SEMINARS FOR CLINICIANS

Antibiotic Management of Lung Infections in Cystic Fibrosis

II. Nontuberculous Mycobacteria, Anaerobic Bacteria, and Fungi
James F. Chmiel1, Timothy R. Aksamit2, Sanjay H. Chotirmall3, Elliott C. Dasenbrook4, J. Stuart Elborn5,
John J. LiPuma6, Sarath C. Ranganathan7, Valerie J. Waters8, and Felix A. Ratjen9
1
Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children’s Hospital,
Cleveland, Ohio; 2Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester,
Minnesota; 3Department of Respiratory Medicine, Beaumont Hospital, Dublin, Republic of Ireland and Lee Kong Chian School of
Medicine, Nanyang Technological University, Singapore; 4Departments of Medicine and Pediatrics, Case Western Reserve University
School of Medicine and University Hospitals Case Medical Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio; 5Medicine
and Surgery, Queens University Belfast and Belfast City Hospital, Belfast, Northern Ireland, United Kingdom; 6Department of Pediatrics
and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; 7Department of Respiratory Medicine, Royal
Children’s Hospital, Infection and Immunity Theme, Murdoch Children’s Research Institute, and Department of Pediatrics, University of
Melbourne, Melbourne, Australia; and 8Division of Infectious Diseases and 9Division of Respiratory Medicine, Department of Pediatrics,
University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada

Abstract best guided by a team of specialized clinicians and microbiologists.

The ability of anaerobic bacteria to contribute to CF lung disease
Airway infections are a key component of cystic fibrosis (CF) lung is less clear, even though clinical relevance has been reported
disease. Whereas the approach to common pathogens such as in individual patients. Anaerobes detected in CF sputum are
Pseudomonas aeruginosa is guided by a significant body of often resistant to multiple drugs, and treatment has not yet been
evidence, other infections often pose a considerable challenge to shown to positively affect patient outcome. Fungi have gained
treating physicians. In Part I of this series on the antibiotic significant interest as potential CF pathogens. Although the role
management of difficult lung infections, we discussed bacterial of Candida is largely unclear, there is mounting evidence that
organisms including methicillin-resistant Staphylococcus aureus, Scedosporium species and Aspergillus fumigatus, beyond the
gram-negative bacterial infections, and treatment of multiple classical presentation of allergic bronchopulmonary aspergillosis, can
bacterial pathogens. Here, we summarize the approach to be relevant in patients with CF and treatment should be considered. At
infections with nontuberculous mycobacteria, anaerobic bacteria, present, however there remains limited information on how best to
and fungi. Nontuberculous mycobacteria can significantly impact select patients who could benefit from antifungal therapy.
the course of lung disease in patients with CF, but differentiation
between colonization and infection is difficult clinically as Keywords: anaerobic bacteria; Aspergillus fumigatus;
coinfection with other micro-organisms is common. Treatment Mycobacterium abscessus; Mycobacterium avium complex;
consists of different classes of antibiotics, varies in intensity, and is Scedosporium species complex

(Received in original form May 12, 2014; accepted in final form August 7, 2014 )
Supported by National Institutes of Health grant P30-DK27651. The U.S. Cystic Fibrosis Foundation is gratefully acknowledged.
Author Contributions: J.F.C. organized the manuscript; wrote the abstract, introduction, and summary; and edited the manuscript. E.C.D. reviewed, edited,
and revised the manuscript and organized the references. J.J.L. reviewed, edited, and revised the manuscript. V.J.W. created Table 1 and reviewed, edited, and
revised the manuscript. J.S.E. reviewed, edited, and revised the manuscript. T.R.A. was the lead author for the section on nontuberculous mycobacteria and
created Figure 1. S.H.C. was the lead author for the section on fungi. S.C.R. was the lead author for the section on anaerobic bacteria. F.A.R. co-wrote the
abstract, introduction, and summary, and served as the deciding editor of the manuscript.
Correspondence and requests for reprints should be addressed to James F. Chmiel, M.D., M.P.H., Division of Pediatric Pulmonology and Allergy/Immunology,
Room 3001, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44106. E-Mail: [email protected]
Ann Am Thorac Soc Vol 11, No 8, pp 1298–1306, Oct 2014
Copyright © 2014 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201405-203AS
Internet address: www.atsjournals.org

Lung disease accounts for the majority of the Staphylococcus aureus, Haemophilus Achromobacter species (2). Many of these
morbidity and mortality in cystic fibrosis influenzae, Pseudomonas aeruginosa, bacteria have been associated with a decline
(CF) (1). Bacteria typically found in airway Burkholderia cepacia complex, in lung function in CF (3–6). However,
secretions of patients with CF include Stenotrophomonas maltophilia, and other microorganisms have been isolated

