Cystic fibrosis (CF), the most common lethal genetic disorder in Caucasians, affects over 60,000 patients worldwide. Its incidence is 1:2500 of live births.1–3 Advances in CF care have been associated with impressive increases in survival during the last 30 years. The mean life expectancy for patients now diagnosed by newborn screening approaches 40 years.1,2 This striking result is mainly because of better treatment of bacterial lung infections, the main cause of pulmonary deterioration.
A relatively limited number of bacteria are involved in lung infections and the prevalence of different pathogens varies according to the patient’s age,1 being usually represented by Staphylococcus aureus in young children and by Pseudomonas aeruginosa (Pa) thereafter. Several emerging pathogens have been described as responsible for severe lung infections, including Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Ralstonia and Pandoraea species, methicillin-resistant S. aureus (MRSA) and nontuberculous mycobacteria (NTM). With aging, recurrent episodes of pulmonary exacerbation cause lung function decline. Because of intensive antibiotic pressure, increasing rates of multidrug-resistant (MDR) bacteria are isolated over time and now represent a major concern. In the absence of adequate isolation measures, bacterial outbreaks have been reported. Burkholderia cepacia complex outbreaks are associated with poor outcomes and sustained mortality rates.1–4
Pa remains the most common bacterial pathogen, detected in about 50% of CF patients overall and in about 80% of adults.1 From a practical point of view, Pa infection is defined chronic when it is detected in >50% of the cultures performed in a time span of 12 months.1 Pa strains isolated in chronic infections usually show a biofilm mode of growth that reduces antimicrobial penetration and allows the bacteria to escape the host’s immune response.
CF patients chronically infected by Pa show a steeper lung function decline (expressed as forced expired volume in 1 second decline over time), a higher number of pulmonary exacerbations, more hospital admissions and higher mortality than Pa-free patients. The effects of Pa are more severe if chronic infection develops early. Therefore, every episode of respiratory exacerbation should be treated with systemic antibiotic therapy.
Long-term inhaled antibiotic therapy is now standard of care for chronic maintenance treatment in stable patients.1,2 Effective antibiotic concentrations can be achieved in the airways by nebulization, avoiding side effects of intravenous antibiotics. Colistimethate sodium has been used by inhalation in Europe for many years. Tobramycin solution for inhalation was introduced in clinical practice after results of a rigorous clinical trial showed lung function improvement and reduction of pulmonary exacerbations. More recently, aztreonam lysine was found to be superior to tobramycin inhalation solution in a 6-month active comparator trial.2
Several randomized trials have clearly demonstrated that inhaled antibiotics (tobramycin and aztreonam lysine) reduce the number of pulmonary exacerbations over time, slow lung function decline, reduce hospitalizations and the need for intravenous antibiotics. The most often adopted inhaled strategy includes an alternate month schedule with tobramycin but other regimens, including continuous therapy with colistimethate sodium or continuous alternating therapy with tobramycin and aztreonam lysine, are currently under investigation.1,2
The recently introduced tobramycin dry powder showed similar efficacy and tolerability to tobramycin inhalation solution with a small increase of coughing. Colistimethate sodium inhalation powder was not inferior to tobramycin inhalation solution on forced expired volume in 1 second change after 24 weeks of treatment.1,2
Inhaled antibiotic therapy is also used to prevent the establishment of a chronic Pa infection by early eradication treatment. Several Pa eradication trials, mainly using inhaled anti-Pa antibiotics, with or without oral quinolones, have been reported.2,5 In the ELITE trial eradication rate reached 90% using a 28-day course of inhaled tobramycin.2,5 In the EPIC trial, no difference in several clinical outcomes was observed adding oral ciprofloxacin to inhaled tobramycin.2,5 In most studies, eradication policies have not yet been proven to lead to improve long-term pulmonary function. This finding could be associated with a short follow-up period after treatment.2 These findings underline that the gold standard for early eradication treatment still has to be established.2
Frequent use of antibiotics, repeated hospitalizations and long-term inhaled tobramycin are considered risk factors for MDR Pa. In Pa isolates from CF patients, many different mechanisms of antibiotic resistance coexist. Restricted permeability and efflux are commonly described for β-lactams, aminoglycosides and quinolones.2 The percentage of patients with MDR Pa strains increases with age.1 The clinical and pulmonary outcomes of patients harboring MDR strains need to be carefully evaluated.
