Pseudomonas aeruginosa in Patients with Cystic Fibrosis

Cystic fibrosis (CF) is the most common inherited disease of Caucasians in the United States with nearly 35,000 people currently living with CF. Understanding the treatment of chronic infection in the CF patient is complex and unique and no longer confined to pediatric multi-disciplinary teams. With >30% of patients with CF currently over the age of 18 years of age, treatment of chronic infection is commonplace in the adult medicine world.

Pseudomonas aeruginosa is the predominant bacterial pathogen, associated with more aggressive decline in pulmonary function in the CF lung. Daily maintenance therapy is an important part of suppression of chronic infection, with frequent need of periodic aggressive IV antibiotics for treatment of pulmonary exacerbation in the routine care of the CF patient.

Epidemiology

Chronic airway infection is the most important cause of morbidity and mortality in CF, and Pseudomonas aeruginosa is the most significant pathogen in CF (9,11,13,48). The median life expectancy of a patient with CF in 2007 is 36.9 years (12). However patients with P. aeruginosa infection have a decreased life expectancy of 30 years, compared with 40 years in non-colonized patients, experiencing a more rapid decline in pulmonary function with more frequent hospitalizations (20,33,36).

A study of 3,323 children aged 1-5 years revealed a 2.6 times higher risk of death if P. aeruginosa is present in the lower airway (17). In these children, at age 8 years of age, the clinical outcome demonstrated both a lower forced expiratory volume at 1 second (FEV1) and a lower weight percentile. This increased risk continued if the child remained P. aeruginosa positive. Other studies also demonstrate an acceleration of lung disease in CF children associated with P. aeruginosa infection (33,36,40). In a prospective CF cohort of 56 infants in New Zealand identified by newborn screening, P. aeruginosa infection was common by age 7 years (43%) and was associated with increased morbidity and mortality (40).

Experience with CF infants identified by newborn screening, has shown an increased acquisition of P. aeruginosa with use of frequent treatment with non- P. aeruginosa antibiotics, as well as when integrated into a CF clinic with older P. aeruginosa (+) patients (19,63). However additional data from newborn screening experience failed to show a significant relationship between diagnostic approach to CF (i.e. infants diagnosed by newborn screening versus conventional symptomatic diagnosis) and risk of the first respiratory infection with P. aeruginosa (5).

Clinical Manifestations

P. aeruginosa infects approximately 60 percent of CF patients overall, with an 80% prevalence in the group of patients >18 years of age (12).

Respiratory Tract Infection

Definition of Infection

The terminology colonization and infection are often used interchangeably in CF patients, confusing patients, families and caregivers alike. Colonization implies the finding of bacteria without inflammation or tissue destruction. Since inflammation is ongoing in the lower airway in patients with CF, infection is the appropriate term. In the young child with CF, infection in the lower airway may only be present at times of cough and pulmonary symptoms. Strains of non-mucoid P. aeruginosa cause acute infection that is cleared with proper treatment. When and why the transition to permanent residence of bacteria (which become mucoidP. aeruginosa strains) in the CF lower airways is a poorly understood part of disease progression. Typically young children only cough with illness; at some point the cough becomes permanent, with sputum production. It is usually at this point that bacteria can almost always be cultured from the lower airway.

Pseudomonas serology (antibody precipitans) may help to differentiate the continuum between acute or transient infection that clears, and chronic infection of the CF airway. Antibody seropositivity to P. aeruginosa has been demonstrated 6-12 months prior to the detection of a positive culture in CF patients. Pseudomonas serology can differentiate the absence or presence of chronic P. aeruginosa infection, with a sensitivity of 86-96%, specificity of 79-96%, and a positive predictive value as high as 97% (21,26,31,32,58,59,63).

A prospective study of infants in the first 3 years of life revealed an antibody precipitans response to P. aeruginosa 6 months before the first P. aeruginosa-positive OCS-culture (at 21 months of age), and 8 months before the BAL-positive culture (at 23 months of age) (21,26). With aggressive treatment of the first P. aeruginosa infection, infants cleared the infection and become P. aeruginosa-antibody seronegative and infection-free (31). The median age for chronic infection in CF children with P. aeruginosa has risen from the age of 9.3 years in 1981-1986 to 13.8 years in 1987-2000. Once infection is established, levels of P. aeruginosa antibody precipitans also relate to the degree of inflammation and tissue damage found in the lung; high and rapidly increasing P. aeruginosaantibody levels indicates a poor prognosis (31).