1298 AnnalsATS Volume 11 Number 8 | October 2014

 SEMINARS FOR CLINICIANS

from CF lung fluids including than 15 years and increases with age, has other NTM isolates. Therefore, close
nontuberculous mycobacteria (NTM), been estimated to be 13–20% (9–11). collaboration with the infection control
anaerobic bacteria, and fungi. Although the Mycobacterium avium complex (MAC) and team and abiding by infection control
isolation of some of these microorganisms Mycobacterium abscessus represent the procedures in CF and bronchiectasis
is temporally associated with deterioration two most common NTM species causing clinics, including respiratory isolation for
in baseline health in some individuals, it infection in CF. Accelerated loss of lung patients with M. abscessus, is warranted in
is not clear whether they are relevant function has been observed in patients with outpatient as well as inpatient settings to
pathogens in all patients. Clinicians must M. abscessus (12). In patients with CF prevent transmission of M. abscessus in
discern how to proceed if one of these under evaluation for lung transplantation, high-risk situations.
organisms is isolated in the absence of up to 20% of patients were found to The diagnosis of NTM lung disease is
clinical manifestations, changes in lung have NTM (13). M. abscessus in particular based on criteria outlined by the ATS,
function, or radiographic changes. In is associated with worse outcome and the including a combination of clinical,
addition, the clinician must also balance the need for NTM treatment posttransplantation radiographic, and microbiologic elements
potential for development of toxicities from (13). As a result, many transplant centers (9). It is worth noting that in most
prescribed therapies with the possibility of now consider the presence of NTM lung circumstances and for most NTM
beneficial effect. Further complicating the disease a relative contraindication for respiratory isolates (especially MAC), one
decision on whether treatment should be transplantation (13). positive culture, especially with low
initiated is the need to determine the best NTM is ubiquitous in water and soil, numbers of organisms, smear negative, or
therapeutic regimen for the individual and can frequently be isolated from growth on liquid media only, is not
patient. These regimens may carry a large residential sources including showerheads adequate to establish a diagnosis of NTM
treatment burden and interfere with other and other home water sources (14–16). Peat lung disease. A presumptive diagnosis
therapies. moss exposure in some studies has been based on clinical and radiographic features
A scientific symposium was held at the identified as a potential exposure risk for is equally inappropriate for the initiation
2013 American Thoracic Society (ATS) NTM lung disease (14, 17, 18). However, of empiric therapy. As such, longitudinal
International Conference in Philadelphia, case–control studies have not clearly monitoring and multiple cultures may
Pennsylvania to discuss the management demonstrated an association between be required before a diagnosis of NTM
of difficult-to-treat lung infections in CF. exposure to residential water sources or lung disease is firmly established. Further
From this symposium, two companion other activities including gardening and contributing to this conundrum is the
manuscripts were written to summarize NTM lung disease (19). Furthermore, well-recognized waxing and waning of
the current evidence presented at that patient NTM isolates do not always match radiographic abnormalities, without
meeting. In Part I, the lung microbiome, environmental NTM isolates, matching in overall radiographic progression, that is
methicillin-resistant S. aureus, gram-negative 22–41% of cases when the same MAC known to occur in patients with NTM
bacteria, and the treatment of multiple species were isolated (14, 16). Nonetheless, lung disease regardless of treatment
infections in CF were discussed (7). In this certain environmental precautions may status. Establishing a more certain
article (Part II), NTM, anaerobic bacteria, reduce exposure. Simple environmental diagnosis before committing to treatment
and fungi are discussed. Practical treatment controls implemented at home that may of NTM lung disease is thus required.
approaches are discussed in both articles. reduce exposure to NTM include increasing Overdiagnosis results in the unnecessary
These approaches summarize the current the temperature of hot water heaters to exposure to complicated drug regimens,
evidence. However, it is imperative to greater than 1308 F, installing large droplet and underdiagnosis may result in the
recognize that these treatment approaches showerheads to reduce aerosolization, development of progressive lung disease
are evolving as the results of ongoing and avoiding tap water rinses of equipment and with irreversible loss of lung function from
future research studies become available. avoiding tap water mouth rinses before inadequate treatment.
The reader should realize that these sputum collection, and avoiding peat moss The decision regarding whether to treat
documents are not portrayed as guideline dust exposure by wearing a facemask NTM lung disease must therefore balance
documents or consensus recommendations. and moistening the soil before working the risks and benefits of treatment versus
The discussions contained within these with it (18, 20). It is not clear, however, observation. Individualized patient factors
articles are not meant to represent the whether these risk modifications impact include the risk of progression, goals
finish line for treating lung infections in CF the development of NTM lung disease. of therapy (sputum conversion vs.
but rather should be taken to represent the Reports of the transmissibility of M. suppression), status of comorbid medical
starting line. abscessus species in two outpatient CF conditions (gastroesophageal reflux, sinus
clinics is worth noting given the previous disease, and bronchiectasis), medication
experience of lack of human-to-human tolerance, and patient acceptance (Figure 1).
Nontuberculous Mycobacteria transmissibility of NTM lung disease (21, Similarly, the intensity of the NTM regimen
22). Although both reports describe the should be proportionate to disease severity
NTM lung infections are increasingly transmissibility of M. abscessus ssp. and goals of therapy. In the case of MAC
observed in the general population and in massiliense, it is unclear whether the risk lung disease, the treatment options range
patients with CF (8). The incidence of of transmission is restricted to only this from observation to three times weekly oral
NTM lung disease in patients with CF, subspecies or whether it may be therapy to daily therapy plus parenteral
which most often occurs in patients older generalized to all M. abscessus or even therapy. Special attention regarding

Seminars for Clinicians 1299

 SEMINARS FOR CLINICIANS

po Daily for 14 days before a determination of

plus Injectable macrolide susceptibility and, by inference, the
Observation po 3×/week po Daily plus nebulized presence or absence of an active erm gene.
Other potential mechanisms of drug
resistance have been described, but the
clinical significance of these requires further
Diagnosis + / – Treatment study (36). Thus, the approach to the
treatment of M. abscessus ssp. abscessus lung
Disease severity (risk of progression) disease most often involves a regimen
Goals (sputum conversion vs. suppression)
Co-morbid conditions
including other nonmacrolide agents, such as
Gastroesophageal reflux disease amikacin with a combination of two or more
Sinus disease additional antibiotics including cefoxitin or
Bronchiectasis imipenem, tigecycline, or linezolid. In the
Medication tolerance absence of inducible macrolide resistance or
Patient acceptance
Cost an active erm gene, regimens for M. abscessus
ssp. bolletii (M. massiliense) should include
Figure 1. Determining treatment of nontuberculous mycobacteria (NTM) lung disease requires clarithromycin or azithromycin in addition to
assessment of diagnostic strategies, treatment options, and individualized risk–benefit analyses. multiple other antibiotics. A typical practice
When deciding whether to treat a patient with NTM lung disease, the risk and benefits of treatment pattern, even without clear supporting data in
must be weighed against observation. This decision is influenced by many factors including the risk of the literature, is to begin with an intensive
progression, goals of therapy, and patient factors. Po = per os (by mouth). treatment regimen including both parenteral
and oral agents followed by deescalation to
macrolide use for antiinflammatory with variable clinical response to an inhaled and oral regimen after a period of
purposes is warranted to avoid the macrolide-based regimens for M. abscessus weeks or months. The timing and specifics of
development of resistance in macrolide- (33–35). This may also explain some of the this transition can be particularly variable
susceptible NTM lung disease (23–27). CF apparent macrolide resistance in other given the essential need to avoid
guidelines have reaffirmed the need to NTM organisms such as M. fortuitum. This monotherapy and to maintain a multidrug
screen patients at baseline and then every is in contrast to M. chelonae, which does regimen with effective nonparenteral agents;
6–12 months (28). This recommendation not express an active erm gene. The erm the efficacy of which must be weighed against
has not changed despite preliminary data gene encodes enzymes that methylate the the risks of toxicity and the technical
not finding increased macrolide resistance 23S ribosomal RNA within the 50S challenges of extended use of parenteral
in CF patients with NTM infections ribosomal subunit, resulting in reduced agents. Consultation with a pulmonary
receiving chronic macrolide therapy (29). binding affinity of macrolides for their disease, infectious disease, and/or NTM
Specific treatment regimens for NTM specific target, to impair protein synthesis. expert is generally recommended. Common
lung disease are outlined in the ATS The additional importance of the presence treatment regimens for NTM lung disease are
statement (9). Although these or absence of an active erm gene is given in Table 1. Surgical resection in
recommendations remain appropriate for highlighted by the difference between conjunction with medical therapy should be
treating MAC lung disease, the use of M. abscessus subspecies. M. abscessus ssp. considered for localized cavitary NTM lung
nebulized amikacin and increased abscessus has universal expression of an disease, macrolide-resistant MAC lung
understanding of the various treatment active erm gene conferring macrolide disease, and M. abscessus ssp. abscessus lung
approaches for M. abscessus lung disease resistance whereas other M. abscessus disease in highly selected patients. Surgery,
warrant special comment. Inhaled amikacin subspecies, such as M. abscessus ssp. bolletii, when considered, should be undertaken by
has been increasingly used for the also known as M. massiliense, do not an experienced team of mycobacterial
treatment of both MAC and M. abscessus express an active erm gene. It is important physicians including surgeons with robust
lung disease despite limited published to note, however, that even in the absence experience in mycobacterial lung surgery.
clinical experience (30–32). Dosing of of the erm gene, NTM species may be In summary, NTM lung disease in
nebulized amikacin is variable but most resistant to macrolides through other patients with CF presents variably and
often ranges between 250 and 500 mg once mechanisms. Expression of the erm gene remains a complex problem with respect to
or twice daily. Higher dosing is generally can be variable; there are some data to establishing a diagnosis and treatment
less well tolerated (32). Results from suggest that clarithromycin induces program when indicated. Longitudinal
a completed phase 2 study of liposomal greater expression of the gene than does follow-up may be required before specific
amikacin for refractory NTM lung disease azithromycin (34). The inclusion of treatment recommendations can be made.
are expected to be released soon. The use of a macrolide in treatment regimens for M. Patients with CF with NTM lung disease are
nebulized amikacin when treating NTM abscessus lung disease thus relies heavily on best cared for by teams of clinicians
lung disease should be considered as part of the presence or absence of an active erm gene experienced in the care of patients with
a multidrug mycobacterial regimen. or, as a surrogate, differentiation of M. mycobacterial infections and who work
The recognition of a variably expressed abscessus ssp. abscessus from M. abscessus ssp. closely with their laboratory colleagues to
erythromycin ribosomal methylation (erm) bolletii (M. massiliense). Initial M. abscessus optimize the timing and intensity of
gene in M. abscessus has been associated isolates should be incubated with macrolide multidrug mycobacterial lung disease

