Early antibiotic therapy has the potential to eradicate initial Pseudomonas aeruginosa infection and postpone chronic infection. There are limited data evaluating the efficacy and safety of inhaled tobramycin in patients with cystic fibrosis (CF) who are younger than 1 year. The objective of this study was to evaluate the effectiveness of inhaled tobramycin in early eradication of P aeruginosa in infants with CF.
This retrospective study evaluated patients with CF younger than 1 year with first time infection with P aeruginosa. The primary outcome was the frequency of P aeruginosa eradication. Secondary outcomes were sustained culture negativity at 12 and 18 months and safety assessments.
Of 18 patients included in the study, 9 received inhaled tobramycin and an enteral fluoroquinolone and 9 received inhaled tobramycin alone. Microbiologic clearance of respiratory cultures was observed in 83% patients at end of therapy and 78% of patients at 1 month posttherapy. Eradication of P aeruginosa was observed in 56% of patients at 6 months posttreatment with sustained culture negativity observed in 39% of patients up to 18 months.
Inhaled-tobramycin therapy is effective in early eradication of P aeruginosa infection and is well tolerated in infants younger than 1 year.
Introduction
Early Pseudomonas aeruginosa colonization has been shown to adversely affect long-term pulmonary disease and survival in cystic fibrosis (CF) patients.1,2 A longitudinal study evaluating newly diagnosed patients with CF born from 1985 to 1994 found that approximately 29% and 65% initially acquired P aeruginosa by 6 months and by 1 year of age, respectively.3 Initial P aeruginosa isolates from the environment are typically non-mucoid strains, which are generally susceptible to antibiotics.4 Mucoid strains are a mutant phenotype of P aeruginosa that produce alginate, an exopolysaccha-ride, which confers antibiotic resistance.5 The transition from non-mucoid to mucoid strains of P aeruginosa occurred at a median of 10.9 years.3 Early antibiotic therapy would have the potential to eradicate initial P aeruginosa infection with non-mucoid strains and therefore postpone chronic infection, and it has since become the standard of care in the United States.2,6
A more recent cohort study7 evaluating patients diagnosed with CF prior to 2 years of age in 2006–2015, a period during which P aeruginosa eradication therapy was more common practice, observed the prevalence of the initial acquisition of P aeruginosa to be much less, at 28% by 1 year of age. Progression to chronic infection occurred in 13% of patients who had acquired P aeruginosa. The overall prevalence of chronic infection increased with age, with less than 1% observed by 1 year of age and 7% by 9 years of age.
Surveillance cultures and eradication therapy for newly acquired P aeruginosa have now become a part of routine care. It is currently recommended that infants younger than 2 years and newly infected with P aeruginosa be treated regardless of the presence of symptoms.6,8,9 Commercially available tobramycin inhalation is approved for the treatment of pulmonary infections and chronic colonization in CF patients older than 6 years and has been studied in patients as young as 6 months.10–13 However, there are limited data evaluating the effectiveness and safety of inhaled tobramycin in patients with CF younger than 1 year, and particularly in those younger than 6 months.
This retrospective study aimed to evaluate the effectiveness and safety of inhaled tobramycin in early eradication of P aeruginosa in infants with CF. We hypothesized that use of compounded tobramycin nebulization solution at a reduced dose in infants <6 months of age is as effective as use of commercially available products dosed 300 mg twice daily in older infants as determined by local CF center data as well as in comparison with published literature.
Materials and Methods
Study Population. This was a retrospective descriptive study conducted at Nationwide Children's Hospital, a free-standing pediatric hospital in Columbus, OH, with more than 600 licensed beds and currently serving approximately 250 pediatric and 240 adult CF patients. Infants with a diagnosis of CF with newly acquired P aeruginosa infection isolated on a respiratory culture prior to 1 year of age at Nationwide Children's Hospital between January 1, 2009, and January 1, 2017, were eligible for analysis. Patients who received intravenous or inhaled antibiotics with anti–P aeruginosa activity in the preceding 6 months of index P aeruginosa culture were excluded. Patients who also received these agents prior to completion of inhaled-tobramycin therapy were also excluded.
