What is the optimum duration of antibiotic therapy to treat chest exacerbations in CF?
In this article…
- The significance of respiratory infections in cystic fibrosis
- Use of intravenous antibiotics to treat respiratory infections
- Variations in treatment regimens
5 key points
- Life expectancy for people with cystic fibrosis has risen in the past 40 years to over 50
- Respiratory disease is the major cause of mortality and morbidity in CF
- Antibiotic therapy is a major reason for increased life expectancy in CF
- Antibiotic resistance is common in people with CF
- Response to therapy can be used as a guide to decide optimum duration of therapy
Keywords: Cystic fibrosis, Intravenous antibiotics, Respiratory infection
- This article has been double-blind peer reviewed
Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder in Caucasians, and respiratory disease is the major cause of mortality and morbidity in people with the condition (Penketh et al, 1987).
About 40 years ago, most people with CF died in their first decade of life and median life expectancy was two years, but the current projected median survival is over 50 years of age (Dodge et al, 2007).
The use of intravenous antibiotics to treat chest exacerbations caused by bacterial infections has led to this dramatic increase in life expectancy. A Cochrane systematic review investigated whether there was an optimum duration of antibiotic therapy to treat respiratory infections in CF.
Infective organisms in CF
At birth the lungs of infants with CF are normal, but many become infected with bacteria soon after (Accurso, 1997).
The most common organism isolated from the sputum of adults is Pseudomonas aeruginosa(Horre et al, 2004)which is associated with a rapid decline in lung function (Emerson, 2002). Prevalence data from the UK indicates that 45% of 16-19-year-olds with CF have chronic P aeruginosa infection; this rises to 67% in 28-31-year-olds (Cystic Fibrosis Trust, 2009).
At the time of initial infection, P aeruginosa is usually susceptible to antibiotics but, with repeated courses, patients often develop drug resistance (Gilligan, 1999). Multi-resistant P aeruginosa is associated with more severe lung disease, more rapid decline in FEV1 and progression to end-stage lung disease (Lechtzin et al, 2006). People with CF with multi-resistant P aeruginosa need longer courses of IV antibiotics, more courses per year and more hospital visits (Lechtzin et al, 2006), while these epidemic strains can spread among people with CF.
Other organisms that infect people with CF and are known to be multi-resistant to antibiotics areBurkholderia cepacia complex,Stenotrophomonas maltophiliaand Achromobacter xyloxidans (Elborn, 2004).
Intravenous antibiotic therapy
IV antibiotics for respiratory infections in CF are usually given in combinations to reduce the risk of drug resistance developing.
The choice of antibiotics is often based on culture results of airway secretions. If a suitable antibiotic combination is chosen, response to treatment is usually good. Deciding on an optimal combination depends on: the type of organisms; antibiotic sensitivity; allergies; previous response to treatment; and local policies.
The duration of these courses of IV antibiotics varies and are often 10-21 days (CF Trust, 2009), but optimal duration is not clearly defined. However, response to therapy (Box 1) can be used to guide clinicians (CF Trust, 2009).
- Improved pulmonary function
- Oxygen saturation returning to pre-exacerbation levels
- Levelling-off of weight loss
- Normalisation or significant falls in inflammatory markers
- Decreased bacterial density in sputum
Patients are usually given a 14-day course of IV antibiotics (CF Trust, 2009), which may be extended in those with severe exacerbations and incomplete recovery (Doring et al, 2000). However, some studies mention 10 days (CF Trust, 2009; Doring et al, 2000) and 21 days (Gibson et al, 2003; Ramsey, 1996) as the required duration. With shorter courses, there is a risk that the infection will not be cleared, which could lead to further lung damage, while prolonged courses are expensive, inconvenient to patients, and associated with increased incidence of allergic reactions (Parmar and Nasser, 2005).
In addition, when aminoglycosides are used, frequent monitoring of antibiotic levels is necessary to avoid side-effects such as ototoxicity and nephrotoxicity.
Objectives of the review
To assess the optimal duration of IV antibiotic therapy for treating chest exacerbations in people with CF.
It included studies whose participants were people with CF, of all ages and with all degrees of disease severity, who were being treated with IV antibiotics for an acute chest exacerbation.
The authors searched for studies comparing different durations of IV antibiotic courses – the same drugs at the same dosage, the same drugs at a different dosage or frequency, or different antibiotics altogether. A range of outcome measures were included, such as:
- Lung function;
- Change in sputum bacteriology;
- Adverse effects of antibiotics;
- Quality of life;
- Time to next exacerbation;
- Change in inflammatory markers;
- Development of antibiotic-resistant strains.
A total of 220 papers were obtained but none were eligible for inclusion in the review.