1300 AnnalsATS Volume 11 Number 8 | October 2014

 SEMINARS FOR CLINICIANS

Table 1. Empiric antibiotic therapy for the treatment of nontuberculous mycobacteria lung infections in cystic fibrosis*

Organism Antibiotic Pediatric Dose Adult Dose Side Effects

Mycobacterium Clarithromycin or azithromycin† Clarithromycin 15 mg/kg Clarithromycin 500 mg GI, ototoxicity

abscessus orally (max 500 mg) twice orally twice daily or
daily or azithromycin azithromycin 250–500 mg
5 mg/kg/d (max 250 mg) orally daily
‡
Plus amikacin 10–30 mg/kg intravenously 10–30 mg/kg intravenously Ototoxicity,
daily or 25–30 mg/kg three daily or 25–30 mg/kg nephrotoxicity
times weekly followed by three times weekly
250–500 mg nebulized daily followed by 250–500 mg
to twice daily nebulized daily to twice
daily
And cefoxitin 200–250 mg/kg/d in divided 200–250 mg/kg/d in divided GI, rash,
doses (max 12 g) doses (max 12 g) myelosuppression
Or imipenem 60–100 mg/kg/d intravenously 1–2 g intravenously divided GI, rash,
divided doses (max 2 g) doses myelosuppression,
rarely seizures
Or tigecycline 1.2 mg/kg intravenously every 25–50 mg daily intravenously GI, cholestasis,
12 h (max 50 mg) myelosuppression
Or linezolid (include If , 11 yr: 10 mg/kg 300–600 mg intravenously or Optic/peripheral
pyridoxine 50 mg daily) intravenously or orally every orally daily to twice daily neuropathy,
8h myelosuppression
If . 11 yr: 10 mg/kg (max
600 mg) intravenously or
orally daily to twice daily
Mycobacterium Clarithromycin or azithromycin Clarithromycin 15 mg/kg orally Clarithromycin 500 mg orally GI, ototoxicity
avium complex (max 500 mg) twice daily or twice daily or azithromycin
azithromycin 5 mg/kg/d (max 250–500 mg orally daily
250 mg)
Plus rifampin 10–20 mg/kg orally once daily 450–600 mg orally once daily Hepatotoxicity,
(max 600 mg) body fluid
discoloration
And ethambutol 15 mg/kg orally once daily 15 mg/kg orally once daily Optic/peripheral
neuritis
Plus for advanced disease: 10–30 mg/kg intravenously 10–30 mg/kg intravenously Ototoxicity,
amikacin‡ daily or 25–30 mg/kg three daily or 25–30 mg/kg three nephrotoxicity
times weekly followed by times weekly followed by
250–500 mg nebulized daily 250–500 mg nebulized daily
to twice daily to twice daily

Definition of abbreviations: GI = gastrointestinal; min, minimum; max, maximum.

*The antibiotic doses given come from a compilation of sources and practice patterns including commonly prescribed off-label doses and uses. Sources
include the pharmacy formulary of the Hospital for Sick Children (Toronto, ON, Canada), which is based on product inserts and the published literature.
The doses given are general guidelines, and may vary somewhat between institutions. It is recommended that the clinician consult his/her institution’s
pharmacy, product inserts, and published literature before prescribing these drugs. Consultation with a pulmonary disease, infectious disease, and/or
nontuberculous mycobacteria expert to individualize treatment regimens is recommended.
†
Consider alternative antibiotic if the erm gene (encoding inducible macrolide resistance) is detected or inducible macrolide resistance is noted.
‡
Serum concentrations should be monitored, and aim for a maximal serum concentration (Cmax) in the range of 80–120 mg/L with a minimal serum
concentration (Cmin) of less than 1 mg/L. Alternatively, peak levels may also be used with a target peak serum level between 20 and 35 mg/ml. It is
known that patients with CF generally have an increased volume of distribution and more rapid clearance, which may require higher dosing than for others
without CF.

treatment regimens, carefully weighing risks Obligate anaerobes have been implicated appropriate. Several studies on tracheal
and benefits and, when necessary, also in a number of non-CF infections, such aspirates, sputum, or bronchoalveolar
considering surgical intervention. as infections of the upper respiratory lavage (BAL) fluid have confirmed the
tract and aspiration pneumonia. Steep presence of anaerobes in the lower
oxygen gradients exist within CF mucus airways in CF in up to 80% samples and
Anaerobic Bacteria such that even at relatively shallow at bacterial densities of between 10 7 and
depths within mucus, the environment is 109 colony-forming units/ml in sputum
Anaerobes are organisms that do not require considered to be hypoxic, or even frankly (38–43). The most common genera
oxygen for growth. They can be obligate or anaerobic (37). Conventional culture- identified were Prevotella, Veillonella,
facultative; P. aeruginosa is an example of dependent approaches are not optimized Propionibacterium, Actinomyces,
the latter. In this state, P. aeruginosa exists for identifying anaerobes. Specific Staphylococcus saccharolyticus,
as a slow-growing organism that is anaerobic culture methods, or culture- Peptostreptococcus, and Clostridium (44).
relatively resistant to antibiotics. independent techniques, may be more Using terminal restriction fragment

