Optimal treatment of the underlying aetiology is the most effective antimicrobial stewardship for chronic respiratory disease: a lesson learned from cystic fibrosis

To the Editor:

The increasing occurrence of antimicrobial resistance in bacterial infections has emerged as one of the biggest threats to global health. Antimicrobial stewardship (AMS) programmes have grown rapidly [1, 2] over recent decades due to increasing evidence of their effect on the quality of medical care, by reducing adverse outcomes, bacterial resistance, drug-related toxicity and secondary infections [3]. Furthermore, they play a crucial role in reducing community resistance rates. National surveillance programmes of antimicrobial resistance providing yearly reports and interactive data platforms are well developed in most high-income countries. In low- and middle-income countries, major gaps exist, ranging from limited expertise, infrastructure, investment and access to antimicrobials, and lack of microbiological diagnostic capabilities [4]. AMS strategies aim at choosing the right antimicrobial for the right patient at the right time in optimised doses and routes of administration, and for an appropriate duration. Thus, the result is individualised therapy to ensure the best outcome while reducing the risk for toxicity and adverse effects, and avoiding an inappropriately broad antimicrobial spectrum. Fundamental aspects inherent to this process are timely and accurate diagnostics to identify the target organism, identifying an appropriate antimicrobial based on pertinent clinical trials (if this is possible), the use of drug susceptibility testing, and the dynamic integration of relevant host factors.

Antimicrobial stewardship for people with chronic lung disease, like people with cystic fibrosis (pwCF), is challenging and there is a known lack of AMS-guided antibiotic prescription behaviour among cystic fibrosis clinicians. Antimicrobials have played a critical role in the improved outcomes of pwCF over the last several decades [5]. They are recommended for eradication of certain pathogens, such as Pseudomonas aeruginosa; suppression of certain persistent micro-organisms in chronic infection; and treatment of acute pulmonary exacerbations [6]. Registry analyses of anti-infective management in cystic fibrosis have found that frequent monitoring and increased use of appropriate medications, including more intravenous antimicrobials, was associated with improved outcome [7]. In addition, top-quartile cystic fibrosis centres were shown to initiate antimicrobials more frequently for symptoms of pulmonary exacerbations [8]. Furthermore, there is a well-described discordance between clinical outcomes and drug susceptibility testing results [9]. The association of AMS programmes, which are perceived to aim for reduced antimicrobial consumption, may therefore prevent cystic fibrosis clinicians from integrating AMS programmes in their daily routine for fear of adverse outcomes due to reduced antibiotic consumption and lack of clinical utility.

Small-molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein are transforming the care for pwCF. A combination of three modulators, elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA), was approved by the US Food and Drug Administration in October 2019 and by the European Medicines Agency in August 2020. ELX/TEZ/IVA effectively increases the function of the most common F508del mutation to approximately 40–50% of wild-type function [10], leading to more effective mucus clearance from the airways [11]. Its introduction into clinical care led to unprecedented improvements in lung function, sweat chloride concentration, weight gain and respiratory symptoms, and a reduction in pulmonary exacerbations [12, 13]. Open-label extension studies and real-world research suggest that treatment benefits are sustained over time and that maximal impact may be obtained with early use [14–16].

The aim of the present investigation was to evaluate inpatient antibiotic consumption in two of the largest German cystic fibrosis centres (Hannover Medical School (centre 1) and Charité-Universitätsmedizin Berlin (centre 2)) from 2017 to 2021, with particular attention paid to the start of CFTR modulator therapies. Consumption data were obtained through the hospital pharmacy services, extracting data from the designated cystic fibrosis wards of the participating centres. A consensus definition was used (recommended daily dose (RDD)). Drug use density was calculated as yearly RDDs per 100 patient-days (i.e. occupied bed days). To calculate RDDs per 100 bed-days, the total monthly use of every antibiotic in the entire hospital was divided by the occupied bed-days and the assumed normal daily dose. AMS programmes in these two hospitals include yearly antimicrobial consumption meetings between clinicians from different specialties and the AMS team (infectious disease physician, clinical pharmacist and microbiologist). No other specific AMS interventions on the designated wards were carried out (e.g. infectious disease specialist consultation or AMS rounds). The annual antibiotic consumption in RDDs and the percentage of ward occupancy by pwCF were evaluated in both centres within the aforementioned period.

A comparison of the first (2017) and last (2021) RDDs per 100 inpatient-days and occupancy in both centres was conducted using two-sided Chi-squared statistics. A two-sided p-value <0.05 was considered statistically significant.

For the time period we analysed, initial data on CFTR modulator use has been made available via the German Cystic Fibrosis Registry annual report, starting where documentation of this aspect began in 2018. During that time period, a continuous increase was observed for overall CFTR modulator treatment from 41% of all eligible pwCF receiving CFTR modulator therapy in 2018 to 56% in 2019, 68% in 2020 and 81% in 2020 in 2021 [17]. Reimbursement for ELX/TEZ/IVA was granted by the German federal authority in August 2020. The percentage of pwCF eligible for CFTR modulator therapy receiving ELX/TEZ/IVA increased from 0% in 2019 to 32% in 2020 to 64% in 2021 [17]. These data demonstrate rapid and widespread adoption of CFTR modulator therapy during the time we studied, particularly for ELX/TEZ/IVA.