BURKHOLDERIA CEPACIA COMPLEX
B. cepacia complex (Bcc) is a group of at least 17 related species (genomovars) and represents a challenge because of its intrinsic antibiotic resistance. Although infection caused by Bcc may be transient, most patients become chronically infected and about 20% of patients infected by Bcc develop fatal clinical syndrome characterized by necrotizing pneumonia and sepsis, named as “cepacia syndrome”. High mortality rates were associated with B. cepacia complex outbreaks, mainly because of B. cenocepacia or B. multivorans infection.2,3,6 The epidemiology of Bcc is changing. Due to the adoption of strict surveillance and isolation measures, B. cenocepacia outbreaks are decreasing and new B. multivorans infections are now mainly because of environmental acquisition.2,6 Although few studies have examined the efficacy of intravenous antibiotics on Bcc infection, pulmonary exacerbation should be treated with combination antibiotic therapy after susceptibility test results. To date, no consensus exists regarding early eradication treatment and chronic maintenance therapy.2,6
OTHER GRAM-NEGATIVE BACTERIA
Achromobacter xyloxidans (Ax) may play an important role in lung disease as chronic infection has been associated to a deterioration of clinical conditions.2,3,7 The prevalence rates vary considerably among CF centers but are usually higher in adult patients. Several novel species have been recently described in the Achromobacter genus, where Ax accounts for 42% of infections. At present, the virulence of every single species needs to be defined. Meropenem, piperacillin-tazobactam and trimethoprim-sulfamethoxazole are usually active in chemotherapy-naïve Ax strains, whereas isolates from patients chronically infected are highly resistant to antibiotics. A retrospective study recently described the possibility of preventing or delaying chronic Ax infections with early inhaled antibiotic treatment.7 No consensus exists regarding chronic maintenance therapy.
S. maltophilia (Sm) can be responsible of airways infection in CF patients and its prevalence ranges between 3% and 25% in different CF Centers.2,3,8 Such variability is due in part to different diagnostic methods of CF laboratories. Sm is resistant to many antimicrobials (carbapenems, β-lactams and cephalosporins). Doxycycline, chloramphenicol and ticarcillin are the most active antibiotics, inhibiting 80%, 70% and 50% of isolates, respectively. Levofloxacin and trimethoprim-sulfamethoxazole are usually effective.
The role of Sm in CF is still a matter for debate.2,3,8 The clinical impact on lung function is considered modest and its presence in CF airways has no association with shorter survival. However, the chronic presence of the germ in the airways can be considered a risk factor for pulmonary exacerbation and recently Sm infection has been associated with an increased risk of death in the post-transplant period. To date, no clear consensus exists regarding early eradication treatment and chronic maintenance therapy.
The genus Ralstonia has been recovered from respiratory cultures from CF patients with Ralstonia mannitolilytica being the most frequently described species.3 Molecular analysis has confirmed the possibility of chronic infections but the prevalence and clinical impact of the genus Ralstonia has not been systematically studied.
The genus Pandoraea was originally recovered from CF airways’ cultures from isolates originally misidentified as Burkholderia or Ralstonia species. Genus Pandoraea accounts for several species, Pandoraea apista, Pandoraea pnomenusa and Pandoraea sputorum being described with equal frequency.3 The genus Pandoraea is responsible for chronic infection in CF patients. Bacteraemia and cross-infections among patients associated with significant lung function deterioration have also been described. Ralstonia and Pandoraea species are highly resistant to antibiotics.2–4 No clear consensus exists in patients colonized by these species regarding early eradication treatment and chronic maintenance therapy.
METHICILLIN-RESISTANT S. AUREUS
Although methicillin-susceptible S. aureus (MSSA) continues to be an important pathogen in CF,2,3 the emergence of MRSA causes concern. Data from the American CF Foundation Patient Registry show that the prevalence of MRSA infection in CF patients has increased from 4% in 1999 to 25.9% in 2011.1 In a large Register Study population persistent infection with MRSA was found to be associated with higher mortality and an increased rate of lung function decline.2 It is well-known that lung exacerbations sustained by MSSA or MRSA require intensive intravenous antibiotic treatment. It is still under debate whether early treatment of the first MSSA or MRSA infection should be applied to eradicate this pathogen from the CF airways, similar to that currently performed with Pa. Anti-staphylococcal therapy will potentially eradicate a new infection with MSSA.2 Data regarding MRSA eradication in CF populations are scanty instead. Few studies regarding this issue have been published, reporting eradication rates ranging from 58.8% to 94%. Unfortunately, limited numbers of patients were included in these studies and therapeutic protocols largely differ. To date, no clear consensus exists regarding the efficacy of chronic maintenance therapy against S. aureus infections in CF.9 Ongoing studies are evaluating safety and efficacy of aerosolized vancomycin in the treatment of early and persistent MRSA lung infection.
Over the last 20 years, NTM have been increasingly isolated from airways of CF patients.10 The isolates most frequently detected belong to Mycobacterium avium complex and Mycobacterium abscessus complex. NTM may be intermittently isolated in airways’ secretions without causing any clinically relevant effect, but sometimes progressive lung deterioration has also been described. Annual screening for NTM is now recommended and recent surveys have underlined the role of NTM as a CF pathogen. Diagnosis and treatment of NTM pulmonary disease should be conducted according to existing guidelines. Recommendations for antimicrobial treatment are not specific for CF patients, and no evidence exists regarding different efficacy of antibiotic treatment between CF and non-CF patients.
The increase of MDR Pa, other Gram-negative pathogens, MRSA and NTM represent a worrisome phenomenon. Clinical trials to evaluate the role of early eradication therapy for these pathogens and the efficacy of chronic suppressive antibiotic treatment, at the moment clearly demonstrated only for Pa, have yet to be conducted.
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