Seminars for Clinicians 1301

 SEMINARS FOR CLINICIANS

length polymorphism, Rogers and in nearly all Peptostreptococcus and dysfunction, and antibiotic use. Although
colleagues (45) identified differences Streptococcus species, whereas resistance to CF lung disease is classically dominated by
between paired mouthwash and sputum meropenem is more rare (44). Although bacteria, fungal isolates are increasingly
samples obtained from subjects with CF, meropenem is commonly included in CF described because the respiratory tract
both in the bands identified and the antibiotic protocols as a second- or third- anatomically communicates with the
band volume, suggesting that the finding line intravenous drug in the treatment of atmosphere, a rich source of airborne fungal
of anaerobes in the lower airways is not pulmonary exacerbations, it remains spores. Inability to clear such inhaled
explained by aspiration of the oral anaerobiota. unclear whether any clinical improvements particles results in their persistence,
Although the inflammatory response to associated with its administration are colonization, and potential airway infection.
individual aerobic organisms identified in related directly to its targeting of anaerobes. This spectrum of clinical consequences
BAL fluid from infants and young children Data from culture-based studies, and combined with enhanced detection methods
with CF has been described (46), no such more recently from studies using culture- makes it probable that we have thus far
data linking anaerobes to inflammation independent techniques, therefore indicate underestimated fungal prevalence and
or clinical outcomes are available. that anaerobes are prevalent in the importance in clinical practice over the last
Studies in younger subjects might help to lower airways of people with CF, but decade of CF care (51–58).
elucidate the role of anaerobes in disease whether these organisms play a part in the Vast arrays of fungal species are
pathogenesis and whether or not their pathophysiology of progressive lung damage described in CF; however, methods used for
presence in the lower airways represents remains unknown. How anaerobes interact their isolation primarily dictate the species and
an epiphenomenon (47). Existing studies with the microbiota of the lower airways and populations detected. Although traditional
are in older subjects who have therefore other CF organisms also requires study. methodologies of fungal culture remain,
experienced a more complex infection Resistance in vitro is common, meaning emerging molecular techniques and
history. Longitudinal studies are also that antibiotics usually considered for the genotyping provide greater sensitivity. Despite
lacking, although a comprehensive treatment of anaerobes may not be fungal biodiversity (Figure 2), the major
longitudinal study conducted in a single effective. Anaerobes appear to play a role in clinical challenges are caused by Aspergillus
patient suggested that anaerobes of the CF lung disease, but this requires fumigatus (59, 60), Candida albicans (61, 62),
Streptococcus milleri group contributed clarification before the targeting of obligate and Scedosporium species complex. Clinicians
to the development of pulmonary anaerobes in the treatment of CF lung are often left wondering about the
exacerbations (48). Ulrich and colleagues infections becomes routine. significance of isolating fungi from a patient
reported that 16 of 17 patients with CF with CF and whether treatment is indicated.
produced antibodies against two A. fumigatus is detected in sputum in
immunoreactive antigens of Prevotella Fungi approximately 30% of patients with CF.
intermedia compared with 0 of 30 controls Allergic bronchopulmonary aspergillosis
(49), suggesting that anaerobes are, indeed, Patients with CF are at increased risks of (ABPA) remains a key consequence, but
immunogenic in CF. Culture supernatant fungal colonization owing to impaired sputum isolation does not correlate with
fluid of P. intermedia was also cytotoxic to mucus clearance, local immunogenic ABPA occurrence (63). The difficulty in
respiratory epithelial cell lines, associated
with neutrophil and macrophage
Pathogenicity
recruitment into lung tissue in mice, and
established
cytotoxic to human-derived neutrophils. Aspergillus fumigatus
Its pathogenicity is estimated as being Scedosporium species complex
intermediate between that of aerobic and C. glabrata C. parapsilosis
(S. apiospermum, P. boydii, S. aurantiacum,
anaerobic P. aeruginosa. In studies where P. minutispora)
anaerobes were specifically targeted during T. mycotoxinivorans E. dermatitidis
R. argillacea, R. aegroticola, R. piperina
treatment for pulmonary exacerbations, the A. terreus S. prolificans C. dubliniensis

results have been conflicting. Worlitzsch Frequency

and colleagues (43) did not identify any E. phaeomuriformis A. lentulus
Candida albicans
significant reduction in the density of P. jirovecii A. flavus A. nidulans A.niger
anaerobes in sputum after treatment A. fusispora N. pseudofischeri
with antibiotics despite an increase in C. bracarensis, C. nivariensis
C. metapsilosis, C.orthopsilosis
pulmonary function during the period of
treatment. Similarly, Tunney and colleagues Pathogenicity Low Chronicity High Chronicity
identified only limited reduction in the still unknown
density of anaerobes at the end of 2 weeks
Figure 2. Cystic fibrosis fungal biodiversity grouped according to frequency of isolation (x axis) and
of treatment (50). An important factor to established pathogenicity (y axis). The fungi are further divided in terms of chronicity as illustrated. The
consider when treating anaerobic infections most frequently isolated filamentous fungi, Aspergillus fumigatus and Scedosporium species complex,
is that anaerobic organisms are often and yeast Candida albicans are highlighted and further discussed in text. Low-chronicity genera:
resistant to the commonly administered A. = Aspergillus; C. = Candida; E. = Exophiala; P. = Pneumocystis; R. = Rasamsonia. High-chronicity
antibiotics. For example, resistance to genera: A. = Aspergillus (flavus, nidulans, niger); A. = Acrophialophora (fusispora); C. = Candida;
metronidazole was reported to occur E. = Exophiala; N. = Neosartorya; P. = Pseudallescheria; S. = Scedosporium; T. = Trichosporon.

