381 results found
Davies J, King J, Nichols A, et al., 2022, Review article: An update on CFTR modulators as new therapies for Cystic Fibrosis, Paediatric Drugs, ISSN: 1174-5878
Irving S, Bayfield K, Davies JC, et al., 2022, Curvilinearity provides additional information to lung clearance index only in a minority of children with early cystic fibrosis lung disease, ERJ Open Research, Vol: 8, ISSN: 2312-0541
Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4.
Sawicki GS, Chilvers M, McNamara J, et al., 2022, A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant., J Cyst Fibros
BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study. METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96. CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.
Davies J, Horsley A, Brightling C, et al., 2022, Early phase trials in a pandemic – how we can do better for the next one, The Lancet Respiratory Medicine, ISSN: 2213-2600
Davies J, Goss C, Fajac I, et al., 2022, Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE–CF™ 1 – a randomised, Phase II study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936
Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.Objective: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.Results: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.Conclusion: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.
Hughes DA, Archangelidi O, Coates M, et al., 2022, Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 129-135, ISSN: 1569-1993
Short C, Semple T, Saunders C, et al., 2022, A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 146-154, ISSN: 1569-1993
Thursfield RM, Shafi N, Davies JC, 2022, COUNTERPOINT: In the Era of Cystic Fibrosis Transmembrane Regulator Protein Modulator Therapy, Are the Treatment Goals for Adults Now Different From Those for Children With Cystic Fibrosis? No, CHEST, Vol: 161, Pages: 21-24, ISSN: 0012-3692
Davies J, Kos R, Brinkman P, et al., 2022, Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients, Journal of Cystic Fibrosis, Vol: 21, Pages: e28-e34, ISSN: 1569-1993
BackgroundPseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively.MethodsThis study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture.Results241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71–1.0) and 0.87 (CI 0.72–1.0) for adults and children, respectively.ConclusionsTargeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.
Edmondson C, Westrupp N, Seddon P, et al., 2022, The feasibility of home monitoring of young people with cystic fibrosis: results from CLIMB-CF, Journal of Cystic Fibrosis, Vol: 21, Pages: 70-77, ISSN: 1569-1993
BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.
Ahmed B, Cox MJ, Cuthbertson L, et al., 2021, Comparison of the airway microbiota in children with chronic suppurative lung disease, BMJ Open Respiratory Research, Vol: 8, Pages: 1-10, ISSN: 2052-4439
Rationale:The airway microbiota is important in chronic suppurative lung diseases (CSLD), such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). This comparison has not previously been described but is important because difference between the two diseases may relate to the differing prognoses and lead to pathological insights and potentially, new treatments. Objectives:To compare the longitudinal development of the airway microbiota in children with PCD to that of CF and relate this to age and clinical status. Methods:Sixty-two age-matched children (age range 0.5–17 years) with PCD or CF (n=31 in each group) were recruited prospectively and followed for 1.1 years. Throat swabs or sputum as well as clinical information were collected at routine clinical appointments. 16S rRNA gene sequencing was performed. Measurements and Main Results:The microbiota was highly individual and more diverse in PCD and differed in community composition when compared with CF. Whilst Streptococcus was the most abundant genus in both conditions, Pseudomonas was more abundant in CF with Haemophilus more abundant in PCD (Padj=0.0005). In PCD only, an inverse relationship was seen in the relative abundance of Streptococcus and Haemophilus with age. Conclusions:Bacterial community composition differs between children with PCD and those with CF. Pseudomonas is more prevalent in CF and Haemophilus in PCD, at least until infection with Pseudomonas supervenes. Interactions between organisms, particularly members of Haemophilus, Streptococcus, and Pseudomonas genera appear important. Study of the interactions between these organisms may lead to new therapies or risk stratification.
Davies JC, 2021, The life rafts sailed; Now let's take stock and set the course ahead (Commentary), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: S29-S30, ISSN: 1569-1993
Balfour-Lynn IM, Puckey M, Simmonds NJ, et al., 2021, Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations., Paediatr Respir Rev
There is now increased knowledge and experience of newborn screening around the world. There is also a better understanding of CF gene analysis, informed by international databases. This has resulted in a small number of children and adults having their diagnosis of CF reversed. This article illustrates this issue with three cases. It considers how best to tell children and adults with their families, and the reactions that may be encountered. It also discusses practical issues of removing the diagnosis.
Derichs N, Taylor-Cousar JL, Davies JC, et al., 2021, Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 1018-1025, ISSN: 1569-1993
Dobra R, Elborn JS, Madge S, et al., 2021, Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 986-993, ISSN: 1569-1993
Bayfield KJ, Douglas TA, Rosenow T, et al., 2021, Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis, THORAX, Vol: 76, Pages: 1255-1265, ISSN: 0040-6376
Bentley S, Davies J, Gastine S, et al., 2021, Clinical pharmacokinetics and dose recommendations for posaconazole gastro-resistant tablets in children with Cystic Fibrosis, Journal of Antimicrobial Chemotherapy, Vol: 76, Pages: 3247-3254, ISSN: 0305-7453
ObjectivesTo investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses.Patients and methodsChildren from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function.Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients.ConclusionsA starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L.
Dobra R, Davies G, Pike K, et al., 2021, Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?, Journal of Cystic Fibrosis, Vol: 20, Pages: 978-985, ISSN: 1569-1993
Background:Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients’ engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes.Methods:We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis.Results:We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation.Conclusions:Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.
Johnson H, Piggin M, McKibben S, et al., 2021, Insight Report: Respiratory medicine research prioritisation online survey
Insight report summarising the findings from an online survey aiming to help shape respiratory medicine research priorities in North West London.
