Changes in strategies for optimal antibacterial therapy in cystic fibrosis

doi:10.1016/S0924-8579(00)00333-2

International Journal of Antimicrobial Agents

Volume 17, Issue 2, February 2001, Pages 93-96

https://doi.org/10.1016/S0924-8579(00)00333-2 Get rights and content

Abstract

Aggressive antibiotic therapy of bacterial airway infection is one of the main reasons for the dramatic increase in life expectancy over the last few decades. Staphylococcus aureus and Haemophilus influenzae are the predominant pathogens in younger patients, but the choice of antibiotic therapy against these pathogens remains highly controversial. There is general agreement that patients with pulmonary exacerbations should be treated and many cystic fibrosis (CF) centres will also try to eradicate bacteria in the absence of symptoms. Prophylactic antibiotic therapy, with anti-staphylococcal medications started at the time of diagnosis, is advocated by some groups but its positive effect remains unproven. In fact, recent studies have suggested that continuous prophylactic treatment with anti-staphylococcal antibiotics may increase the risk of early colonisation with P. seudomonas aeruginosa. P. aeruginosa is the main pathogen in older children with CF. While chronic airway infection with mucoid P. aeruginosa is considered irreversible, both the combination of oral ciprofloxacin with inhaled colistin and inhaled to bramycin alone has been used successfully in the early phase of colonisation. In patients chronically infected with P. aeruginosa, standard treatment of pulmonary exacerbations consists of intravenous combination therapy for 2–3 weeks. Controversy exists whether this treatment should be performed routinely every 3 months or only in the presence of a pulmonary exacerbation. Inhaled antibiotics such as tobramycin have been shown to improve lung function and reduce sputum density of P. aeruginosa, but both the optimal dose and the duration of therapy are unclear at the present time.

Introduction

Although much progress has been made in other areas in the treatment of CF lung disease, bacterial airway infections still dictate the clinical course of CF patients and improvements in antibiotic therapy against respiratory tract infections can be considered the main reason for the increased life expectancy that has been achieved over the last decades [1]. A variety of micro organisms are found in airway cultures from patients with cystic fibrosis, but two bacteria, Staphylococcus aureus and Pseudomonas aeruginosa, remain the most prevalent pathogens in CF lung disease [2]. This article will review the current approach in the antibiotic treatment of S. aureus and P. aeruginosa by highlighting recent advances and areas of controversy.

Section snippets

Diagnosis of airway infection

Antibiotic therapy in CF should be guided by appropriate microbiological cultures of airway secretions in combination with sensitivity tests. While most patients can produce sputum that adequately reflects the bacterial colonisation of the lower respiratory tract, throat swabs are used in younger children and infants, as well as in patients with mild disease. Throat swabs have been shown to lack both sensitivity and specificity especially for pathogens such as P. aeruginosa [3]. Recent studies

S. aureus

Most CF patients are initially colonised with bacterial pathogens such as S. aureus or Haemophilus influenzae. The strategy of antibiotic therapy against these pathogens remains highly controversial. There is general agreement to treat patients who harbour these bacteria in respiratory secretions with antibiotics such as fluclocaxillin, cephalosporins or cotrimoxazole for two to four weeks in the presence of a pulmonary exacerbation [9]. Recent studies with bronchoalveolar lavage in

P. aeruginosa

Whereas the prevalence of S. aureus decreases with age, P. aeruginosa increases in frequency and becomes the main pathogen in older children with CF. The mechanisms favouring initial colonisation are incompletely understood and may include alterations in the airway surface fluid as well as structural differences in airway epithelial cells [17], [18]. Initial colonisation may be transient, but is often followed by a period of persistence of bacteria in the lower airways. Even this form of

References (32)

R.F.H. Taylor et al.
Antibiotic prescribing practice in the UK and Eire
Respir. Med.
(1993)
J.J. Smith et al.
Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid
Cell
(1996)
J. Levy
Antibiotic activity in sputum
J. Pediatr.
(1986)
J.M. Littlewood et al.
Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis
Lancet
(1985)
N.H. Valerius et al.
Prevention of chronic Pseudomonas aeruginosa colonisation by early treatment
Lancet
(1991)
F.C. Fitzsimmons
The changing epidemiology of cystic fibrosis
J. Pediatr.
(1993)
N. Hoiby
Microbiology of lung infections in cystic fibrosis patients
Act. Paed. Scand.
(1982)
B.W. Ramsey et al.
Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients
Am. Rev. Respir. Dis.
(1991)
Khan TZ, Wagener JS,Bost T, Martinez F, Accurso FJ, Early pulmonary inflammation in cystic fibrosis, Am J Respir Crit...
D.S. Armstrong et al.
Lower respiratory infection and inflammation in newly diagnosed cystic fibrosis
Br. Med. J.
(1995)

F. Ratjen et al.

Fractional analysis of bronchoalveolar lavage fluid cytology in cystic fibrosis patients with normal lung function

Eur. Respir. J.