Infection in the lower airway due to P. aeruginosa in patients with CF therefore can be described as four stages:

P. aeruginosa-free by culture with lung disease; P. aeruginosa-free by culture with (+) P. aeruginosa serology (with or without lung disease); P. aeruginosa-infection, non-mucoid with signs and symptoms of lung disease; P. aeruginosa-infection with mucoid strain. Chronic infection with P. aeruginosa is a complex interaction between this pathogen and the pulmonary environment (20,36).

Sinus Disease

Pseudomonas aeruginosa in the paranasal sinuses in CF patients frequently leads to acute and chronic infections, commonly complicated by nasal polyps. Nearly all CF patients are found to have thickening of the sinuses at any given time; plain radiographs are therefore not helpful in differentiating acute from chronic sinus disease. Symptoms of headache, facial or dental pain, congestion, postnasal drainage, epistaxis, and nasal blockage are indications for antimicrobial treatment. In CF patients with ongoing cough and lack of response to pulmonary treatments, attention to the chronic sinus disease is important for comprehensive management.

P. aeruginosa is otherwise an extremely rare bacteria to find in the sinuses in the non-CF population. Therefore the diagnosis of CF should be suspected in any such patient with P. aeruginosa cultured from the sinuses. Suspicion of CF in an older individual with primarily sinus disease may lead to the diagnosis of mild, atypical CF, with no growth problems (i.e.the patient is pancreatic sufficient); typically such patients have minimal or non-apparent pulmonary disease.

Laboratory Diagnosis

Isolation of bacteria from the respiratory tract specimens (expectorated sputum, oropharyngeal cough swab, or bronchoalveolar lavage (BAL)) is used to detect infection (4,44,47,59). Use of a microbiology laboratory familiar with processing of CF-respiratory specimens will improve the detection of P. aeruginosa, in addition to other CF-related bacteria. Expectorated sputum in patients with CF is the easiest and most logical way to detect P. aeruginosa infection. By the age of 8 years, many children, with practice, can expectorate sputum, if coughing. The challenge occurs in the patient with CF who is unable to expectorate due to age, neurologic impairment, or pain. Molecular techniques such as polymerase chain reaction (PCR) to detect bacteria in respiratory cultures are not available for clinical use (59).

In nonexpectorating patients, a deep oropharyngeal cough swab culture is the only option in routine CF care, since bronchoalveolar lavage (BAL) is invasive and requires general anesthesia. Comparing the culture from the oropharynx to BAL-culture specimens, the positive predictive value for P. aeruginosa is 83% (95% confidence interval 36-100%). The negative predictive value for P. aeruginosa is 70% (95% confidence interval 48-86%) (4,44,47). The lack of an organism from an oropharynx-culture does not rule-out the presence of bacteria in the CF airway. Culture from oropharynx culture or expectorated sputum following inhalation of hypertonic saline may provide additional microbiologic information (30). In older children and symptomatic patients the positive predictive value of a P. aeruginosa (+) Oropharyngeal culture is higher (44,59). Predictive values of oropharyngeal cultures may be improved by performing cultures more regularly (59).

Pathogenesis 

Cystic fibrosis (CF) is an autosomal recessive disorder that results in chronic sino-pulmonary infection and pancreatic insufficiency. Thick sticky mucous is the hallmark in CF. The genetic defect is on chromosome 7, leading to the abnormal production of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, resulting in malfunction of the chloride channel on all cell surfaces.

