Journal Information
Vol. 57. Issue 10.
Pages 662-664 (October 2021)
Vol. 57. Issue 10.
Pages 662-664 (October 2021)
Scientific Letter
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Prolonged treatment with inhaled ampicillin in children with non-cystic fibrosis bronchiectasis
Tratamiento prolongado con ampicilina inhalada en pacientes pediátricos con bronquiectasias no relacionadas con la fibrosis quística
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María Rosario Pérez-Torres Lobatoa, Marta Mejías Truebab, Héctor Rodríguez Ramallob, Concepción Álvarez del Vayo Benitob, Maria del Carmen Iglesias Aguilarc, Mirella Gabolid,
Corresponding author
a Servicio de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain
b Servicio de Farmacia, Hospital Universitario Virgen del Rocío, Sevilla, Spain
c Microbiología, Megalab Microsur
d Unidad de Neumología Pediátrica, Servicio de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Table 1. Descriptive summary of the main variables collected and study results.
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To the Editor:

Non-cystic fibrosis-associated bronchiectasis (NCFB) is a chronic lung disease characterized by frequent exacerbations. In patients with NCFB, inhaled antibiotics provide higher infection site concentrations without systemic side effects. However, little evidence is available on nebulized antibiotic therapy in children1,2.

This study, based on the work of Máiz et al.3,4, aimed to analyze the effectiveness and safety of inhaled ampicillin therapy in children with NCFB colonized by ampicillin-sensitive Haemophilus influenzae (H. influenzae), penicillin-sensitive Streptococcus pneumoniae (PSSP), methicillin-sensitive Staphylococcus aureus (MSSA), or polymicrobial flora.

Medical records collected between 31/07/2014 and 31/03/2020 were reviewed. We included patients younger than 18 years of age diagnosed with NCFB colonized with any of the respiratory pathogens listed above who had ≥ 3 respiratory exacerbations per year and/or persistent symptoms without meeting respiratory exacerbation criteria5 (prolonged productive cough, unexplained recurrent fever, qualitative or quantitative change in expectoration). Patients were administered inhaled ampicillin after their parents or guardians gave consent for off-label use of the antibiotic.

The drug was prepared by diluting one vial of intravenous sodium ampicillin in 4 mL of water for injection. The resulting osmolarity was approximately 650 mOsm/kg. The dose used was 500 mg/12 h, and the solution was administered using either a vibrating mesh nebulizer (e-Flow®rapid) or a high-flow nebulizer (Pari Boy® SX), via an oronasal mask or a mouthpiece, depending on patient age and/or collaboration.

The minimum treatment time was 4 months. Rest periods took place in the months of lower circulation of respiratory viruses6.

Criteria for discontinuation were: resolution of respiratory symptoms; number of respiratory exacerbations ≤ 1 every 6 months; isolation of Pseudomonas aeruginosa (PA) or aminopenicillin-resistant pathogens; adverse effects; refusal of treatment.

A total of 6 patients were included, 4 of whom were boys. The median age at baseline was 13 years (IQR 10−13.6). Five patients presented other comorbidities, 3 of whom (patients 1, 5 and 6) were children with highly complex chronic disease7 (Table 1).

Table 1.

Descriptive summary of the main variables collected and study results.

Variables  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Patient 6  Median, IQR 
Demographic data
Sex  Male  Female  Female  Male  Male  Male  NA 
Age at diagnosis of lung disease (years)  10.5  2.5  0.9  8.1  4.6  3.5  4,05 (IQR 2.75–7.23) 
Etiology of bronchiectasis  Aspiration syndrome  Post-infectious  Vasculitis, immune dysregulation (low Treg cells)  Idiopathic  Post-infectious  Post-infectious  NA 
Comorbidity  HCCP Rett syndrome, GERD, dysphagia  Down syndrome, PHT  Interstitial lung disease, PHT  No  HCCP GERD, operated Tetralogy of Fallot, complete AVB, PM carrier  HCCP ICP, dysphagia, GERD  NA 
Microbiology
Isolates in the year prior to starting inhaled ampicillin (sputum/pharyngeal swab)  Mixed flora, AS Hib, MSSA  Mixed flora, AS Hib, PSSP  Mixed flora, AS Hib, PSSP  Mixed flora, AS Hib  Mixed flora  Mixed flora, AS Hib  NA 
BAL isolates in the 2 months prior to starting inhaled ampicillin  MSSA  MSSA, PSSP, AS Hib  AS Hib  AS Hib  AS Hib  AS Hib  NA 
Ampicillin MIC (μg/mL) in BAL sample  Not applicable  0.5  0.75  0.75  0.38  0.75  0.75 (IQR 0.5−0.75) 
Treatment-related data
Age at start of treatment (years)  14.6  13.8  7.6  13  13  13 (IQR 10−13.6) 
Years from diagnosis to start of treatment (n)  4.1  11.3  7.4  6.5  6.25 (IQR 5.25−7.18) 
Months of treatment (n)  26  35  21  17  19 (IQR 8.75−24.75) 
Months off (n)  19  6 (IQR 1.25−7.75) 
Months follow-up (n)  31  43  40  24  27.5 (IQR 10.5−37.75) 
Macrolide therapy  Yes  Yes  Yes  Yes  Yes  Yes  NA 
Microbiological isolates during follow-up (sputum/pharyngeal smear)  PSSP  Mycobacterium haemophilum  AS Hib  Mixed flora  Mixed flora  Mixed flora  NA 
Outcomes Pre-treatment (12 months)
Admissions (n)  2 (IQR 1.25−2.75) 
Days of admission to the ward (n)  10  3 (IQR 2−6.25) 
Respiratory exacerbations (n)  7 (IQR 7−7.75) 
During follow-up
Admissions (n) 
Respiratory exacerbations (n)  2.5 (IQR 1.25−3.75) 
Negativization of BAL culture  Yes  Yes  Yes  Yes  Yes  Yes  NA 
Months until negativization of the BAL culture (n)  7.97  8.93  5.87  1.33  1.3  1.97  3.92 (IQR 1.49−7.45) 