1302 AnnalsATS Volume 11 Number 8 | October 2014

 SEMINARS FOR CLINICIANS

diagnosis of ABPA exists because of aspergillosis has been proposed. On the (if any) is unclear, and there is no evidence
overlapping clinical, radiological, basis of serum IgE and IgG concentrations to suggest treatment benefit.
immunological, and microbiological combined with sputum galactomannan Members of the Scedosporium species
features similar to that of an infective and the presence of PCR-detectable complex are chronic colonizers and
exacerbation in CF (63, 64). To address Aspergillus, four distinct subgroups are emerging pathogens in CF (80, 81). A
this, biomarkers such as recombinant defined. These include those with ABPA, major risk exposure includes potted plants.
Aspergillus antigens, precipitins, anti- those who are Aspergillus sensitized, those However, they also have an environmental
Aspergillus IgG, thymus activation and with Aspergillus bronchitis, and those presence (82, 83). Colonization is not
regulated chemokine (TARC), and the without disease. Improved classification associated with FEV1 or steroid or
basophil surface marker CD203c have been and definition can assist with clinical antifungal use. Interestingly, those
proposed, but pose difficulties because of phenotyping and may impact future harboring the fungus are less likely to be
their variability and lack of sensitivity, treatment decisions in Aspergillus- colonized with P. aeruginosa (84).
standardization, and accessibility (65). In associated CF disease (74). Discordance between relatively high
acute ABPA, corticosteroids suppress the Controversy persists over the isolation frequency (6.5–10%) and low
inflammatory response. One treatment significance of non-ABPA Aspergillus environmental abundance prompts
protocol employed includes prednisone at colonization. It is often associated with questions about how initial acquisition
40 mg once daily for 2 weeks with taper worse radiologic findings and is an actually occurs in CF (80, 81). Genotype
over 3 months tailored to clinical independent risk factor for hospitalization analysis of sequential isolates demonstrates
symptoms, lung function, and total (75, 76). Itraconazole treatment reduces that individual patients are colonized by
serum IgE concentration. Concerns the burden of Aspergillus, attenuates unique phenotypes that remain conserved
over side effects of long-term steroid radiological mosaic perfusion, reduces over time (85). Clinical consequences
administration has prompted the use of exacerbations, and stabilizes pulmonary include allergic responses and risk of
alternative regimens such as high-dose function in this setting (77). Such effects are dissemination in immunocompromised
methylprednisolone (10–15 mg/kg) daily mediated by down-regulation of the hosts (86). Eradication remains difficult
for 3 days monthly for up to 10 months vitamin D receptor through the virulence once colonization is established, with
(66). Antifungal therapy may be factor gliotoxin. Itraconazole treatment has voriconazole the agent of choice.
concurrently administered. However, no been shown to decrease BAL gliotoxin Although our knowledge regarding the
randomized controlled trials to date concentrations and to restore vitamin D role of fungi in CF is improving, many
support use in CF-ABPA (67). receptor expression with concomitant questions remain. Are certain fungi
Itraconazole is preferred with a favorable reduction in helper T-cell type 2 cytokines pathogenic and if so, what mechanisms
side effect profile, but it does possess IL-5 and IL-13, drivers of ABPA (77). do they use? When do they become
variable absorption and food interactions Despite these findings, a double-blind, pathogenic? Are they pathogenic from the
necessitating close serum monitoring. In placebo-controlled trial failed to time they enter into the airway or only after
addition, the development of azole demonstrate clinical benefit, but treatment a certain time of colonization and
resistance remains a concern (68). efficacy may have been impacted by sensitization? Does clinical setting matter?
Voriconazole is an alternative drug failing to achieve therapeutic itraconazole Should attempts be made to eradicate them?
option but has significant associated concentrations in a significant proportion If so when, with what drugs, and for how
photosensitivity especially in patients of patients (78). Further study in this long? These are all valid questions, which are
with CF (69). Steroid-resistant cases area is warranted before treatment difficult to answer on the basis of existing
may necessitate antifungal therapy or recommendations can be issued (if data (60).
administration of an anti-IgE monoclonal necessary) for the non-ABPA Aspergillus– There is limited knowledge regarding
antibody, but existing evidence is limited colonized population. treatment approaches for fungi in CF. A.
to case series reports (70). C. albicans is capable of causing oral fumigatus is commonly detected in the CF
Clinically distinct from ABPA, and genital candidiasis and vascular device airway. It is a proven fungal pathogen in
Aspergillus sensitization independently infections in CF (62, 79). It is frequently CF-ABPA. Sputum isolation is discordant
affects pulmonary function; however, the isolated from CF sputum. Patients with CF with ABPA occurrence, thereby making
mechanism through which it does so are at increased risk of pulmonary diagnosis difficult. Treatment should always
remains unclear (71). Allergic sensitization colonization because of inhaled steroid be pursued in CF-ABPA. However, it
does not correlate with sputum detection of use, CF-related diabetes, and lifelong remains controversial in the non-ABPA
Aspergillus. Unlike Candida sensitization, antibiotic exposure. A prospective Aspergillus–colonized patient. There is no
Aspergillus sensitization is associated with longitudinal study showed high (49.4%) evidence that C. albicans isolated from CF
greater lung function decline and colonization rates best predicted by sputum should be treated because its
pulmonary exacerbations (72). The pancreatic insufficiency, osteopenia, and pathological significance in the airway is
presence of severe CF mutations, mild lung cocolonization with P. aeruginosa, all unknown. No current evidence exists to
disease (FEV1 . 70%), absence of features of advanced disease (61). suggest treatment benefit in this context.
Pseudomonas, and prior azithromycin Colonization presaged increases in However, when C. albicans causes mucosal
exposure all remain predictive for hospitalizations for exacerbations and or vascular device infection, prompt
Aspergillus sensitization (73). A novel longitudinal declines in body mass index treatment is indicated. Infection rates with
immunological classification for CF and FEV1 (61). At present, its clinical role Scedosporium species are underestimated

Seminars for Clinicians 1303

 SEMINARS FOR CLINICIANS

because of difficulties with diagnosis, as airway (2). Under selective pressure of regimen is often frustrating to even the
this mold’s clinical, radiological, and frequent antibiotic use and with improved most experienced individual. The airway
pathological appearance is similar to techniques to identify microorganisms, that environment in CF is continually evolving.
Aspergillus. Such misdiagnosis may be array is expanding. Physicians must treat Niches are being created that will allow new
lethal considering that Scedosporium is not only the classic pathogens associated potential pathogens to gain a foothold in
almost always resistant to amphotericin B, with CF, such as S. aureus and P. the CF airway. Therefore, clinicians must
the agent frequently used in presumptive aeruginosa, they may also have to treat be constantly vigilant for the emergence of
Aspergillus infection. Consequently, other microorganisms such as NTM, new microorganisms infecting the CF
eradication should be attempted at first anaerobic bacteria, and fungi. Less evidence airway, and researchers must be prepared
isolation in view of its potentially devastating regarding treatment of these organisms is to develop novel antimicrobial therapies to
clinical consequences if misdiagnosed or available than for the typical bacteria treat these infections. n
allowed to persist long term. known to infect the CF airway. These
organisms often grow slowly, if at all, on Author disclosures are available with the text
typical microbiological cultures. However, of this article at www.atsjournals.org.
Summary when a new organism is identified, CF
clinicians are often left wondering about the Acknowledgment: The authors acknowledge
For decades, clinicians have been treating pathologic significance of this new finding. Jay Hilliard for help with editing and refining the
a narrow array of bacteria that infect the CF Furthermore, determining a treatment figures and tables.