P. aeruginosa infection in the CF lung may represent a multi-stage process. There is a complex interaction between the P. aeruginosa pathogen and the unique environment of the CF lung. Adhesion of P. aeruginosa to the lining of the respiratory tract may be transient and intermittent, with antimicrobial therapy initially eradicating the infection. It is believed patients with cystic fibrosis acquire the organism from environmental sources, however CF-patient-to-CF-patient spread of P. aeruginosa has occurred. Few patients with CF have a new strain of P. aeruginosa when ill with a pulmonary exacerbation; infection is usually from their same chronic P. aeruginosa strain isolated on prior cultures (1,24). Interestingly in healthy CF newborn infants, numerous inflammatory cells are present in the lower airway, without evidence of infection (i.e. sterile cultures), suggesting that CF is first an inflammatory disease.

There is an observed relationship between pancreatic insufficiency and the ∆F508 homozygous genotype status with P. aeruginosa infection, showing that patients with CF who are homozygous for the ∆F508 mutation generally have more severe disease, and an increased risk of detection of P. aeruginosa (11,13,33,36). However only 40-60% of CF patients in the United States are homozygous or heterozygous with the ∆F508 genotype, and the lifetime risk for chronic infection with P. aeruginosa is >80% for all patients.

Once chronic infection/colonization occurs, the phenotypes of P. aeruginosa change to alginate producers, forming biofilms (11,48,60). Both the presence of P. aeruginosa and its mucoid phenotype (e.g., developing a mucoid biofilm due to production of alginate as well as high-level resistance to multiple antibiotics) have been shown to correlate with severity of patient illness (14). This mucoidy property predicts chronic infection that cannot be cleared.

Biofilm production and formation in nature is an adaptive response of mobile planktonic bacteria, allowing them to persist in turbulent aqueous environments (e.g. on rocks in streams). Biofilms occur as effective physical and metabolic barriers in human infections, and as an adaptation by organisms (such as P. aeruginosa) to survive in the planktonic condition (i.e. as encountered in the CF lung). Established chronic P. aeruginosa lung infection is not eradicated with antibiotic therapy, regardless of the in vitro antibiotic susceptibility of the infecting bacteria, with biofilms likely a major habitat factor in the survival of P. aeruginosa (42,60).

ANTIMICROBIAL THERAPY

The CF patient is not immunocompromised; the clinical problem is in the thick secretions that allow an environment for eventual chronic infection to take hold. Antipseudomonal therapy that decreases sputum burden density is associated with improved pulmonary function and improvement in clinical scores (45).

Acute Treatment

Antimicrobial agents remain the mainstay of treatment of patients with CF, in both acute and chronic infections. Oral, inhaled, and parenteral antibiotics are used for treatment as well as suppression of CF sino-pulmonary infection with P. aeruginosa. The goals of treatment in a very young child may be eradication of the P. aeruginosa, shift toward suppression and palliation of the chronic infection/ inflammatory response in the lung (see Table 3) (37).

Oral Agents

The only oral antimicrobial agents available for treatment of P. aeruginosa are the fluoroquinolones. These agents are often the first-line therapy given to a CF patient for treatment of a pulmonary exacerbation. Over time, the P. aeruginosa isolates acquire resistance to fluoroquinolones; in addition, the disease burden in the CF lungs worsens, making fluroquinolones less effective as a single agent.

Experience with use of the fluroquinolones in cystic fibrosis in children has demonstrated safety, although arthropathy was seen in juvenile dog models. Consensus guidelines for fluoroquinolone use in children by the American Academy of Pediatrics (AAP) lend validity to their selective use in the ambulatory setting for CF pediatric population (3). Consultation with a pediatric infectious disease specialist may be warranted.

Intravenous (IV) Antimicrobials

During IV therapy in treatment of patients with CF, combination therapy is standard because of concerns about development of antibiotic resistance in isolates of P. aeruginosa with single drug usage (13,49). The most frequently used drug combination in CF care includes a β-lactam antibiotic plus an aminoglycoside (See Tables 6 & 7). Since these two classes of drugs have different bacterial targets, as well as different modes of entry into the bacterial cell, they mutually enhance antimicrobial activity. Improved efficacy with specific dosing regimens may provide even better benefit in patients with CF (i.e. high dose aminoglycoside once daily and continuous infusion of a β-lactam antibiotic) (28,34,38).

