DOI: 10.5061/dryad.5dv41ns71
title: Data from: The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease

description: Background: Selection for resistance to azithromycin (AZM) and other
 antibiotics such as tetracyclines and lincosamides remains a concern with
 long-term AZM use for treatment of chronic lung diseases (CLD). We
 investigated the impact of 48 weeks of AZM on the carriage and antibiotic
 resistance of common respiratory bacteria among children with
 HIV-associated CLD. Methods: Nasopharyngeal (NP) swabs and sputa were
 collected at baseline, 48 and 72 weeks from participants with
 HIV-associated CLD randomised to receive weekly AZM or placebo for 48
 weeks and followed post-intervention until 72 weeks. The primary outcomes
 were prevalence and antibiotic resistance of Streptococcus pneumoniae
 (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and
 Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic
 regression and Fisher's exact test were used to compare carriage and
 resistance respectively. Results: Of 347 (174 AZM, 173 placebo)
 participants (median age 15 years [IQR =13–18], females 49%),NP carriage
 was significantly lower in the AZM (n=159) compared to placebo (n=153) arm
 for SP (18% vs 41%, p&lt;0.001), HI (7% vs 16%, p=0.01), and MC (4% vs
 11%, p=0.02); SP resistance to AZM (62% [18/29] vs 13%[8/63],
 p&lt;0.0001) or tetracycline (60%[18/29] vs 21%[13/63],
 p&lt;0.0001) were higher in the AZM arm. Carriage of SA resistant to
 AZM (91% [31/34] vs 3% [1/31], p&lt;0.0001), tetracycline (35% [12/34]
 vs 13% [4/31], p= 0.05) and clindamycin (79% [27/34] vs 3% [1/31],
 p&lt;0.0001) was also significantly higher in the AZM arm and
 persisted at 72 weeks. Similar findings were observed for sputa.
 Conclusions: The persistence of antibiotic resistance and its clinical
 relevance for future infectious episodes requiring treatment needs further
 investigation.
description: This is a sub-study of the BREATHE trial (ClinicalTrials.gov
 Identifier: NCT02426112).  Approval for the main trial was obtained from
 local regulatory bodies at the study sites and the research ethics
 committees of the London School of Hygiene and Tropical Medicine, the
 University of Cape Town, and the Medical and Health Research in Norway.
 This sub-study was approved by the Human Research Ethics Committee of the
 University of Cape Town (HREC/REF: 092/2019). Written informed consent and
 age-appropriate assent were provided by guardians and participants under
 18 years, respectively. Older participants (≥18 years) consented
 independently. BREATHE (Bronchopulmonary function in response to
 azithromycin treatment for chronic lung disease in HIV- infected children)
 is a two-site, double-blind, placebo- controlled, individually randomised
 trial that enrolled 346 perinatally HIV-infected children and adolescents
 aged 6–19 years with HIV-associated chronic lung disease (CLD) who have
 been receiving ART for a minimum of 6 months. Participants were enrolled
 from the outpatient HIV clinics in Harare, Zimbabwe, and Blantyre,
 Malawi. CLD was defined as forced expiratory volume in 1 second
 (FEV<sub>1</sub>) <i>z</i>-score less than -1.0
 with no reversibility [&lt;12% improvement in FEV<sub>1
 </sub>after 200 µg of salbutamol inhaled using a spacer].
 Participants were individually randomised to receive weight-based dosing
 of AZM (10 to 19.9 kg, 250 mg; 20 to 29.9 kg, 500 mg; 30 to 39.9 kg, 750
 mg; and 40 kg or more, 1250 mg) or placebo once-weekly up to 48 weeks,
 with follow-up for a further 24 weeks post-intervention. Adherence to
 trial medication was defined as not missing, on average, more than two of
 the 12 dispensed doses, as assessed by pill count, splitting time in the
 study into four 12-week periods, according to visit and study medication
 dispensing schedule. Socio-demographic and clinical data were obtained
 through questionnaire administered by a study nurse. Nasopharyngeal (NP)
 swabs and sputa were collected from participants at baseline, 48- and
 72-week visits. Samples were immediately stored in 1 ml of skim milk,
 tryptone, glucose, and glycerine (STGG) medium, placed on ice for a
 maximum of 1 h and then frozen down to at -80 °C. <i>Streptococcus
 pneumoniae </i>(SP)<i>, Staphylococcus aureus
 </i>(SA)<i>, Haemophilus influenzae </i>(HI) and
 <i>Moraxella catarrhalis </i>(MC) were recovered from the
 samples and identified using conventional microbiological culture and
 biochemical techniques. Gram negative bacilli were identified using matrix
 assisted laser desorption ionization-time of flight mass spectrometry
 (MALDI-TOF MS). Antibiotic susceptibility testing (AST) to AZM,
 tetracycline and cotrimoxazole was conducted for all four bacterial
 species using the Kirby-Bauer disk diffusion method. Additionally, AST was
 done for SP to oxacillin, SA to clindamycin, cefoxitin, and penicillin, HI
 to amoxicillin-clavulanate, cefuroxime, and ampicillin, and MC to
 amoxicillin-clavulanate. Inducible clindamycin resistance was assessed as
 previously reported. SA susceptibility to cefoxitin was tested as a
 surrogate for methicillin resistance. Beta lactamase production by HI and
 MC was assessed using nitrocefin disc. AST was conducted in accordance
 with the 2018 Clinical and Laboratory Standards Institute guidelines and
 breakpoints.
description: The meaning of each variable in the dataset is detailed in the
 file labelled "data_dictionary_for_variables".