References Herrmann for the OMA Group. Multicenter study of prevalence of

nontuberculous mycobacteria in patients with cystic fibrosis in
1 Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med 2006; France. J Clin Microbiol 2009;47:4124–4128.
173:475–482. 12 Esther CR Jr, Esserman DA, Gilligan P, Kerr A, Noone PG. Chronic
2 Chmiel JF, Davis PB. State of the art: why do the lungs of patients with Mycobacterium abscessus infection and lung function decline in
cystic fibrosis become infected and why can’t they clear the cystic fibrosis. J Cyst Fibros 2010;9:117–123.
infection? Respir Res 2003;4:8. 13 Chalermskulrat W, Sood N, Neuringer IP, Hecker TM, Chang L, Rivera
3 Courtney JM, Dunbar KE, McDowell A, Moore JE, Warke TJ, Stevenson MP, Paradowski LJ, Aris RM. Non-tuberculous mycobacteria in end
M, Elborn JS. Clinical outcome of Burkholderia cepacia stage cystic fibrosis: implications for lung transplantation. Thorax
complex infection in cystic fibrosis adults. J Cyst Fibros 2004; 2006;61:507–513.
3:93–98. 14 Falkinham JO III. Nontuberculous mycobacteria from household
4 Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. plumbing of patients with nontuberculous mycobacteria disease.
Persistent methicillin-resistant Staphylococcus aureus and rate of Emerg Infect Dis 2011;17:419–424.
FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med 2008;178: 15 Feazel LM, Baumgartner LK, Peterson KL, Frank DN, Harris JK, Pace
814–821. NR. Opportunistic pathogens enriched in showerhead biofilms. Proc
5 Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Natl Acad Sci USA 2009;106:16393–16399.
Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48: 16 Nishiuchi Y, Maekura R, Kitada S, Tamaru A, Taguri T, Kira Y, Hiraga T,
1041–1049. Hirotani A, Yoshimura K, Miki M, et al. The recovery of
6 Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, Mycobacterium avium-intracellulare complex (MAC) from the
Drevinek P, Gulmans V, Krivec U, Olesen H; ECFS Patient Registry residential bathrooms of patients with pulmonary MAC. Clin Infect
Steering Group. Factors associated with FEV1 decline in cystic Dis 2007;45:347–351.
fibrosis: analysis of the ECFS Patient Registry. Eur Respir J 2014;43: 17 De Groote MA, Pace NR, Fulton K, Falkinham JO III. Relationships
125–133. between Mycobacterium isolates from patients with pulmonary
7 Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, mycobacterial infection and potting soils. Appl Environ Microbiol
LipPuma JJ, Ranganathan SC, Waters V, Ratjen F. Antibiotic 2006;72:7602–7606.
management of lung infections in cystic fibrosis: the microbiome, 18 Falkinham JO III. Reducing human exposure to Mycobacterium avium.
MRSA, gram-negative bacteria, and multiple infections. Ann Am Ann Am Thorac Soc 2013;10:378–382.
Thorac Soc 2014;11:1120–1129. 19 Kim RD, Greenberg DE, Ehrmantraut ME, Guide SV, Ding L, Shea Y,
8 Kendall BA, Winthrop KL. Update on the epidemiology of pulmonary Brown MR, Chernick M, Steagall WK, Glasgow CG, et al. Pulmonary
nontuberculous mycobacterial infections. Semin Respir Crit Care nontuberculous mycobacterial disease: prospective study of
Med 2013;34:87–94. a distinct preexisting syndrome. Am J Respir Crit Care Med 2008;
9 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin 178:1066–1074.
F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS 20 Saiman L, Siegel J; Cystic Fibrosis Foundation. Infection control
Mycobacterial Diseases Subcommittee; American Thoracic Society; recommendations for patients with cystic fibrosis: microbiology,
Infectious Diseases Society of America. An official ATS/IDSA important pathogens, and infection control practices to prevent
statement: diagnosis, treatment, and prevention of nontuberculous patient-to-patient transmission. Infect Control Hosp Epidemiol 2003;
mycobacterial diseases. Am J Respir Crit Care Med 2007;175: 24(5, Suppl):S6–S52.
367–416. [Published erratum appears in Am J Respir Crit Care Med 21 Aitken ML, Limaye A, Pottinger P, Whimbey E, Goss CH, Tonelli MR,
175:744–745.] Cangelosi GA, Dirac MA, Olivier KN, Brown-Elliott BA, et al.
10 Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Respiratory outbreak of Mycobacterium abscessus subspecies
Brown-Elliot BA, Handler A, Wilson RW, Schechter MS, et al.; massiliense in a lung transplant and cystic fibrosis center. Am J
Nontuberculous Mycobacteria in Cystic Fibrosis Study Respir Crit Care Med 2012;185:231–232.
Group. Nontuberculous mycobacteria. I. Multicenter prevalence 22 Bryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T,
study in cystic fibrosis. Am J Respir Crit Care Med 2003;167: Reacher M, Haworth CS, Curran MD, Harris SR, et al. Whole-genome
828–834. sequencing to identify transmission of Mycobacterium abscessus
11 Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, between patients with cystic fibrosis: a retrospective cohort study.
Bellis G, Vibet MA, Le Roux E, Lemonnier L, et al.; Jean-Louis Lancet 2013;381:1551–1560.

