuppression Therapy; Isoniazid; Latent Tuberculosis; Lung Transplantation; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Pseudomonas aeruginosa; Rifampin; Tissue Donors; Tuberculosis, Pulmonary

Effective microbiogical eradication of methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) can be obtained, but its effect is not always clear-cut in terms of spirometric indices. The aim of this observational prospective cohort study was to study the potential effect of eradication of chronic MRSA infection on lung function including ventilation distribution. Six CF patients, chronically colonized with MRSA (median age: 21 years (range 14-46); median FEV1: 76 (95%CI 58-98)%pred) were successfully eradicated using oral rifampicin and fusidic acid in combination with topical decolonization measures. Lung function and multiple breath washout test were performed at the start and at the end of the eradication protocol and after an average follow-up period of 7·5±1·5(SD) months. One patient cultured MRSA again 4 months after successful eradication. All patients reported reduced sputum production and viscosity. By the end of the follow-up period, there was an increase in ventilated FRCMBW and no change in plethysmographic FRCPL. This resulted in a significant decrease of trapped air by half a litre (from 579 to 40 ml; P = 0·013). Lung clearance index (LCI) also showed a small but significant decrease (from 7·2 to 6·7; P = 0·014) after eradication of MRSA. We conclude that MRSA eradication can be successful, also in terms of recruitment of previously unventilated air spaces, potentially due to reduced sputum production and/or viscosity.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Cystic Fibrosis; Fusidic Acid; Humans; Lung; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Prospective Studies; Respiratory Function Tests; Rifampin; Staphylococcal Infections; Young Adult

The purpose of this study was to characterize the utilization of antibiotics for chronic methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients with acute pulmonary exacerbations (PEx).. An anonymous national cross-sectional survey of CF Foundation accredited care programs was performed using an electronic survey tool.. Fifty-eight percent (152/261) CF Foundation accredited programs completed the survey. Ninety-eight percent (149/152) of respondents reported using antibiotics (oral or intravenous) against MRSA. Variability exists in the use of antibiotics amongst the programs and in the dosages utilized. For oral outpatient treatment, sulfamethoxazole/trimethoprim was the most commonly utilized antibiotic by both pediatric (109/287, 38%) and adult (99/295, 34%) respondents, of which, ten percent of reported to use it in combination with rifampin. For inpatient treatment, linezolid (both intravenous (IV) and oral) was most commonly utilized in both pediatric (IV 35/224, 16%; oral 41/224, 18%), and adult (IV 44/235, 19%; oral 38/235, 16%) respondents for inpatient treatment. IV vancomycin was the second most commonly utilized antibiotic by pediatric (70/224, 31%) and adult (71/235, 30%) respondents. Most respondents reported dose titration to achieve a vancomycin trough level of 15-20 mg/L (150/179, 84%). Topical or inhaled antibiotic utilization was reported to be an uncommon practice with approximately 70% of pediatric and adult respondents reporting to use them either rarely or never. The concomitant use of anti-MRSA and anti-pseudomonal antibiotics was common with 96% of pediatric and 99% of adult respondents answering in the affirmative.. We conclude that anti-MRSA antibiotics are utilized via various dosage regimens by a majority of CF Foundation accredited care programs for the treatment of chronic MRSA in PEx, and there is no consensus on the best treatment approach.

Topics: Adult; Anti-Bacterial Agents; Child; Cross-Sectional Studies; Cystic Fibrosis; Drug Administration Schedule; Drug Therapy, Combination; Health Care Surveys; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Practice Patterns, Physicians'; Rifampin; Staphylococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