While every effort needs to be focused on treating chest infections aggressively, there are no clear guidelines on the optimum duration of IV antibiotics.
Most studies show chest exacerbations are treated for 14 days routinely (Burkhardt et al, 2006; Aaron et al, 2005; Smyth et al, 2005); however, others show 10 days are sufficient (Master et al, 2001; Penketh et al, 1984)while Mendelman et al (1985) found 21 days more effective.
None of these studies is a randomised controlled trial comparing different durations of antibiotic courses and the trials are therefore not eligible to be included in the review. There are no clear reasons for choosing 14 or 21 days as the optimum duration.
Not all exacerbations are due to the usual bacteria known to infect the lungs of people with CF viruses, atypical bacteria and fungi are also implicated (Olesen et al, 2006). Since it is difficult to distinguish between these exacerbations, clinicians usually err on the side of caution and treat them with antibiotics.
In most adults and adolescents with CF, it is almost impossible to eradicate the infecting bacterial organism, so extending duration of antibiotic therapy would not be expected to result in clearance of infection. Unlike acute infections associated with other diseases, the duration of antibiotic therapy for CF exacerbations should, therefore, probably be based on improvement in clinical status rather than on attempts to render the airways sterile of bacteria.
Reducing treatment to 10 days may improve quality of life and adherence while cutting costs and drug reactions. However, it is uncertain whether this is long enough to clear a chest infection and does not result in an early recurrence of next exacerbation. Also, multi-resistant organisms may need longer duration to treat them effectively.
Implications for practice
There are no published data to recommend the optimum duration of IV antibiotic therapy for treating exacerbations in CF.
Duration of treatment is decided based on unit policies and the individual’s response to treatment and the review found no evidence to change this practice.
The authors recommend a well-designed, multi-centre RCT be undertaken to assess the optimum duration of IV antibiotic therapy. They suggest randomising participants to receive either seven, 10, 14 or 21 days of IV antibiotics and comparing
outcome measures. They add long-term follow-up will be needed to monitor the time to next exacerbation, frequency of chest exacerbations and development of antibiotic-resistant strains. NT
For the full Cochrane review click here
Aaron SD et al (2005) Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. The Lancet; 366: 9484, 463-471.
Accurso FJ (1997) Early pulmonary disease in cystic fibrosis. Current Opinion in Pulmonary Medicine; 3: 6, 400-403.
Burkhardt O et al (2006) Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development? Journal of Antimicrobial Chemotherapy; 58: 4, 822-829.
Cystic Fibrosis Trust (2009) Antibiotic Treatment for Cystic Fibrosis. London: CF Trust.
Dodge JA et al (2007) Cystic fibrosis mortality and survival in the UK: 1947-2003. European Respiratory Journal; 29: 3, 522-526.
Doring G et al (2000) Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. European Respiratory Journal; 16 4, 749-767.
Emerson J (2002) Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatric Pulmonology; 34: 2, 91-100.
Elborn JS (2004) Difficult bacteria, antibiotic resistance and transmissibility in cystic fibrosis. Thorax; 59: 11, 914-915.
Gibson RL et al (2003) Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine; 168: 8, 918-951.
Gilligan PH (1999) Microbiology of CF Lung Disease. In: Yankaskas JR, Knowles MR (eds) Cystic Fibrosis in Adults. Philadelpia PA: Lippincott.
Horre R et al (2004) Isolation of fungi, especially Exophiala dermatitidis, in patients suffering from cystic fibrosis. Respiration; 71: 4, 360-366.
Lechtzin N et al (2006) Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration; 73: 1, 27-33.
Master V et al (2001) Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study. Pediatric Pulmonology; 31: 5, 367-376.
Mendelman PM et al (1985) Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis sputum. American Review of Respiratory Disease; 132: 4, 761-765.
Olesen HV et al (2006) Viral and atypical bacterial infections in the outpatient pediatric cystic fibrosis clinic. Pediatric Pulmonology; 41: 12, 1197-1204.
Parmar JS, Nasser S (2005) Antibiotic allergy in cystic fibrosis. Thorax; 60: 6, 517-520.
Penketh AR et al (1987) Cystic fibrosis in adolescents and adults. Thorax; 42: 7, 526-532.
Penketh A et al (1984) Azlocillin compared with carbenicillin in the treatment of bronchopulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis. Thorax; 39: 4, 299-304.
Ramsey BW (1996) Management of pulmonary disease in patients with cystic fibrosis. New England Journal of Medicine; 335: 3, 179-188.
Smyth A et al (2005) Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis – the TOPIC study: a randomised controlled trial. The Lancet; 365: 9459, 573-538.