Studies on the combinations of other antibiotics to treat P. aeruginosa infections are limited. Parenteral (intravenous or IV) colistin is associated with high toxicity and renal insufficiency, and is not indicated for routine use by this route. However experience from several CF-research laboratories offer direction with synergy testing of multi-drug resistant (MDR) gram negative organisms, including P. aeruginosa. Azithromycin and clarithromycin were paired with other antibiotics to test synergistic activity against 300 multidrug-resistant pathogens isolated from patients with CF. Clarithromycin-tobramycin was most active against P. aeruginosa and inhibited 58% of strains (2). Other combinations of agents that may offer synergy treatment against many a MDR gram negative include: Trimethoprim-sulfamethoxazole and doxycycline, trimethoprim- sulfamethoxazole and meropenem, and doxycycline and meropenem. The CF Referral Center for Susceptibility & Synergy Studies of Columbia University will test multi-drug resistant gram-negative isolates in CF patients (http://synergy.columbia.edu/).

Aminoglycosides 

Never used alone as a parenteral agent, aminoglycosides are a mainstay of P. aeruginosa therapy in treatment combination of a CF pulmonary exacerbation. Even when the antibiogram of P. aeruginosa exhibits resistance, most CF care providers still use IV aminoglycoside therapy. Tobramycin is the most commonly used aminoglycoside given its superior in vitro activity.

This class of antimicrobial agents is concentration-dependent; therefore higher peak level achieves better killing. Once-daily dosing of aminoglycosides therefore make perfect sense as the optimal way to administer the medication in CF care (35,39). Knowledge of the minimum inhibitory concentration (MIC) of P. aeruginosa to tobramycin is useful information in guiding the daily-dose of tobramycin. A peak level of 10 times the P. aeruginosa MIC of the bacterium may be desirable to achieve maximum usefulness of tobramycin. The Clinical & Laboratory Standards Institute (formerly NCCLS) standard for resistance of tobramycin to P. aeruginosais >4mcg/ml.

β-lactam Antimicrobials

Choice of which antimicrobial agent will depend on the P. aeruginosa antibiogram. With pan-susceptibleP. aeruginosa strains, the decision will often depend on the local hospital practices. fourth 4th generation (cefepime), semi-synthetic penicillins (piperacillin/ tazobactam & ticarcillin/ clavulenate), carbapenems (meropenem and imipenem), and monobactam (aztreonam), should be equivalent if the P. aeruginosa organism is susceptible. Dosing of antimicrobial agents in CF patients is often higher than conventional doses (See Table 7).

Oral quinolone therapy is commonly administered as an outpatient; are infrequently used as IV therapy. Quinolones may be considered as a component with two or three drug combination against multi-drug resistant P. aeruginosa. As CF patients get more advanced disease, failure to respond to the oral quinolone is common such that IV therapy may be the initial therapy. Choice of the antimicrobial agent should include the following consideration(s);

• Antibiogram of P. aeruginosa, including MIC of P. aeruginosa (if available from microbiology laboratory) to various antimicrobial agents;

• Past patient response to specific oral and/or IV therapy;

• Allergy or toxicity to class of antimicrobial agents.

In vitro susceptibilities may not predict treatment outcome which makes care for the CF patient with a pulmonary exacerbation all the more challenging and perplexing for the CF caregiver (54).

Antimicrobial Resistance

Antibiotic resistance is currently one of the most important problems faced by CF caregivers. Multiply drug-resistant (MDR)P. aeruginosa were identified in 11.6% of CF patients in a large multicenter study of patients with moderate disease; testing for synergistic combination of agents in these resistant organisms failed to identify potential therapy for 17% (9,50). The presence of antibiotic-resistant P. aeruginosa not only limits potential antimicrobial treatment, but can also preclude patients from eligibility for lung transplantation and other potentially life-saving modalities. An additional concern is that the introduction of new broad-spectrum antimicrobial agents could be contributing to the emergence of other, intrinsically antibiotic resistant pathogens that may be associated with increased morbidity in CF (i.e. methicillin-resistant Staphylococcus aureus, atypical mycobacteria, as well as B. cepacia complex,S. maltophilia, or A. xylosoxidans).