The prevalence of MRSA in patients with CF is increasing. There is no consensus as to the optimum treatment.. An observational cohort study of all patients with MRSA positive sputum, 2007-2012. All eradication attempts with subsequent culture results were reviewed. Single vs dual antibiotic regimens were compared for both new and chronic infections.. 37 patients (median FEV1 58.7 (27.6-111.5)% predicted) were identified, of which 67.6% (n = 25) had newly acquired MRSA. Compared with single regimens, a high proportion of dual regimens achieved MRSA eradication (84.6% vs 50%; p = 0.1) for new infections. Rifampicin/Fusidic acid was associated with high success rates (100% vs 60% for other dual regimens (p = 0.13)). Compared with new infections, chronic MRSA was much less likely to be eradicated (18.2%, p = 0.01).. Combined antibiotic therapy, particularly Rifampicin/Fusidic acid, is a well-tolerated and effective means of eradicating MRSA in patients with cystic fibrosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Body Mass Index; Cystic Fibrosis; Disease Eradication; Drug Therapy, Combination; Female; Fusidic Acid; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Outpatient Clinics, Hospital; Pneumonia, Staphylococcal; Prevalence; Respiratory Tract Infections; Retrospective Studies; Rifampin; Treatment Outcome; United Kingdom

The Burkholderia cepacia complex (Bcc) represents an important group of pathogens involved in long-term lung infection in cystic fibrosis (CF) patients. A positive selection of hypermutators, linked to antimicrobial resistance development, has been previously reported for Pseudomonas aeruginosa in this chronic infection setting. Hypermutability, however, has not yet been systematically evaluated in Bcc species. A total of 125 well characterized Bcc isolates recovered from 48 CF patients, 10 non-CF patients and 15 environmental samples were analyzed. In order to determine the prevalence of mutators their spontaneous mutation rates to rifampicin resistance were determined. In addition, the genetic basis of the mutator phenotypes was investigated by sequencing the mutS and mutL genes, the main components of the mismatch repair system (MRS). The overall prevalence of hypermutators in the collection analyzed was 13.6%, with highest occurrence (40.7%) among the chronically infected CF patients, belonging mainly to B. cenocepacia, B. multivorans, B. cepacia, and B. contaminans -the most frequently recovered Bcc species from CF patients worldwide. Thirteen (76.5%) of the hypermutators were defective in mutS and/or mutL. Finally, searching for a possible association between antimicrobial resistance and hypermutability, the resistance-profiles to 17 antimicrobial agents was evaluated. High antimicrobial resistance rates were documented for all the Bcc species recovered from CF patients, but, except for ciprofloxacin, a significant association with hypermutation was not detected. In conclusion, in the present study we demonstrate for the first time that, MRS-deficient Bcc species mutators are highly prevalent and positively selected in CF chronic lung infections. Hypermutation therefore, might be playing a key role in increasing bacterial adaptability to the CF-airway environment, facilitating the persistence of chronic lung infections.

Topics: Anti-Bacterial Agents; Burkholderia cepacia complex; Burkholderia Infections; Chronic Disease; Cohort Studies; Cystic Fibrosis; DNA Mismatch Repair; DNA Repair Enzymes; DNA, Bacterial; Drug Resistance, Bacterial; Environmental Microbiology; Humans; Molecular Sequence Data; Mutation Rate; Respiratory Tract Infections; Rifampin; Sequence Analysis, DNA

Chronic airway infection with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) is an increasing clinical problem, and therapeutic options are limited. Because chronic infection with MRSA can be associated with accelerated decline in lung function, eradication of MRSA is attempted in most CF centres today. The aim of this observational prospective cohort study was to determine whether it is possible to eradicate MRSA from airways of CF patients using prolonged oral antibiotic combination therapy together with topical decolonization measures.. Eleven CF patients, (median age: 9 years (range 1-43); median FEV1: 91%pred (95%CI 74%-100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and fusidic acid orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonization measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days. Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation. In only one patient MRSA reappeared in the six-month follow-up period after the initial study period. Side-effects, like nausea, vomiting and diarrhoea were seen in five out of eleven patients, but did not lead to therapy cessation.. Chronic MRSA infection can be eradicated from respiratory tract samples using a six month dual antibiotic regimen and topical MRSA decolonization measures.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Disease Eradication; Female; Forced Expiratory Volume; Humans; Infant; Male; Methicillin-Resistant Staphylococcus aureus; Mupirocin; Nasal Mucosa; Nucleic Acid Synthesis Inhibitors; Ointments; Prospective Studies; Rifampin; Staphylococcal Infections; Young Adult