AVB: Atrioventricular block; AS Hib: ampicillin-sensitive Haemophilus influenzae; BAL: bronchoalveolar lavage; BCH: Bronchiectasis; GERD: gastroesophageal reflux; HCCP: highly complex chronic patient; ICP: infantile cerebral palsy; MIC: Minimum inhibitory concentration; MSSA: methicillin-sensitive Staphylococcus aureus; PM: pacemaker; PSSP: penicillin-sensitive S. pneumoniae; Treg: regulatory T cells.

The median duration of treatment and follow-up were 17.5 (IQR 8.75–24) and 25.5 (IQR 10.5–30) months, respectively. Only patient 4 had discontinued ampicillin by the end of the study.

During follow-up, no aminopenicillin-resistant microorganisms or PA were isolated. In patient 2, Mycobacterium haemophilum was isolated but this finding was neither confirmed in subsequent cultures nor was it clinically relevant.

After treatment initiation, no admissions were recorded (p = 0.0003) and a significant decrease in the median number of exacerbations (p = 0.027) from 7 (IQR 7−7.75) to 2.5 (IQR 1.25−3.75) was observed. In the 2 years following drug discontinuation, patient 4 received more than 10 antibiotic cycles for respiratory exacerbations.

In all patients, cultures of secretions became negative during treatment, with a median of 3.92 (IQR 1.49−7.45) months until negativization.

No adverse effects were detected. Table 1 summarizes patient characteristics and outcomes.

Nebulized aminopenicillin therapy in patients with chronic lung diseases has been studied by other authors who reported favorable results8. Clinical trials with inhaled amoxicillin-clavulanic acid have also demonstrated the safety and good tolerance of this treatment9. However, this is the first study to explore nebulized ampicillin in children with NCFB. In 2009, Maiz et al.3,4 published a series of 13 patients with bronchiectasis caused by cystic fibrosis and chronic MSSA colonization, showing a decrease in the number of hospital admissions and the use of systemic antibiotics after prolonged treatment with inhaled ampicillin. Although the MSSA isolated in sputum cultures were penicillin-resistant, the efficacy of treatment was probably due to the high lung concentrations achieved by administering the antibiotic by inhalation, levels that were higher than the minimum inhibitory concentration (MIC) for the targeted microorganisms10,11. In our study, all ampicillin-sensitive H. influenzae isolates in BAL were sensitive to ampicillin, although the MICs for MSSA or PSSP were not reached. However, despite this, and in line with other studies, our patients responded to nebulized ampicillin, probably for the reason stated above10–12. In contrast to Maiz’s series, none of our patients presented chronic colonization by these pathogens: apart from during exacerbations and in the year before starting ampicillin, mixed polymicrobial flora or a single microorganism were identified in the respiratory samples. Some of these exacerbations may have been initiated by respiratory viruses6. However, exacerbations could have declined because, rather than eradicating a single pathogen, prolonged treatment with nebulized ampicillin decreases the pulmonary bacterial load that is probably high in patients with bronchiectasis13–15. Furthermore, the pathogens commonly identified in children with NCFB15 are mostly sensitive to aminopenicillins (more so if higher drug concentrations are achieved by inhalation), which would also explain our patients’ improvement.

The outcomes mentioned in previous studies were favorable3,4,8,9, although it must be said that they were conducted in adults with diseases other than those presented by our patients. We must remember that the main reason for the off-label use of a drug that has only been tested in adults was the shortage of therapeutic options: our patients mostly had multiple conditions and no option for curative treatment, despite having tried other treatments administered according to the recommendations of the latest clinical practice guidelines1,2,12,16.

This study has limitations: it was a retrospective, before-and-after study without a control group, conducted in a small, heterogeneous group of cases with varying lengths of follow-up. Even so, we observed a statistically significant decrease in admissions and respiratory exacerbations.

Therefore, we conclude that long-term inhaled ampicillin therapy appears to be a safe and effective option in children with NCFB colonized by common pathogens who have frequent exacerbations. However, more extensive, randomized, homogeneous studies are needed to confirm these results and determine the optimal duration and regimen of inhaled ampicillin therapy.

Funding Acknowledgements

The authors received no financial support for the research, authorship, and publication of this article.

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Please cite this article as: Pérez-Torres Lobato MR, Mejías Trueba M, Rodríguez Ramallo H, Álvarez del Vayo Benito C, Iglesias Aguilar MC, Gaboli M. Tratamiento prolongado con ampicilina inhalada en pacientes pediátricos con bronquiectasias no relacionadas con la fibrosis quística. Arch Bronconeumol. 2021;57:662–664.

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Archivos de Bronconeumología

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