(2000)

S. Copenhaver et al.

BALF PCR and ELISA identification of nonculturable Pseudomonas aeruginosa in infants and toddlers with cystic fibrosis

Pedaitr. Pulmonol.

(1996)

The Cystic Fibrosis Foundation Center Committee and Guidelines Subcommittee. The Cystic Fibrosis Foundation guidelines...

Hoiby N, Frijs B, Jensen K, Koch C, Moller NE, Stovring S, Szaff M, Antimicrobial chemotherapy in cystic fibrosis, Acta...

M. Szaff et al.

Antibiotic treatment of Staph. aureus infection in cystic fibrosis

Acta Paediatr. Scand.

(1982)

Ratjen F, Comes G, Paul K, Posselt HG, Wagner TOF, Harms K, Effect of continuous anti-staphylococcal therapy on the...

Cited by (43)

Cystic Fibrosis Frequently Asked Questions. Question 4: What is the appropriate duration of therapy for respiratory exacerbations in Cystic Fibrosis patients infected with Pseudomonas aeruginosa?
2016, Paediatric Respiratory Reviews
Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients
2014, Clinical Microbiology and Infection
Citation Excerpt :
Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young CF patients, often being replaced later by Pseudomonas aeruginosa [2–4]. The high prevalence of S. aureus in respiratory tract secretions from CF patients has led to different strategies for antimicrobial therapy, including monthly surveillance cultures combined with culture-directed antimicrobial therapy [5], the use of long-term antistaphylococcal therapy [6,7], and treatment depending on clinical symptoms [8]. When S. aureus is repeatedly cultured from a patient's specimens for a prolonged period of time, the patient is categorized as chronically infected.
Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young patients with cystic fibrosis (CF), and several treatment strategies are used to control the infection. However, it is not known whether intensified treatment with antimicrobial agents causes eradication of S. aureus clones. We retrospectively determined the impact of intravenous (IV) antimicrobial agents on the suppression and eradication of S. aureus clones. One thousand and sixty-one S. aureus isolates cultured from 2526 samples from 130 CF patients during a 2-year study period were subjected to spa typing. Intervals between positive samples and the occurrence of clone replacements were calculated in relation to courses of IV antimicrobial agents. Of 65 patients chronically infected with S. aureus, 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6–31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003). When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60–1.61). In conclusion, we show that 2 weeks of IV antimicrobial treatment can significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.
High rhinovirus burden in lower airways of children with cystic fibrosis
2013, Chest
Citation Excerpt :
Our findings emphasize the importance of viral respiratory infections in lower respiratory tract morbidity in young children with CF, especially in those with advanced lung disease, and highlight the potential therapeutic relevance of IFNs because they have been shown to restore antiviral properties in CF in vitro.12 So far, CF therapies are mainly targeted against bacterial infection and/or inflammation.39 There are few therapeutic approaches for the treatment of virus-induced exacerbations, and apart from influenza virus prevention/therapy and passive respiratory syncytial virus immunoprophylaxis, there are no effective antiviral treatment options available.40,41
Rhinovirus (RV)-induced pulmonary exacerbations are common in cystic fibrosis (CF) and have been associated with impaired virus clearance by the CF airway epithelium in vitro. Here, we assess in vivo the association of RV prevalence and load with antiviral defense mechanisms, airway inflammation, and lung function parameters in children with CF compared with a control group and children with other chronic respiratory diseases.
RV presence and load were measured by real-time reverse transcription-polymerase chain reaction in BAL samples and were related to antiviral and inflammatory mediators measured in BAL and to clinical parameters.
BAL samples were obtained from children with CF (n = 195), non-CF bronchiectasis (n = 40), or asthma (n = 29) and from a control group (n = 35) at a median (interquartile range [IQR]) age of 8.2 (4.0-11.7) years. RV was detected in 73 samples (24.4%). RV prevalence was similar among groups. RV load (median [IQR] × 10³ copies/mL) was higher in children with CF (143.0 [13.1-1530.0]), especially during pulmonary exacerbations, compared with children with asthma (3.0 [1.3-25.8], P = .006) and the control group (0.5 [0.3-0.5], P < .001), but similar to patients with non-CF bronchiectasis (122.1 [2.7-4423.5], P = not significant). In children with CF, RV load was negatively associated with interferon (IFN)-β and IFN-λ, IL-1ra levels, and FEV₁, and positively with levels of the cytokines CXCL8 and CXCL10.
RV load in CF BAL is high, especially during exacerbated lung disease. Impaired production of antiviral mediators may lead to the high RV burden in the lower airways of children with CF. Whether high RV load is a cause or a consequence of inflammation needs further investigation in longitudinal studies.
Impact of antibiotic treatment for pulmonary exacerbations on bacterial diversity in cystic fibrosis
2013, Journal of Cystic Fibrosis
A diverse array of bacterial species is present in the CF airways, in addition to those recognised as clinically important. Here, we investigated the relative impact of antibiotics, used predominantly to target Pseudomonas aeruginosa during acute exacerbations, on other non-pseudomonal species.