Trimethoprim/sulfamethoxazole (SXT), alone and in combination with rifampicin (RIF), is a therapeutic option against Staphylococcus aureus, including strains expressing meticillin resistance. However, the antimicrobial activity of SXT is antagonised by thymidine, which can be present in infected and/or inflamed tissues such as the airways of cystic fibrosis (CF) patients. In this study, thymidine concentrations in CF sputa were determined and the antimicrobial activities of SXT, 5-iodo-2'-deoxyuridine (IdUrd) and RIF alone and in combination against S. aureus were analysed. Thymidine concentrations in the sputa of ten different CF patients varied from <100 μg/L to 38845 μg/L. The abolished antimicrobial activity of SXT against 22 S. aureus strains in the presence of thymidine was restored by combination with IdUrd. In contrast, SXT combined with RIF in the presence of thymidine did not show a synergistic effect and, furthermore, allowed the emergence of RIF-resistant bacteria. Adding RIF to the combination of SXT and IdUrd did not improve antimicrobial activity against S. aureus. In conclusion, the combination of SXT and RIF as a therapeutic option against S. aureus infections in chronic inflamed tissues should be judged critically.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Cystic Fibrosis; Drug Interactions; Humans; Idoxuridine; Microbial Sensitivity Tests; Rifampin; Sputum; Staphylococcus aureus; Trimethoprim, Sulfamethoxazole Drug Combination

Small-colony variant (SCV) strains of Staphylococcus aureus show reduced antibiotic susceptibility and intracellular persistence, potentially explaining therapeutic failures. The activities of oxacillin, fusidic acid, clindamycin, gentamicin, rifampin, vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline, moxifloxacin, telavancin, and oritavancin have been examined in THP-1 macrophages infected by a stable thymidine-dependent SCV strain in comparison with normal-phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient. The SCV strain grew slowly extracellularly and intracellularly (1- and 0.2-log CFU increase in 24 h, respectively). In confocal and electron microscopy, SCV and the normal-phenotype bacteria remain confined in acid vacuoles. All antibiotics tested, except tigecycline, caused a net reduction in bacterial counts that was both time and concentration dependent. At an extracellular concentration corresponding to the maximum concentration in human serum (total drug), oritavancin caused a 2-log CFU reduction at 24 h; rifampin, moxifloxacin, and quinupristin-dalfopristin caused a similar reduction at 72 h; and all other antibiotics had only a static effect at 24 h and a 1-log CFU reduction at 72 h. In concentration dependence experiments, response to oritavancin was bimodal (two successive plateaus of -0.4 and -3.1 log CFU); tigecycline, moxifloxacin, and rifampin showed maximal effects of -1.1 to -1.7 log CFU; and the other antibiotics produced results of -0.6 log CFU or less. Addition of thymidine restored intracellular growth of the SCV strain but did not modify the activity of antibiotics (except quinupristin-dalfopristin). All drugs (except tigecycline and oritavancin) showed higher intracellular activity against normal or revertant phenotypes than against SCV strains. The data may help rationalizing the design of further studies with intracellular SCV strains.

Topics: Anti-Bacterial Agents; Cell Line; Cystic Fibrosis; Dose-Response Relationship, Drug; Fusidic Acid; Gentamicins; Humans; Macrophages; Microbial Sensitivity Tests; Oxacillin; Phenotype; Protein Binding; Staphylococcus aureus; Thymidine

Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatment-resistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthase-encoding thyA gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different S. aureus phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate > or = 10(-7)) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of mutS and mutL, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs, mutL was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Phenotype; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Thymidine

Susceptibility (18 antimicrobial agents including high-dose tobramycin) and checkerboard synergy (23 combinations) studies were performed for 2,621 strains of Burkholderia cepacia complex isolated from 1,257 cystic fibrosis patients. Minocycline, meropenem, and ceftazidime were the most active, inhibiting 38%, 26%, and 23% of strains, respectively. Synergy was rarely noted (range, 1% to 15% of strains per antibiotic combination).