1304 AnnalsATS Volume 11 Number 8 | October 2014

 SEMINARS FOR CLINICIANS

23 Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, 42 Tunney MM, Field TR, Moriarty TF, Patrick S, Doering G, Muhlebach
Koppers RJ, van der Werf TS, Boersma WG. Effect of azithromycin MS, Wolfgang MC, Boucher R, Gilpin DF, McDowell A, et al.
maintenance treatment on infectious exacerbations among patients Detection of anaerobic bacteria in high numbers in sputum from
with non-cystic fibrosis bronchiectasis: the BAT randomized patients with cystic fibrosis. Am J Respir Crit Care Med 2008;177:
controlled trial. JAMA 2013;309:1251–1259. 995–1001.
24 Ratjen F, Saiman L, Mayer-Hamblett N, Lands LC, Kloster M, 43 Worlitzsch D, Rintelen C, Böhm K, Wollschläger B, Merkel N, Borneff-
Thompson V, Emmett P, Marshall B, Accurso F, Sagel S, et al. Effect Lipp M, Döring G. Antibiotic-resistant obligate anaerobes during
of azithromycin on systemic markers of inflammation in patients with exacerbations of cystic fibrosis patients. Clin Microbiol Infect 2009;
cystic fibrosis uninfected with Pseudomonas aeruginosa. Chest 15:454–460.
2012;142:1259–1266. 44 Lambiase A, Catania MR, Rossano F. Anaerobic bacteria infection in
25 Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, Biga cystic fibrosis airway disease. New Microbiol 2010;33:185–194.
S, Schlebusch S, Dash P, Bowler SD. Effect of long-term, low-dose 45 Rogers GB, Carroll MP, Serisier DJ, Hockey PM, Jones G, Kehagia V,
erythromycin on pulmonary exacerbations among patients with Connett GJ, Bruce KD. Use of 16S rRNA gene profiling by terminal
non-cystic fibrosis bronchiectasis: the BLESS randomized restriction fragment length polymorphism analysis to compare
controlled trial. JAMA 2013;309:1260–1267. bacterial communities in sputum and mouthwash samples from
26 Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics patients with cystic fibrosis. J Clin Microbiol 2006;44:2601–2604.
for cystic fibrosis. Cochrane Database Syst Rev [serial on the 46 Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T, Brennan S,
Internet]. 2012 [accessed September 2014];11:CD002203. Available Ranganathan S, Robins-Browne R, Sly PD; AREST CF. Inflammatory
from: http://summaries.cochrane.org/ responses to individual microorganisms in the lungs of children with
27 Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, cystic fibrosis. Clin Infect Dis 2011;53:425–432.
Fergusson W, Tuffery C, Sexton P, et al. Azithromycin for prevention 47 Tai A, Ranganath S. Anaerobic bacterial infection in patients with cystic
of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): fibrosis. Am J Respir Crit Care Med 2008;178:994.
a randomised, double-blind, placebo-controlled trial. Lancet 2012; 48 Sibley CD, Parkins MD, Rabin HR, Duan K, Norgaard JC, Surette MG.
380:660–667. A polymicrobial perspective of pulmonary infections exposes an
28 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, enigmatic pathogen in cystic fibrosis patients. Proc Natl Acad Sci
Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B; Pulmonary USA 2008;105:15070–15075.
Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary 49 Ulrich M, Beer I, Braitmaier P, Dierkes M, Kummer F, Krismer B,
guidelines: chronic medications for maintenance of lung health. Schumacher U, Gräpler-Mainka U, Riethmüller J, Jensen PO, et al.
Am J Respir Crit Care Med 2013;187:680–689. Relative contribution of Prevotella intermedia and Pseudomonas
29 Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of aeruginosa to lung pathology in airways of patients with cystic
nontuberculous mycobacterial infections and associated chronic fibrosis. Thorax 2010;65:978–984.
macrolide use among persons with cystic fibrosis. Am J Respir Crit 50 Tunney MM, Klem ER, Fodor AA, Gilpin DF, Moriarty TF, McGrath SJ,
Care Med 2013;188:807–812. Muhlebach MS, Boucher RC, Cardwell C, Doering G, et al. Use
30 Davis KK, Kao PN, Jacobs SS, Ruoss SJ. Aerosolized amikacin for of culture and molecular analysis to determine the effect of antibiotic
treatment of pulmonary Mycobacterium avium infections: an treatment on microbial community diversity and abundance during
observational case series. BMC Pulm Med 2007;7:2. exacerbation in patients with cystic fibrosis. Thorax 2011;66:
31 Colin AA, Ali-Dinar T. Aerosolized amikacin and oral clarithromycin to 579–584.
eradicate Mycobacterium abscessus in a patient with cystic fibrosis: 51 Delhaes L, Monchy S, Fréalle E, Hubans C, Salleron J, Leroy S,
an 8-year follow-up. Pediatr Pulmonol 2010;45:626–627. Prevotat A, Wallet F, Wallaert B, Dei-Cas E, et al. The airway
32 Leung JM, Olivier KN. Nontuberculous mycobacteria in patients with microbiota in cystic fibrosis: a complex fungal and bacterial
cystic fibrosis. Semin Respir Crit Care Med 2013;34:124–134. community—implications for therapeutic management. PLoS One
33 Nash KA, Brown-Elliott BA, Wallace RJ Jr. A novel gene, erm(41), 2012;7:e36313.
confers inducible macrolide resistance to clinical isolates of 52 Haase G, Skopnik H, Kusenbach G. Exophiala dermatitidis infection in
Mycobacterium abscessus but is absent from Mycobacterium cystic fibrosis. Lancet 1990;336:188–189.
chelonae. Antimicrob Agents Chemother 2009;53:1367–1376. 53 Haase G, Skopnik H, Groten T, Kusenbach G, Posselt HG. Long-term
34 Choi GE, Shin SJ, Won CJ, Min KN, Oh T, Hahn MY, Lee K, fungal cultures from sputum of patients with cystic fibrosis. Mycoses
Lee SH, Daley CL, Kim S, et al. Macrolide treatment for 1991;34:373–376.
Mycobacterium abscessus and Mycobacterium massiliense 54 Horré R, Schaal KP, Siekmeier R, Sterzik B, de Hoog GS, Schnitzler N.
infection and inducible resistance. Am J Respir Crit Care Med Isolation of fungi, especially Exophiala dermatitidis, in patients
2012;186:917–925. suffering from cystic fibrosis: a prospective study. Respiration 2004;
35 Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, Park YK, Kim CK, 71:360–366.
Shin SJ, Huitt GA, et al. Clinical significance of differentiation of 55 Kusenbach G, Skopnik H, Haase G, Friedrichs F, Döhmen H. Exophiala
Mycobacterium massiliense from Mycobacterium abscessus. dermatitidis pneumonia in cystic fibrosis. Eur J Pediatr 1992;151:
Am J Respir Crit Care Med 2011;183:405–410. 344–346.
36 van Ingen J, Boeree MJ, van Soolingen D, Mouton JW. Resistance 56 Blaschke-Hellmessen R, Lauterbach I, Paul KD, Tintelnot K, Weissbach
mechanisms and drug susceptibility testing of nontuberculous G. [Detection of Exophiala dermatitidis (Kano) De Hoog 1977 in
mycobacteria. Drug Resist Updat 2012;15:149–161. septicemia of a child with acute lymphatic leukemia and in patients
37 Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer with cystic fibrosis]. Mycoses 1994;37:89–96.
P, Bellon G, Berger J, Weiss T, et al. Effects of reduced mucus 57 Kondori N, Gilljam M, Lindblad A, Jönsson B, Moore ER, Wennerås C.
oxygen concentration in airway Pseudomonas infections of cystic High rate of Exophiala dermatitidis recovery in the airways of patients
fibrosis patients. J Clin Invest 2002;109:317–325. with cystic fibrosis is associated with pancreatic insufficiency. J Clin
38 Bittar F, Richet H, Dubus JC, Reynaud-Gaubert M, Stremler N, Sarles J, Microbiol 2011;49:1004–1009.
Raoult D, Rolain JM. Molecular detection of multiple emerging 58 Giraud S, Favennec L, Bougnoux ME, Bouchara JP. Rasamsonia
pathogens in sputa from cystic fibrosis patients. PLoS One 2008; argillacea species complex: taxonomy, pathogenesis and clinical
3:e2908. relevance. Future Microbiol 2013;8:967–978.
39 Brook I, Fink R. Transtracheal aspiration in pulmonary infection in 59 Chotirmall SH, Al-Alawi M, Mirkovic B, Lavelle G, Logan PM, Greene
children with cystic fibrosis. Eur J Respir Dis 1983;64:51–57. CM, McElvaney NG. Aspergillus-associated airway disease,
40 Jewes LA, Spencer RC. The incidence of anaerobes in the sputum of inflammation, and the innate immune response. Biomed Res Int
patients with cystic fibrosis. J Med Microbiol 1990;31:271–274. 2013;2013:723129.
41 Thomassen MJ, Klinger JD, Badger SJ, van Heeckeren DW, Stern RC. 60 Chotirmall SH, McElvaney NG. Fungi in the cystic fibrosis lung:
Cultures of thoracotomy specimens confirm usefulness of sputum bystanders or pathogens? Int J Biochem Cell Biol 2014;52:
cultures in cystic fibrosis. J Pediatr 1984;104:352–356. 161–173.