Patient demographic data including age at detection of first P aeruginosa isolate, sex, and CF genotype were obtained. Microbiologic data were based on culture results from throat swab, bronchoalveolar lavage, and sputum specimens. Pseudomonas aeruginosa characteristics including mucoid and non-mucoid strains and susceptibility patterns were also recorded. For patients who underwent infant pulmonary function testing, forced expiratory volume in 0.5 second (FEV0.5) results were collected and summarized.
Early P aeruginosa Eradication Protocol. At our institution, standard practice is use of commercially available tobramycin products (TOBI, Canonsburg, PA; Bethkis, Bethesda, MD) off-label at 300 mg/dose twice daily in infants ≥6 months of age and compounded nebulized tobramycin solution at a lower dose of 80 mg/dose twice daily in infants <6 months of age. This may be in conjunction with an enteral fluoroquinolone depending on the presence of clinical symptoms and provider preference. Routine surveillance cultures were obtained at CF clinic visits and therapy was initiated when P aeruginosa was first isolated on culture. Inhaled tobramycin was generally continued for 28 days alone or in combination with an enteral fluoroquinolone for 14 days if prescribed. Respiratory cultures were obtained at the end of eradication treatment and at subsequent clinic visits, which varied from 1 to 3 months. All respiratory cultures obtained during the study period were included in our analysis.
Outcomes. The primary outcome was to determine the frequency of early P aeruginosa eradication at 6 months after completion of therapy. Secondary outcomes were to determine the incidence of sustained culture negativity at 12 and 18 months and safety assessments. Eradication was defined as at least 3 negative cultures for 6 months with at least 1-month interval between each culture. Colonization was defined as the presence of P aeruginosa for 6 months, based on 3 positive respiratory cultures.10
Statistical Analysis. Group comparisons were assessed by using 2-sample t tests or Wilcoxon rank sum tests and chi-square/Fisher exact test. The proportion of patients with sustained culture negativity at 6-, 12-, and 18-month time points were evaluated by using Fisher exact test. Time to subsequent positive P aeruginosa infection after treatment was evaluated by using Kaplan-Meier estimates and log-rank test. Statistical significance was defined as a p value <0.05. Statistical analysis was performed by using GraphPad Prism version 7.05 (GraphPad Software, San Diego, CA).
Results
A total of 31 patients met study inclusion criteria; 13 patients were excluded owing to use of antibiotics with anti–P aeruginosa activity in the preceding 6 months of the first P aeruginosa isolate. Of the 18 patients evaluated, 9 patients received inhaled tobramycin and enteral ciprofloxacin and 9 patients received inhaled tobramycin monotherapy. Baseline characteristics are described in Table 1. There were no significant differences between the 2 therapy groups. The mean age at detection of first P aeruginosa isolate was 0.34 ± 0.24 years with 13 (72%) patients younger than 6 months. Of all initial Pseudomonas isolates, none were mucoid stains.
Most infants <6 months of age received inhaled tobramycin dosed at 80 mg twice daily (n = 9). Of the 3 patients who received non-standard doses, 2 infants received 60 mg twice daily and 1 infant received 120 mg twice daily (Table 2). Varied dosing was observed in infants ≥6 months. Two patients received inhaled tobramycin dosed at 300 mg twice daily, while 4 patients received doses ranging from 120 to 160 mg twice daily.
Most patients, 14 (78%), were treated with inhaled tobramycin for 28 days, while 4 (22%) infants were treated for 14 days. All patients treated with a fluoroquinolone received ciprofloxacin enterally for a duration of 14 days. Ciprofloxacin was dosed 15 mg/kg/dose every 12 hours in all patients except for 1 patient who received 10 mg/kg/dose every 12 hours. Time to start of treatment once a respiratory culture was obtained was median (IQR) of 6.5 (6, 7.75) days and time to subsequent culture after completion of therapy was median (IQR) of 5.5 (0, 8.75) days.