Topics: Anti-Bacterial Agents; Burkholderia cepacia complex; Burkholderia Infections; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests

Methicillin-resistant Staphylocosis aureus (MRSA) is an emerging infection in patients with cystic fibrosis (CF). MRSA may be a management dilemma for healthcare workers (HCWs) with CF. Eradication of MRSA with long-term rifampicin and fusidic acid can be achieved in patients with CF. We describe a case of recurrent MRSA infection in a HCW with CF. Molecular typing of the MRSA isolates supported re-infection rather than re-emergence of an earlier MRSA infection. Infection control advice for HCWs with CF who acquire MRSA remains controversial.

Topics: Adult; Anti-Bacterial Agents; Cystic Fibrosis; Drug Therapy, Combination; Female; Follow-Up Studies; Fusidic Acid; Health Personnel; Humans; Methicillin Resistance; Rifampin; Sputum; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Drug Therapy, Combination; Gentamicins; Gram-Negative Bacterial Infections; Humans; Lactoferrin; Microbial Sensitivity Tests; Recombinant Proteins; Rifampin; Stenotrophomonas maltophilia

Nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) to patients with cystic fibrosis (CF) frequently results in chronic respiratory tract carriage. This is an increasing problem, adds to the burden of glycopeptide antibiotic use in hospitals, and represents a relative contraindication to lung transplantation. The aim of this study was to determine whether it is possible to eradicate MRSA with prolonged oral combination antibiotics, and whether this treatment is associated with improved clinical status. Adult CF patients (six male, one female) with chronic MRSA infection were treated for six months with rifampicin and sodium fusidate. Outcome data were examined for six months before treatment, on treatment and after treatment. The patients had a mean age of 29.3 (standard deviation=6.3) years and FEV(1) of 36.1% (standard deviation=12.7) predicted. The mean duration of MRSA isolation was 31 months. MRSA isolates identified in these patients was of the same lineage as the known endemic strain at the hospital when assessed by pulsed-field gel electrophoresis. Five of the seven had no evidence of MRSA during and for at least six months after rifampicin and sodium fusidate. The proportion of sputum samples positive for MRSA was lower during the six months of treatment (0.13) and after treatment (0.19) compared with before treatment (0.85) (P<0.0001). There was a reduction in the number of days of intravenous antibiotics per six months with 20.3+/-17.6 on treatment compared with 50.7 before treatment and 33.0 after treatment (P=0.02). There was no change in lung function. Gastrointestinal side effects occurred in three, but led to therapy cessation in only one patient. Despite the use of antibiotics with anti-staphylococcal activity for treatment of respiratory exacerbation, MRSA infection persists. MRSA can be eradicated from the sputum of patients with CF and chronic MRSA carriage by using rifampicin and sodium fusidate for six months. This finding was associated with a significant reduction in the duration of intravenous antibiotic treatment during therapy.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Carrier State; Chronic Disease; Cross Infection; Cystic Fibrosis; Female; Fusidic Acid; Humans; Male; Methicillin Resistance; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Hypermutable bacterial pathogens exist at surprisingly high prevalence and benefit bacterial populations by promoting adaptation to selective environments, including resistance to antibiotics. Five hundred Haemophilus influenzae isolates were screened for an increased frequency of mutation to resistance to rifampicin, nalidixic acid and spectinomycin: of the 14 hypermutable isolates identified, 12 were isolated from cystic fibrosis (CF) sputum. Analysis by enterobacterial repetitive intergenic consensus (ERIC)-PCR and ribotyping identified eight distinct genetic fingerprints. The hypermutable phenotype of seven of the eight unique isolates was associated with polymorphisms in conserved sites of mutS. Four of the mutant mutS alleles were cloned and failed to complement the mutator phenotype of a mutS : : TSTE mutant of H. influenzae strain Rd KW20. Antibiotic susceptibility testing of the hypermutators identified one beta-lactamase-negative ampicillin-resistant (BLNAR) isolate with two isolates producing beta-lactamase. Six isolates from the same patient with CF, with the same genetic fingerprint, were clonal by multilocus sequence typing (MLST). In this clone, there was an evolution to higher MIC values for the antibiotics administered to the patient during the period in which the strains were isolated. Hypermutable H. influenzae with mutations in mutS are prevalent, particularly in the CF lung environment, and may be selected for and maintained by antibiotic pressure.