During the study period, in the respiratory wards in Hannover and Berlin respectively, 8141 and 3762 patients were hospitalised, among whom, 782 (9.6%) and 1564 (41.6%) were pwCF, respectively. Antibiotic consumption substantially decreased in both centres: from 76 to 37 (centre 1) and 216 to 114 (centre 2) RDDs per 100 patient-days (figure 1). For all antibiotic classes, the mean drug use density decreased by 51% and 47%, respectively (p<0.001 for each). The strongest effect was seen in the class of aminoglycosides, with reductions of 73% and 66% (p<0.001 for each), whereas the decrease in fluoroquinolone and third-generation cephalosporin use was 50% and 45%, and 33% and 63%, respectively. Similarly, in 2020 and 2021, we observed a significant reduction in meropenem use, which was the preferred carbapenem (50% and 51%; p<0.001, each). There was no significant reduction in the penicillin/β-lactamase inhibitor combinations. Total antibiotic consumption in centre 2 was higher due to higher cystic fibrosis occupancy on the ward (figure 1). We observed a reduced occupancy of pwCF on the wards at both centres with a reduction of 55% and 60% in centre 1 (p=0.118) and centre 2 (p<0.001), respectively. During the observational period, no specific AMS interventions (i.e. decision tools for appropriate antibiotic use, interdisciplinary AMS rounds and AMS in-house guidelines) were carried out on the designated respiratory wards.

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FIGURE 1

a and b) Antibiotic consumption in recommended daily doses (RDDs) per 100 patient-days; c and d) patient occupancy from 2017 to 2021.

The most significant limitation of our study lies in the potential influence of the COVID-19 pandemic. Reduction in antibiotic consumption could also be due to changes in healthcare approaches and hygiene measures during the pandemic. However, we observed a continuous reduction in antibiotic consumption from 2017 to 2021, without a particularly pronounced reduction from 2019 to 2020, the time of the strictest lockdown measures throughout Germany. A second limitation of our analyses is the fact that the antibiotic consumption data in our study were derived from surveillance programmes and are not limited to pwCF. Therefore, we cannot exclude that the decrease of anti-infective consumption was due to decreases in disease entities other than cystic fibrosis. However, fewer hospitalisations of pwCF with a simultaneous number of pwCF seen in the outpatient clinics of both centres and the high proportion of pwCF accounting for hospitalisations at centre 2 (41.6%) support our hypothesis. Finally, the data include only inpatients, while milder exacerbations may have been treated with oral antibiotics in an outpatient setting.

Despite these limitations, we show significant reductions in overall antibiotic use and specific antibiotic drug class use in two large-volume cystic fibrosis centres after licensing of CFTR modulator therapy in the absence of any concomitant AMS activities during the time period studied. These observations are most evident after introduction of ELX/TEZ/IVA but were present during the whole observation period. The changes we observed are in line with the overall increase of CFTR modulator therapy, documented in the annual report of the German Cystic Fibrosis Registry. These changes support the notion that additional effects of previous CFTR modulators should not be dismissed. Furthermore, we cannot exclude that therapeutic improvements outside of CFTR modulator treatment have also affected the decline in anti-infective use we observed.

Similar results were also published by Miller et al. [18] using a different design, which showed a rapid reduction in infection-related visits and antimicrobial use among pwCF after initiation of triple CFTR modulator therapy compared to those who did not start this therapy.

Our data and the data published by Miller et al. [18] make a strong case for causal treatment approaches for infectious complications of chronic lung diseases as they show that the anti-infective consumption dramatically decreased with causal treatment of the underlying disease. Yet, current CFTR modulators do not achieve wild-type function of CFTR [10] and current CFTR modulator treatment largely addresses pwCF with irreversible lung damage due to long-standing disease. So far, data suggest that the dysbiosis observed in cystic fibrosis is only partially addressed even by ELX/TEZ/IVA [19–22], the most effective and broadly applicable CFTR modulator therapy developed so far. Until CFTR modulators show even greater improvements of CFTR function and pwCF are treated before the onset of irreversible structural lung damage, symptom-directed anti-infective therapy (e.g. in the event of viral-induced exacerbations and/or loss of lung function) will most likely remain a necessary companion to the causal approach offered by modulator therapies.

AMS in chronic lung disease can be challenging due to the unique aspects of chronic polymicrobial infections, increased frequency of adverse drug events and the lack of evidence-based guidelines. While preservation of lung function in pwCF necessitates frequent antimicrobial use, adverse consequences, such as microbiome alterations in the lung and (more immediately worrisome) in the gut, and development of antimicrobial resistance, occur. Despite these consequences, our data strongly advocate for causal treatment of treatable traits as the most successful AMS strategy for patients with any chronic pulmonary disease.

Similar to CF, the rate of exacerbations as a proxy of insufficient disease control may decrease for other chronic pulmonary diseases, if treated causally. Along that line, for non-cystic fibrosis bronchiectasis, a more heterogenic chronic respiratory disease, a critical treatment approach should focus on the identification of underlying disorders enabling targeted treatment. For example, treatment of immunodeficiency due to hypogammaglobulinaemia with IgG supplementation may reduce the frequency of lower respiratory tract infections and the need for antibiotic therapy [23].

Nevertheless, many of the activities of AMS programmes are broader than restricting antimicrobials. Clinicians may welcome the support of AMS programmes in the choice of less toxic or less expensive antimicrobials when indicated for individualised treatment. AMS interventions reduce overall antimicrobial selective pressure and impact resistance rates in individual institutions. An adaptive and collaborative approach to incorporating AMS into cystic fibrosis and bronchiectasis care requires an interdisciplinary team of physicians and pharmacists from infectious diseases and respiratory medicine, microbiologists, and other front-line practitioners with shared agreement upon the core principles of AMS and their relevance to cystic fibrosis and bronchiectasis [24]. AMS programmes will most likely continue to be highly relevant to cystic fibrosis and bronchiectasis care in order to provide an evidence-based multidisciplinary approach for the optimal treatment of patient populations that remain microbiologically challenging.