Of all patients, 15 (83%) were successfully treated at the end of treatment and 14 (78%) at 1 month post-treatment as indicated by culture negativity of P aeruginosa with subsequent cultures. Eradication of P aeruginosa was observed in 56% patients at 6 months posttreatment and culture negativity was sustained in 39% of patients at 12 and 18 months. There was no difference in frequency of P aeruginosa eradication when comparing monotherapy versus dual therapy (Figure 1; 44% vs 67%, p = 0.64). There was also no difference when comparing age groups <6 months versus >6 months (Figure 1; 42% vs 83%, p = 0.15). Time to subsequent positive P aeruginosa infection was not different between treatment (Figure 2; p = 0.27, log-rank test) and age group (Figure 2; p = 0.86, log-rank test) comparisons. Colonization, defined as the presence of P aeruginosa for 6 months as based on 3 positive respiratory cultures after 2 eradication attempts, occurred in 3 patients with a median time to colonization of 203 ± 5 days (Figure 3).
Proportion of patients free of Pseudomonas aeruginosa for all patients and comparison of (a) treatment and (b) age groups. There were no differences in frequency of P aeruginosa eradication when comparing monotherapy versus dual therapy (p = 0.64) or by age <6 months versus ≥6 months (p = 0.15).
Proportion of patients free of Pseudomonas aeruginosa for all patients and comparison of (a) treatment and (b) age groups. There were no differences in frequency of P aeruginosa eradication when comparing monotherapy versus dual therapy (p = 0.64) or by age <6 months versus ≥6 months (p = 0.15).
Time to subsequent positive Pseudomonas aeruginosa infection in all patients and comparison of (a) treatment and (b) age groups. Median time to subsequent infection was 178 days. No differences were observed when comparing treatment (p = 0.27, log-rank test) and age (p = 0.86, log-rank test).
Time to subsequent positive Pseudomonas aeruginosa infection in all patients and comparison of (a) treatment and (b) age groups. Median time to subsequent infection was 178 days. No differences were observed when comparing treatment (p = 0.27, log-rank test) and age (p = 0.86, log-rank test).
Time to colonization with Pseudomonas aeruginosa for all infected patients. Median time to colonization was 203 ± 5 days.
Time to colonization with Pseudomonas aeruginosa for all infected patients. Median time to colonization was 203 ± 5 days.
Infant pulmonary function testing was performed in 16 patients posttreatment (Table 3). The mean FEV0.5% was 108% ± 15% in all patients. In patients that eradicated P aeruginosa, the mean FEV0.5% was 106% ± 17% compared with 111% ± 11% in those who did not eradicate P aeruginosa.
Inhaled-tobramycin therapy was relatively well tolerated. Of 3 patients who reported cough associated with therapy, 1 patient required discontinuation owing to respiratory distress and was transitioned to therapy with inhaled aztreonam after inhaled tobramycin was held for 2 weeks. Serum concentrations were not obtained while patients received inhaled-tobramycin therapy; however, serum creatinine levels obtained posttherapy did not increase significantly from baseline in all patients. Of 13 patients with audiometric function testing performed, all patients had normal function with the exception of 1 patient who had hearing loss prior to initiation of treatment. Of all subsequent P aeruginosa strains isolated, 1 strain was resistant to tobramycin.
Discussion
Early treatment of initial P aeruginosa infection may postpone chronic colonization, which is associated with rapid decline in lung function and higher mortality rates.2,14 Our study shows that of all infants who received inhaled tobramycin for treatment of initial P aeruginosa infection, repeated cultures were negative for P aeruginosa in 15 (83%) patients at end of treatment and in 14 (78%) patients at 1 month posttreatment. Eradication of P aeruginosa at 6 months was attained in 10 (56%) patients and sustained for up to 18 months in 39% of patients with a median time to recurrent infection of 16.9 months. Although not statistically significant, a greater proportion of patients ≥6 months of age receiving inhaled tobramycin 300 mg twice daily achieved eradication than did patients <6 months of age receiving inhaled tobramycin dosed at 80 mg twice daily. Furthermore, there was no difference in the proportion of patients who achieved eradication when comparing those who received dual therapy with the addition of an enteral fluoroquinolone with those who received inhaled tobramycin therapy alone.