Topics: Adenosine Triphosphatases; Ampicillin Resistance; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cloning, Molecular; Cystic Fibrosis; DNA Fingerprinting; DNA-Binding Proteins; DNA, Bacterial; DNA, Intergenic; Drug Resistance, Bacterial; Genes, Bacterial; Genetic Complementation Test; Haemophilus influenzae; Humans; Molecular Sequence Data; Mutation; MutS DNA Mismatch-Binding Protein; Nalidixic Acid; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Ribotyping; Rifampin; Selection, Genetic; Sequence Analysis, DNA; Spectinomycin; Sputum

Treatment of Burkholderia cepacia-complex infections in cystic fibrosis patients is problematic, since the microorganism is often resistant to most antimicrobial agents. In this study, the Epsilometer test, or E test, was used to assess the activity of antimicrobial combinations against Burkholderia cepacia-complex. In a preliminary evaluation, the E test was compared to the checkerboard method using 10 test organisms. Synergy testing by the E test was then performed on 131 clinical isolates of Burkholderia cepacia-complex using various combinations of antimicrobial agents. Agreement between the E test and the checkerboard method was 90%. The rate of resistance to individual agents ranged from 48% for meropenem to 100% for tobramycin, chloramphenicol, and rifampin. In 71.6%, 15.6%, and 12.6% of the test evaluations performed, the combinations tested resulted in additivity/indifference, synergism, and antagonism, respectively. The highest rates of synergy were observed with combinations of ciprofloxacin-piperacillin (44%), rifampin-ceftazidime (33%), chloramphenicol-ceftazidime (22%), cotrimoxazole-piperacillin/tazobactam (22%), and ciprofloxacin-ceftazidime (21%). Rates of antagonism for cotrimoxazole and chloramphenicol in combination with beta-lactam agents were higher than those observed for ciprofloxacin plus beta-lactam agents. These results suggest that the E test is a valuable and practical method to be considered for improving the identification of possible therapeutic options in cystic fibrosis patients infected with organisms belonging to the Burkholderia cepacia-complex.

Topics: Bacteriological Techniques; Burkholderia cepacia; Burkholderia Infections; Ceftazidime; Chi-Square Distribution; Child; Child, Preschool; Ciprofloxacin; Cystic Fibrosis; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Female; Humans; Lactams; Male; Microbial Sensitivity Tests; Piperacillin; Rifampin; Sensitivity and Specificity

To evaluate the response rate to antimycobacterial drug therapy in patients with cystic fibrosis (CF) suffering from infection by non-tuberculous mycobacteria (NTM).. Ten patients, aged 10-34 y, out of 180 CF patients, were diagnosed with NTM disease. They had been regularly checked and examined for pulmonary symptoms, and had had chest X-rays and sputum cultures (including for mycobacteria) performed. One additional 36-y-old female received her CF diagnosis soon after the NTM diagnosis.. Mycobacterium avium-intracellulare complex (MAC) was found in 10 out of 11 patients and M. kansasii in 1 patient. Treatment with antimycobacterial drugs resulted in clinical improvement (weight gain or stabilization of weight and/or improved or stabilized lung function in 8 out of 11 patients) and mycobacterial culture turned negative in 10 out of 1.. Promising results may be associated with early intervention with antimycobacterial therapy in CF patients.