The relative abundance of viable P. aeruginosa and non-pseudomonal species was determined in sputa from 12 adult CF subjects 21, 14, and 7 days prior to antibiotics, day 3 of treatment, the final day of treatment, and 10–14 days afterwards, by T-RFLP profiling.
Overall, relative P. aeruginosa abundance increased during antibiotic therapy compared to other bacterial species; mean abundance pre-antibiotic 51.0 ± 36.0% increasing to 71.3 ± 30.4% during antibiotic (ANOVA: F_1,54 = 5.16; P < 0.027). Further, the number of non-pseudomonal species detected fell; pre-antibiotic 6.0 ± 3.3 decreasing to 3.7 ± 3.3 during treatment (ANOVA: F_1,66 = 5.11; P < 0.027).
Antibiotic treatment directed at P. aeruginosa has an additional significant impact on non-pseudomonal, co-colonising species.
Genetic fingerprinting and antimicrobial susceptibility profiles of Staphylococcus aureus strains isolated from children with cystic fibrosis
2012, Pediatria Polska
The pathophysiology of cystic fibrosis (CF) is associated with genetically determined abnormal chloride conductance on the apical membrane of the epithelial cell. As a result favourable environment for bacterial and fungal infections is maintained. Respiratory tract infections in CF patients are caused mainly by Staphylococcus aureus, Haemphilus influenzae, and Pseudomonas aeruginosa which is the most destructive pulmonary pathogen.
The aim of this study was to analyse genetic diversity and antimicrobial susceptibility of Staphylococcus aureus strains isolated from children with cystic fibrosis.
A total of 21 patients with confirmed cystic fibrosis were included to the study. Within 8 years 257 specimens from the respiratory tract were collected, and 201 isolates of S. aureus were cultured. Genotyping was performed using the pulsed field gel electrophoresis (PFGE) technique, and antimicrobial susceptibility was determined by the E-test method. The following data were retrieved from medical records: age at CF diagnosis, clinical signs and symptoms, respiratory function (FEV₁), frequency of hospitalization and antibiotic use.
The mean age of patients studied was 7 years (range 0.5–16 years). Over 80% of patients had pulmonary manifestations. The genotyping confirmed that Staphylococcus aureus persistently colonized the respiratory tract of patients with CF. For over 95% of strains the colonization lasted from 6 months to 8 years. Less than 5% of strains did not show a tendency for a long-term colonization, and they were isolated only once. In 34% of patients the same genotype was isolated through the study period, and it could not be eradicated despite antibiotic treatment. As many as 62% of children were persistently colonized with 2 or 3 strains simultaneously. Over 94% of strains were susceptible to β-lactams, fluoroquinolones, trimethoprim/sulfamethoxazole, aminoglycosides, and glycopeptides. The highest rates of resistance were observed for macrolides (23%) which were the second most commonly used antibiotics in bronchopulmonary exacerbations. Some of S. aureus strains were effectively transmitted among the patients. However, only methicillin-susceptible isolates (MSSA) were involved in the transmission. MRSA transmission was not detected.
Novel concepts in evaluating antimicrobial therapy for bacterial lung infections in patients with cystic fibrosis
2011, Journal of Cystic Fibrosis
Citation Excerpt :
The high prevalence of bacterial airway infections in CF patients is linked to mutations in an epithelial chloride channel, the CF transmembrane conductance regulator (CFTR), that result in a number of defects in innate immunity and airway clearance [1]. Antibiotic treatment of these infections remains a cornerstone of therapy, with improvements in this field considered to be a major factor in the increased life expectancy that has been achieved over recent decades [2–5]. Since chronic lung disease is the main determinant of morbidity and mortality in CF [6–8], and infections are thought to be a key driver of CF lung disease [9,10], the issues surrounding antibiotic usage have important implications for the prognosis of these patients.
Cystic fibrosis (CF) patients suffer typically from bacterial infections of their airways. Whilst current antibiotic-based treatment of these infections has brought much benefit to patients, it has been difficult to make either direct or indirect assessments of the in vivo efficacy of any specific treatment used. Traditional culture-based assessment has for example been rarely used to determine the direct impact of therapy on the bacteria in the airways. Instead, the “success” of a treatment is most often gauged through measures of respiratory and general health. New culture-independent approaches though are emerging that offer much promise here however in allowing a more comprehensive evaluation of antimicrobial efficacy. These new methods offer an opportunity to examine bacterial outcomes rather than host outcomes alone. Application of these novel techniques in a systematic way will lead to the rationalisation and, likely greater still individualisation, of therapy for CF patients. This review discusses host and microbiological factors that may influence antibiotic efficacy. Moreover, the degree to which the inherent complexity of CF respiratory infections complicates the process of determining treatment impact and the need to identify more robust microbiological outcome measures will also be reviewed.