Not uncommonly patients with moderate to severe lung disease from CF will develop resistance to one or more antimicrobial class of antibiotics. Frequent culture of sputum at quarterly CF visits, as well as at times of pulmonary exacerbation, will guide choice of antimicrobial. Synergy testing has not proven to be the complete answer to guiding therapy. There are some antibiotic combinations that appear to provide treatment in MDR-P. aeruginosa. However, a blinded study of combination susceptibility testing did not result in better clinical and microbiological outcomes compared to standard susceptibility techniques (2).

A very significant concern about the emergence of resistance of P. aeruginosa during therapy with prolonged intermittent inhaled tobramycin (TOBI®) has also been raised. Microbiology data at completion of the phase 3 trial of inhaled tobramycin did demonstrate some decrease in susceptibility of P. aeruginosa isolates in association with treatment. The number of strains defined as resistant according to standard criteria increased in the tobramycin group, although there is no evidence that the most resistant isolates necessarily become the most predominant strain. There was no increase in the isolation of B. cepacia, S. maltophilia, or A. xylosoxidans. The benefit of improved lung function with TOBI® use outweighs these concerns at this time. Currently studies are monitoring resistance patterns of bacteria isolated in CF sputum to determine the impact of years of chronic intermittent inhaled TOBI® (University of Washington, Jane Burns, MD).

Although low-level resistance may not impact the efficacy of inhaled TOBI®, it could significantly decrease the activity of parenteral tobramycin alone or in synergistic combinations (10). Even when the antibiogram of P. aeruginosa exhibits resistance, most CF care providers still use IV aminoglycoside therapy. Choice of which aminoglycoside is dependant upon the hospital practices, with most CF centers using IV tobramycin.

Past antimicrobial strategies for controlling Staphylococcus aureus infection, with continuous oral cephalexin in children with CF, contributed negatively to the increased earlier rate of isolation of P. aeruginosa, leading to the cessation of chronic anti-Staphylococcus treatment in young children (57).

Pulmonary Exacerbation

Defining the need for antimicrobial treatment in a patient with CF by the care provider requires an understanding of the recognition of infection. Pulmonary exacerbation is clinically manifested by an increase in subjective and objective respiratory symptoms (Table 2). Attempts to define and standardize a pulmonary exacerbation in CF have been done (41,47,61), yet a pulmonary exacerbation is still not well characterized. The majority of exacerbations in CF do not involve an elevated white blood cell count, focal findings on chest radiograph, or fever (41,47,55). High-resolution computerized tomography (HRCT) of the chest may be a better surrogate for the presence of lung infection, but is not practical for the day-to-day treatment of an exacerbation (8).

In a study of 11,692 consecutive patients with CF over a 12 month period revealed 42% received antimicrobial agents. Four clinical characteristics are most associated with treatment in four age groups (Table 3) (41). In 2006, 29.2% of CF patients under 18 years of age and 47.6% of CF patients 18 years of age and older had one or more pulmonary exacerbation treated by hospitalization and/ or a course of home IV antimicrobial agents (12).

The length of treatment for a pulmonary exacerbation is dependent upon improvement or resolution of the abnormal signs and symptoms, in addition to the return to baseline of pulmonary function tests (PFT). Improvement is dependent upon three aspects of care: (1) aggressive chest physiotherapy, (2) rest and nutrition, and (3) appropriate antimicrobial therapy. Benefits of treatment of a patient demonstrate a decrease in resting energy expenditure and an increase in physical activity after a course of IV therapy (6).

Debate continues as to whether home IV therapy is comparable to hospitalization for the pulmonary exacerbation; with a suggestion that hospitalization may be superior to home course (65). In a child younger than 6 years of age, who is unable to perform spirometry, or the patient with severe, advanced disease, PFT’s are not helpful in the assessment of improvement of a pulmonary exacerbation. Monitoring patients during an exacerbation is important to evaluate drug levels, potential drug toxicities, and response to care (Table 4).

Length of IV treatment for a pulmonary exacerbation in patients with CF is typically 10-21 days, with the exact duration dependant on the patient’s response to therapy (26,61). In younger patients this duration is typically 10 days; in patients with more advanced pulmonary disease, a longer course of 14-21 days is often required. The national median length of stay for hospitalization, and total duration of treatment for a pulmonary exacerbation (hospitalization and home IV therapy), is 10 days and 14.5 days for CF patients under 18 years of age, and 9 days and 16.0 days for CF patients greater than 18 years of age, respectively (12).