Topics: Adolescent; Adult; Amikacin; Anti-Bacterial Agents; Antitubercular Agents; Child; Clarithromycin; Cohort Studies; Cystic Fibrosis; Ethambutol; Female; Humans; Male; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Retrospective Studies; Rifampin; Streptomycin

We evaluated the activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime by determination of the MICs for 66 genotypically characterized Burkholderia cepacia isolates obtained from the sputum of cystic fibrosis patients. In vitro synergy assays, as performed by the time-kill methodology, of two- and three-drug combinations of the beta-lactams with tobramycin, rifampin, and/or ciprofloxacin were also performed with 10 strains susceptible, intermediate, or resistant to fluoroquinolones. On the basis of the MICs, meropenem and temocillin were the most active beta-lactam agents, with MICs at which 90% of isolates are inhibited of 8 and 32 micrograms/ml, respectively. The addition of ciprofloxacin significantly enhanced the killing activities of piperacillin, imipenem, and meropenem against the 10 strains tested (P < 0.05). The best killing activity was obtained with the combination of meropenem and ciprofloxacin, with bactericidal activity of 3.31 +/- 0.36 log10 CFU/ml (P < 0.05). Compared to the activity of the two-drug beta-lactam-ciprofloxacin combination, the addition of rifampin or tobramycin did not significantly increase the killing activity (P > 0.05). The three-drug combinations (with or without ciprofloxacin) significantly enhanced the killing activities of piperacillin, imipenem, and meropenem relative to the activities of the beta-lactams used alone (P < 0.05). The combination beta-lactam-ciprofloxacin-tobramycin was the combination with the most consistently synergistic effect.

Topics: Burkholderia cepacia; Burkholderia Infections; Ceftazidime; Ciprofloxacin; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Penicillins; Piperacillin; Rifampin; Thienamycins; Tobramycin

The presence of lactoferrin at the concentration found in cystic fibrosis (CF) sputum (0.9 g/L) reduced MICs and MBCs of doxycycline for Burkholderia cepacia and Pseudomonas aeruginosa strains. MICs for B. cepacia fell by 32- to 64-fold, from highly resistant to clinically achievable values. Rifampicin MICs for B. cepacia strains were reduced by lactoferrin and for some strains MBCs were reduced. These findings suggest new therapeutic approaches to infections and question the relevance of standard sensitivity tests for CF pathogens. Addition of lactoferrin to media for the routine sensitivity testing of CF isolates might give more relevant results.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Burkholderia cepacia; Cystic Fibrosis; Doxycycline; Drug Interactions; Drug Therapy, Combination; Humans; Lactoferrin; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Rifampin; Sputum

Cystic fibrosis (CF) patients require higher dosages of many antibiotics. The relapse of tuberculosis in one CF patient, and the repeated growth of Mycobacterium avium-intracellulare in another, despite conventional therapy, raised the question of whether the serum levels of the antimycobacterial drugs were adequate. Antimycobacterial drug serum concentrations were assayed in 10 CF patients with pulmonary mycobacterial disease. Serum levels below the proposed target range were seen 2 h after drug intake in the initial four patients treated: for rifampicin in 2/3, ethambutol in 3/4 and for clarithromycin in 2/3 patients, despite standard dosages. Reassays after dose adjustment and assays in six other patients showed that adequate levels were not achieved 4 h after clarithromycin in 3/5, ethambutol in 1/5, ciproflaxacin in 1/2 and ofloxacin in 2/2 patients. The patient with relapse of tuberculosis and the patient with continuous growth of M. avium-intracellulare improved and became culture negative after dose adjustment. Low drug serum levels is one reason for therapy failure in cystic fibrosis patients with mycobacterial disease. Therapeutic drug monitoring is recommended.

Topics: Adolescent; Adult; Antitubercular Agents; Biological Availability; Clarithromycin; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Mycobacterium avium-intracellulare Infection; Pregnancy; Rifampin; Tuberculosis, Pulmonary

In continuous flow biofilm cultures in medium resembling cystic fibrosis bronchial secretions, Pseudomonas aeruginosa was not eradicated from biofilms by 1 week of treatment with high concentrations of ceftazidime and gentamicin, to which the strains were sensitive on conventional testing. The addition of rifampicin, which has little activity against the strains as measured by the minimum inhibitory concentration, led to the apparent elimination of the bacteria from the biofilms. The effect was not strain specific.