Barben J, Castellani C, Munck A, et al., 2021, Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 810-819, ISSN: 1569-1993
Hine C, Desai M, Davies J, et al., 2021, Systematic review of lung clearance index (LCI) in non-cystic fibrosis (CF), non-primary ciliary dyskinesia (PCD) bronchiectasis (Bx), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
O'Toole GA, Crabbe A, Kummerli R, et al., 2021, Model Systems to Study the Chronic, Polymicrobial Infections in Cystic Fibrosis: Current Approaches and Exploring Future Directions, MBIO, Vol: 12, ISSN: 2150-7511
Chilvers MA, Davies J, Milla C, et al., 2021, Long-term safety and efficacy of lumacaftor/ivacaftor therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label extension study, The Lancet Respiratory Medicine, Vol: 9, Pages: 721-732, ISSN: 2213-2600
Background: The safety and efficacy of 24 weeks of lumacaftor/ivacaftor combination therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously demonstrated in two phase 3 studies. Here, we report long-term safety and efficacy data in children who rolled over from these two parent studies into a 96-week lumacaftor/ivacaftor open-label extension study (NCT02544451).Methods: The primary endpoint was safety. Secondary endpoints included change from baseline in lung clearance index 2∙5% (LCI2·5), sweat chloride concentration, body mass index, and Cystic Fibrosis Questionnaire–Revised respiratory domain score.Findings: Of 239 children who enrolled in the study and received at least one dose of lumacaftor/ivacaftor, 215 completed 96 weeks of treatment. Most children had adverse events (AEs) that were mild or moderate in severity, and there was a low rate of AEs leading to treatment discontinuation. The most frequently reported AEs were common manifestations or complications of cystic fibrosis or were consistent with the known safety profile of lumacaftor/ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor/ivacaftor treatment. Children treated with placebo in the parent study and who began lumacaftor/ivacaftor in this extension study had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in lumacaftor/ivacaftor-treated children in the parent studies were generally maintained in the extension study. Interpretation: Lumacaftor/ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at ages 6–11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks in this open-label extension study. These data support the long-term use of lumacaftor/ivacaftor to treat children aged ≥6 years homozygous for the F508del-CFTR mutation.
Shteinberg M, Haq IJ, Polineni D, et al., 2021, Cystic fibrosis, LANCET, Vol: 397, Pages: 2195-2211, ISSN: 0140-6736
Dixon E, Dick K, Ollosson S, et al., 2021, Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?, Paediatr Respir Rev
There has been growing interest in telemedicine for cystic fibrosis over recent years based largely on convenience for patients and/or increasing the frequency of surveillance and early detection which, it is assumed, could improve treatment outcomes. During 2020, the covid-19 pandemic catalysed the pace of development of this field, as CF patients were presumed to be at high risk of infection. Most clinics adapted to digital platforms with provision of lung function monitoring and sample collection systems. Here, we present the views of multidisciplinary team members at a large paediatric CF centre on what has worked well and what requires further optimisation in the future. In response to the question posed, 'Do we still need face to face clinics?' our answer is 'Yes, but not every time, and not for everyone'.
MacSweeney R, Reddy K, Davies J, et al., 2021, Trans-epithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome, Thorax, Vol: 76, Pages: 1099-1107, ISSN: 0040-6376
Background: Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.Methods: NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as ‘at-risk’ for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the ‘at-risk’ group) and 8 ARDS survivors on the ward.Results: In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference –8.4 mV; 95% CI –13.8 to –3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (−30.8 mV) than in at-risk subjects (−24.2 mV) and controls (−19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).Conclusions: Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.
Hughes DA, Price H, Rosenthal M, et al., 2021, Pseudomonas aeruginosa in the cystic fibrosis airway: does it deserve its reputation as a predatory 'Bully'?, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 1027-1030, ISSN: 1073-449X
Sepahzad A, Morris-Rosendahl D, Davies J, 2021, Cystic fibrosis lung disease modifiers and their relevance in the new era of precision medicine, Genes, Vol: 12, ISSN: 2073-4425
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
Sabnis A, Haggard K, Kloeckner A, et al., 2021, Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane, eLife, Vol: 10, Pages: 1-26, ISSN: 2050-084X
Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.
Martin I, Kenna D, Morales S, et al., 2021, Variability in bacteriophage and antibiotic sensitivity in serial Pseudomonas aeruginosa isolates from cystic fibrosis airway cultures over 12 months, Mircoorganisms, Vol: 9, ISSN: 2076-2607
Antibiotic treatment for Pseudomonas aeruginosa (Pa) in cystic fibrosis is limited in efficacy and may lead to multi-drug resistance (MDR). Alternatives such as bacteriophages are being explored but well designed, and controlled trials are crucial. The rational selection of patients with bacteriophage susceptible infections is required for both safety and efficacy monitoring. We questioned whether bacteriophage susceptibility profiles were constant or variable over time, variability having been reported with antibiotics. Serial Pa isolates (n = 102) from 24 chronically infected cystic fibrosis (CF) patients over one year were investigated with plaque and antibiotic disc diffusion assays. Variable number tandem repeat (VNTR) analysis identified those patients with >1 isolate. A median (range) of 4 (3–6) isolates/patient were studied. Twenty-one (87.5%) individuals had a single VNTR type; three (12.5%) had two VNTR types at different times. Seventy-five percent of isolates were sensitive to bacteriophage at ≥ 1 concentration; 50% of isolates were antibiotic multidrug resistant. Serial isolates, even when representing a single VNTR type, varied in sensitivity to both bacteriophages and antibiotics. The rates of sensitivity to bacteriophage supports the development of this therapy; however, the variability in response has implications for the selection of patients in future trials which must be on the basis of current, not past, isolate testing.
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