Seminars for Clinicians 1305

 SEMINARS FOR CLINICIANS

61 Chotirmall SH, O’Donoghue E, Bennett K, Gunaratnam C, O’Neill SJ, 74 Baxter CG, Dunn G, Jones AM, Webb K, Gore R, Richardson MD,
McElvaney NG. Sputum Candida albicans presages FEV₁ decline and Denning DW. Novel immunologic classification of aspergillosis
hospital-treated exacerbations in cystic fibrosis. Chest 2010;138: in adult cystic fibrosis. J Allergy Clin Immunol 2013;132:560–566.
1186–1195. e510.
62 Chotirmall SH, Greene CM, McElvaney NG. Candida species in cystic 75 Amin R, Dupuis A, Aaron SD, Ratjen F. The effect of chronic infection
fibrosis: a road less travelled. Med Mycol 2010;48:S114–S124. with Aspergillus fumigatus on lung function and hospitalization in
63 Chotirmall SH, Branagan P, Gunaratnam C, McElvaney NG. patients with cystic fibrosis. Chest 2010;137:171–176.
Aspergillus/allergic bronchopulmonary aspergillosis in an Irish cystic 76 McMahon MA, Chotirmall SH, McCullagh B, Branagan P, McElvaney
fibrosis population: a diagnostically challenging entity. Respir Care NG, Logan PM. Radiological abnormalities associated with
2008;53:1035–1041. Aspergillus colonization in a cystic fibrosis population. Eur J Radiol
64 Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson 2012;81:e197–e202.
MA, Denning DW, Crameri R, Brody AS, Light M, et al.; Participants 77 Coughlan CA, Chotirmall SH, Renwick J, Hassan T, Low TB, Bergsson
in the Cystic Fibrosis Foundation Consensus Conference. Allergic G, Eshwika A, Bennett K, Dunne K, Greene CM, et al. The
bronchopulmonary aspergillosis in cystic fibrosis—state of the art: effect of Aspergillus fumigatus infection on vitamin D receptor
Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis expression in cystic fibrosis. Am J Respir Crit Care Med 2012;
2003;37:S225–S264. 186:999–1007.
65 Gernez Y, Dunn CE, Everson C, Mitsunaga E, Gudiputi L, Krasinska K, 78 Aaron SD, Vandemheen KL, Freitag A, Pedder L, Cameron W,
Davies ZA, Herzenberg LA, Tirouvanziam R, Moss RB. Blood Lavoie A, Paterson N, Wilcox P, Rabin H, Tullis E, et al.
basophils from cystic fibrosis patients with allergic bronchopulmonary Treatment of Aspergillus fumigatus in patients with cystic
aspergillosis are primed and hyper-responsive to stimulation by fibrosis: a randomized, placebo-controlled pilot study. PLoS
Aspergillus allergens. J Cyst Fibros 2012;11:502–510. One 2012;7:e36077.
66 Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, 79 Hassan T, Chotirmall SH, Low TB, Flynn MG, McElvaney NG,
Armoni S, Kerem E. Intravenous monthly pulse methylprednisolone Gunaratnam C. Thrombolysis for indwelling catheter related
treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros thrombosis and superior vena cava obstruction in cystic fibrosis:
2009;8:253–257. a case series. Ir J Med Sci 2010;179:469–470.
67 Elphick HE, Southern KW. Antifungal therapies for allergic 80 Cimon B, Carrère J, Vinatier JF, Chazalette JP, Chabasse D, Bouchara
bronchopulmonary aspergillosis in people with cystic fibrosis. JP. Clinical significance of Scedosporium apiospermum in
Cochrane Database Syst Rev [serial on the Internet]. 2012 [accessed patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis 2000;
September 2014];6:CD002204. Available from: http://summaries. 19:53–56.
cochrane.org/ 81 Williamson EC, Speers D, Arthur IH, Harnett G, Ryan G, Inglis TJ.
68 Burgel PR, Baixench MT, Amsellem M, Audureau E, Chapron J, Kanaan Molecular epidemiology of Scedosporium apiospermum infection
R, Honoré I, Dupouy-Camet J, Dusser D, Klaassen CH, et al. High determined by PCR amplification of ribosomal intergenic spacer
prevalence of azole-resistant Aspergillus fumigatus in adults with sequences in patients with chronic lung disease. J Clin Microbiol
cystic fibrosis exposed to itraconazole. Antimicrob Agents 2001;39:47–50.
Chemother 2012;56:869–874. 82 Tintelnot K, Just-Nübling G, Horré R, Graf B, Sobottka I, Seibold
69 Rondeau S, Couderc L, Dominique S, Pramil S, Leguillon C, Masseline B, M, Haas A, Kaben U, De Hoog GS. A review of German
Favennec L, Marguet C. High frequency of voriconazole-related Scedosporium prolificans cases from 1993 to 2007. Med
phototoxicity in cystic fibrosis patients. Eur Respir J 2012;39:782–784. Mycol 2009;47:351–358.
70 Tanou K, Zintzaras E, Kaditis AG. Omalizumab therapy for allergic 83 Summerbell RC, Krajden S, Kane J. Potted plants in hospitals as
bronchopulmonary aspergillosis in children with cystic fibrosis: reservoirs of pathogenic fungi. Mycopathologia 1989;106:13–22.
a synthesis of published evidence. Pediatr Pulmonol 2014;49:503–507. 84 Blyth CC, Middleton PG, Harun A, Sorrell TC, Meyer W, Chen SC.
71 Fillaux J, Brémont F, Murris M, Cassaing S, Rittié JL, Tétu L, Segonds Clinical associations and prevalence of Scedosporium spp. in
C, Abbal M, Bieth E, Berry A, et al. Assessment of Aspergillus Australian cystic fibrosis patients: identification of novel risk factors?
sensitization or persistent carriage as a factor in lung function Med Mycol 2010;48:S37–S44.
impairment in cystic fibrosis patients. Scand J Infect Dis 2012;44: 85 Defontaine A, Zouhair R, Cimon B, Carrère J, Bailly E, Symoens F,
842–847. Diouri M, Hallet JN, Bouchara JP. Genotyping study of
72 Baxter CG, Moore CB, Jones AM, Webb AK, Denning DW. IgE- Scedosporium apiospermum isolates from patients with cystic
mediated immune responses and airway detection of Aspergillus and fibrosis. J Clin Microbiol 2002;40:2108–2114.
Candida in adult cystic fibrosis. Chest 2013;143:1351–1357. 86 Guarro J, Kantarcioglu AS, Horré R, Rodriguez-Tudela JL, Cuenca
73 Fillaux J, Brémont F, Murris M, Cassaing S, Tétu L, Segonds C, Pipy B, Estrella M, Berenguer J, de Hoog GS. Scedosporium apiospermum:
Magnaval JF. Aspergillus sensitization or carriage in cystic fibrosis changing clinical spectrum of a therapy-refractory opportunist. Med
patients. Pediatr Infect Dis J 2014;33:680–686. Mycol 2006;44:295–327.

1306 AnnalsATS Volume 11 Number 8 | October 2014