Topics: Anti-Bacterial Agents; Biofilms; Bronchi; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Gentamicins; Humans; Polysaccharides, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Rifampin; Time Factors

MlCs of rifampicin and chloramphenicol for mucoid strains of Pseudomonas aeruginosa were lower in the presence of human lactoferrin (0.9 mg/mL, the concentration found in cystic fibrosis sputum) than in its absence. MICs for some strains were lowered to clinically achievable levels of the antibiotics, which is compatible with impressions of greater clinical efficacy in pseudomonas infections than would be predicted by standard sensitivity tests. The routine addition of lactoferrin to sensitivity media for testing of cystic fibrosis isolates may give more useful results than conventional tests as in-vivo conditions are more closely simulated.

Topics: Anti-Bacterial Agents; Chloramphenicol; Cystic Fibrosis; Drug Synergism; Humans; Lactoferrin; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Rifampin

The effects of subinhibitory concentrations of roxithromycin (16 mg/L) or rifampicin (16 mg/L) on alginate production by Pseudomanas aeruginosa were investigated. The weight of purified alginate from antibiotic-free cultures was significantly greater (52.5 +/- 24.0 mg, range 22.4-109.5), compared with alginate from cultures bacteria exposed to sub-MIC of roxithromycin (21.9 +/- 17.0, 0.0-42.1 (P < or = 0.037)) and to sub-MIC of rifampicin (28.6 +/- 15.0, 2.9-47.5 (P < or = 0.038)). Chromatographic analysis of hydrolysed and chemically transformed sub-units of alginate revealed that the presence and the molar ratio of D-mannuronic acid and L-guluronic acid were not affected in the remnant alginate exposed to sub-MIC of roxithromycin in contrast to that in the remnant alginate exposed to sub-MIC of rifampicin.

Topics: Alginates; Anti-Bacterial Agents; Antibiotics, Antitubercular; Child; Culture Media; Cystic Fibrosis; Female; Humans; Male; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Rifampin; Roxithromycin; Sputum

Topics: Administration, Oral; Adolescent; Alkaline Phosphatase; Child; Ciprofloxacin; Cystic Fibrosis; Drug Resistance, Microbial; Female; Follow-Up Studies; Humans; Joint Diseases; Lung Diseases; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Safety

A previous study has shown that non-anti-Pseudomonas aeruginosa antibiotics can modify the mucoid character, a major virulence factor in cystic fibrosis P. aeruginosa. The purpose of the present study was to investigate further this phenomenon using a quantitative approach on fresh sputum. A total of 0.1 to 0.5 ml of sputum were homogenized, decimally diluted, plated on three series of Difco Pseudomonas isolation agar containing no antibiotics, roxithromycin (16.0 microgram/ml) or Rifampicin (16.0 microgram/ml) and incubated at 35 degrees C. In each of the three series, the cfus of PA by ml of sputum were evaluated after 24h, and the entire culture of plates with confluent growth was harvested after 96h and weighed on an analytical scale according to the correlation observed between the mucosity and the density of the culture. To date, 36 sputa from twenty-nine cystic fibrosis patients known to be chronically colonized by mucoid P. aeruginosa have been submitted to the protocol; the mean weight of control, roxithromycin and rifampicin cultures was respectively 3.12 +/- 1.62, 1.90 +/- 1.67 (p less than or equal to 0.0005) and 1.83 +/- 1.24 g (p less than or equal to 0.005) in parallel with mean cfu/ml of 2.24 +/- 6.45 x 10(8) (p less than 0.03) and 1.65 +/- 4.42 x 10(8) (p greater than 0.05); a more constant reduction (greater than or equal to 20%) of mucosity (expressed as the ratio of weight of antibiotic culture/control culture x 100) was observed with rifampicin (29 vs. 23/36 sputa), whereas a more drastic reduction (greater than or equal to 80%) was observed with roxithromycin (12 vs. 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Male; Myxococcales; Pseudomonas aeruginosa; Rifampin; Roxithromycin; Sputum