Differences in definitions of eradication make it difficult to make a direct comparison with other studies. Eradication rates in our study were based on the more stringent European consensus criteria that define eradication as at least 3 negative cultures for 6 months with at least 1-month interval between each culture.10 In the Early Inhaled Tobramycin for Eradication (ELITE) trial, approximately 80% to 90% of patients were free of P aeruginosa at the end of treatment and 1 month posttreatment, and 66% to 70% of patients remained free of P aeruginosa at the time of the final study visit with a median time to recurrence of approximately 26 months in patients aged ≥6 months.12
Inhaled tobramycin allows for antibiotic delivery to the site of pulmonary infection while avoiding systemic toxicity associated with higher systemic exposure following intravenous administration. Therapy was generally well tolerated with 3 patients who reported a mild cough with therapy and 1 patient who reported respiratory distress and required discontinuation of therapy. The dosing regimen used demonstrated a low risk of nephrotoxicity and ototoxicity in this age group. Serum tobramycin concentrations in infants receiving inhaled tobramycin were not obtained given normal renal function, as indicated by serum creatinine obtained post-therapy that did not differ significantly from baseline. Normal audiometric function testing was observed in all patients posttherapy with the exception of 1 patient who had exhibited hearing loss at baseline. However, monitoring of concentrations may be warranted for infants and neonates with poor renal function or undergoing mechanical ventilation, as elevated serum tobramycin concentrations have been reported with doses of 300 mg once daily in this population.15 Our study adds to the currently available literature15–18,20 describing the use of inhaled tobramycin: a dose of 80 mg twice daily in infants with CF younger than 6 months led to successful eradication of P aeruginosa and was not associated with nephrotoxicity or ototoxicity events and was well tolerated even in infants and neonates.
Several limitations of our study include a small sample size at a single center, which limits our ability to adjust for confounding factors. Dosing of tobramycin varied from standard practices owing to prescribing differences, as 3 infants <6 months of age received doses higher than 80 mg twice daily and 4 infants ≥6 months of age received doses lower than 300 mg twice daily. Although most patients were treated with inhaled tobramycin for 28 days, a shorter treatment duration of 14 days was observed in 4 patients, 1 of whom required discontinuation owing to intolerance of therapy consisting of cough and respiratory distress. The limited number of patients may have led to our study lacking power to detect a significant difference and to account for the variation of dosing and duration of tobramycin therapy.
Our endpoints were based on microbiologic outcomes with the use of throat swabs in infants, which poses a separate challenge for an accurate diagnosis of a lower airway infection. However, the presence of P aeruginosa in the upper airway indeed leads to subsequent lower airway infections as seen in studies that describe the development of chronic infections in those untreated for P aeruginosa previously detected on throat swabs.21
Furthermore, microbiologic outcomes may not necessarily correlate with clinical outcomes such as changes in pulmonary function testing. Given the young age of the study population, most infant pulmonary function testing was performed only after treatment, which limited our assessment of clinical outcome in terms of improvement in FEV0.5. Our study, however, proposes that eradication regimens using inhaled tobramycin may be safely initiated in infants younger than 6 months. In the future, this study could be expanded to a multicenter study with a longer duration and consistent doses among age groups to observe the effect of preventing or delaying chronic infection on clinical outcomes, impact on quality of life, and survival. Furthermore, other directions would be to observe the effect of inhaled tobramycin on the CF microbiome over time.
Conclusions
The results of this study suggest that early tobramycin therapy is effective in eradicating P aeruginosa infection and is well tolerated in infants younger than 1 year. There was no difference in outcomes with the addition of an enteral fluoroquinolone compared with inhaled tobramycin therapy alone. Larger-scale studies are warranted in this population to further evaluate this aggressive approach for early eradication of and prevention of colonization by P aeruginosa. The effect of this approach on the prevention of rapid progression of lung disease and preservation of pulmonary function after infection should also be evaluated.
Acknowledgments
Preliminary results previously presented at PPAG Annual Meeting on April 26, 2018, in Salt Lake City, UT; and 2018 North American Cystic Fibrosis Conference on October 18, 2018, in Denver, CO.
Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report.
Ethical Approval and Informed Consent The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and have been approved by the appropriate committees at Nationwide Children's Hospital. Informed consent was waived owing to the retrospective nature of this study.