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International Journal of Antimicrobial Agents

Abstract

Introduction

Section snippets

Diagnosis of airway infection

S. aureus

P. aeruginosa

References (32)

Antibiotic prescribing practice in the UK and Eire

Respir. Med.

Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid

Cell

Antibiotic activity in sputum

J. Pediatr.

Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis

Lancet

Prevention of chronic Pseudomonas aeruginosa colonisation by early treatment

Lancet

The changing epidemiology of cystic fibrosis

J. Pediatr.

Microbiology of lung infections in cystic fibrosis patients

Act. Paed. Scand.

Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients

Am. Rev. Respir. Dis.

Lower respiratory infection and inflammation in newly diagnosed cystic fibrosis

Br. Med. J.

Fractional analysis of bronchoalveolar lavage fluid cytology in cystic fibrosis patients with normal lung function

Eur. Respir. J.

BALF PCR and ELISA identification of nonculturable Pseudomonas aeruginosa in infants and toddlers with cystic fibrosis

Pedaitr. Pulmonol.

Antibiotic treatment of Staph. aureus infection in cystic fibrosis

Acta Paediatr. Scand.

Cited by (43)

Cystic Fibrosis Frequently Asked Questions. Question 4: What is the appropriate duration of therapy for respiratory exacerbations in Cystic Fibrosis patients infected with Pseudomonas aeruginosa?

Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients

High rhinovirus burden in lower airways of children with cystic fibrosis

Impact of antibiotic treatment for pulmonary exacerbations on bacterial diversity in cystic fibrosis

Genetic fingerprinting and antimicrobial susceptibility profiles of Staphylococcus aureus strains isolated from children with cystic fibrosis

Novel concepts in evaluating antimicrobial therapy for bacterial lung infections in patients with cystic fibrosis

ReviewChanges in strategies for optimal antibacterial therapy in cystic fibrosis

Abstract

Introduction

Section snippets

Diagnosis of airway infection

S. aureus

P. aeruginosa

Respir. Med.

Cell

J. Pediatr.

Lancet

Lancet

The changing epidemiology of cystic fibrosis

J. Pediatr.

Microbiology of lung infections in cystic fibrosis patients

Act. Paed. Scand.

Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients

Am. Rev. Respir. Dis.

Lower respiratory infection and inflammation in newly diagnosed cystic fibrosis

Br. Med. J.

Fractional analysis of bronchoalveolar lavage fluid cytology in cystic fibrosis patients with normal lung function

Eur. Respir. J.

BALF PCR and ELISA identification of nonculturable Pseudomonas aeruginosa in infants and toddlers with cystic fibrosis

Pedaitr. Pulmonol.

Antibiotic treatment of Staph. aureus infection in cystic fibrosis

Acta Paediatr. Scand.

Review
Changes in strategies for optimal antibacterial therapy in cystic fibrosis