The in-vitro activity of ciprofloxacin, imipenem and rifampicin, singly, and in two and three drug combinations was evaluated against 16 isolates of Pseudomonas cepacia. All 16 isolates were resistant to rifampicin; nine isolates were susceptible to ciprofloxacin; six were susceptible and seven had intermediate susceptibility to imipenem. The imipenem and rifampicin combination was synergistic for one of 16, imipenem and ciprofloxacin synergistic for seven of 16 and the three antibiotic combination was synergistic for 12 of 16 isolates. The three antibiotic combination demonstrated synergism with two isolates which were resistant to all three drugs. Combinations of two and three antibiotics resulted in enhanced killing of P. cepacia in this in-vitro study.

Topics: Ciprofloxacin; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas; Rifampin; Sputum

In an effort to develop new strategies, the authors are exploring the hypothesis that non-anti-Pseudomonas aeruginosa antibiotics can affect some major virulence factors in cystic fibrosis P. aeruginosa. Recent samples (127) of P. aeruginosa isolated from the sputum of cystic fibrosis patients and manifesting a mucoid growth were stored at -70 degrees C until experimentation. The mucoid character was retested after thawing and one 24-h in-vitro passage at 37 degrees C onto 100-mm blood agar plates to prepare a bacterial suspension for inoculation (Steers or MIC-2000 plus replicator) and cultivation (48 h, 37 degrees C) onto different 100-mm or 150-mm Mueller-Hinton agar plates containing either no antibiotics or antibiotics alone, and antibiotic combinations without presumed anti-P. aeruginosa activity. Some isolates (49, 38.6%) of P. aeruginosa expressed again the mucoid character on antibiotic-free Mueller-Hinton agar and growth was prevented by antibiotics in a number of them: 7 with doxycycline (16.0 micrograms/ml), 2 with rifampicin (16.0 micrograms/ml), 6 with roxithromycin-sulfamethoxazole (16.0-304.0 micrograms/ml) and 23 with trimethoprim-sulfamethoxazole. In the remaining evaluable isolates, the mucoid was modified towards the rough character in 36 out of 42 with doxycyline, 36 out of 47 with rifampicin, 31 out of 43 with roxithromycin-sulfamethoxazole and 20 out of 26 with trimethoprim-sulfamethoxazole. In parallel, the pigmentation was lost in the presence of antibiotics in those P. aeruginosa isolates having manifested this character on Mueller-Hinton agar. These results suggest that non-anti-P. aeruginosa antibiotics can modify the in vitro markers of virulence in cystic fibrosis P. aeruginosa and that they merit further investigation.

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Doxycycline; Drug Combinations; Humans; Leucomycins; Pigmentation; Pseudomonas aeruginosa; Rifampin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Virulence

During the period 1965-79 191 cystic fibrosis patients have been treated with 2349 course of anti-staphylococcal chemotherapy in the Danish Cystic Fibrosis Centre. The standard treatment was orally administered Fusidic acid in combination with Oxacillin or Dicloxacillin given for 14 days. In cases of penicillin allergy Fusidic acid in combination with Rifampicin was given. The overall results showed that S. aureus was eradicated from sputum by a single course of chemotherapy in 74% of the cases, although in 8% the original strains (phage-type) was replaced by a new strain. Repeated or extended treatment was successful in most of the remaining cases and, as a result, only 9% of our patients harboured S. aureus continuously for 6 months or more. On the average each patient received 2 anti-staphylococcal treatment per year, but no decrease in efficacy of repeated treatment was seen. Likewise, no significant increase of S. aureus precipitins and no development of resistant strains was seen in our patients. Due to the efficacy of chemotherapy and the principles of early treatment whether there are clinical symptoms of infection or not, S. aureus infection is now considered a minor problem without relation to poor prognosis in our cystic fibrosis patients.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Dicloxacillin; Female; Fusidic Acid; Humans; Infant; Male; Oxacillin; Probenecid; Pseudomonas Infections; Rifampin; Staphylococcal Infections