In the United States, a clinical trial is ongoing looking at the best approach for short-term and long-term treatment of the infant and/or young child with a newly cultured P. aeruginosa organism from the respiratory tract (EPIC study, CF Foundation). In Denmark, early aggressive treatment of a new finding of P. aeruginosa in a respiratory specimen in the patient with CF consists of inhaled colimycin and oral ciprofloxacin for 3 months. This strategy has demonstrated a postponement of both chronic colonization and deterioration of pulmonary function in patients with CF. Once P. aeruginosa infection is considered chronic in Danish CF patients, routine management consists of an elective 2-week admission for parenteral antimicrobial therapy, rest, and CPT every 3 months (21,31)

Maintenance

Routine daily respiratory treatments of the CF patient is time-consuming, yet an important part of the daily health of the CF lung (See Table 1). Bronchodilators, inhaled corticosteroids, mucolytics, hypertonic saline and chest-physiotherapy (CPT) are part of the routine daily treatment regimens for all CF patients (1,13,26,61).

The majority of patients with cystic fibrosis find that bronchodilators provide symptomatic relief, by opening up & hydrating the lower airway. Used prior to, or during chest physiotherapy (CPT), nebulized β-agonist agents facilitate clearance of thick mucous from the airway. CPT with albuterol is likened to teeth brushing: both are done twice a day for maintenance of good pulmonary/ oral health, respectively. Many patients with CF will demonstrate bronchial hyper-reactivity at some point in their life, but not all are considered asthmatic. Anti-inflammatory treatment of the CF airways is desired, and inhaled corticosteroids are frequently used, with less than optimal benefits.

Pulmozyme® (rhDNase or Dornase) is a standard mucolytic for CF pulmonary airway clearance. As a thinner of proteins in the lower airway, pulmozyme has been shown to benefit patients with CF with both mild to severe lung disease (22,23). Administered by nebulizer, pulmozyme is considered a daily, routine medication. During times of exacerbation, many CF care providers increase the frequency of pulmozyme to twice a day.

Hypertonic saline in the concentration of 7% solution, has been studied recently in patients with CF as an additional way to provide hydration, and more effective clearance of thick secretions in the lower airway. Benefits included longer duration between pulmonary exacerbation and less need for antibiotic treatment (15,16). Drawback to previously available solutions of hypertonic saline in concentrations of 3% and 9% was the lack of single use vial preparation. Open containers of hypertonic saline or home-made hypertonic saline have a potential for contamination with bacteria and molds and is strongly discouraged. HyperSal ® 3% and 7% hypertonic saline is now available in preservative-free, single-use vials for nebulization (Pari).

Suppressive Treatment

Inhaled Antibiotics

Inhaled antibiotics have the theoretical advantage of increasing drug levels in the bronchial secretions, without subjecting the patient to systemic side effects of the drug. Most of the recent experience with inhaled antibiotics with P. aeruginosainfections comes from treatment of chronic infection in cystic fibrosis.

Currently only one antimicrobial agent is licensed for use as a nebulized drug to the CF lung: Inhaled tobramycin (Tobi®). Tobi® is a preservative-free preparation, developed exclusively for inhalation treatment. Inhaled tobramycin (Tobi®) is given in the dosage of 300 mg vial, administered by nebulized treatment twice a day, cycling on and off every 28 days. Use of Tobi® led to improved pulmonary function, weight gain, and diminished need for oral or parenteral antibiotics in adolescent patients with CF (43).

Frequently patients notice an initial increase in their cough at the beginning of a Tobi®-month, a change in their voice (more husky or hoarse-sounding), and a change in the taste of their sputum. Otherwise Tobi® is usually well tolerated. Tobi® has not been studied as a form of treatment of an acute exacerbation, only as chronic suppressive therapy of P. aeruginosa infection.

Nebulized colistin (colistimethate, polymyxin E), available as Coly-Mycin (Monarch Pharmaceuticals), also has been used extensively in CF as long-term intermittent therapy, although it is not FDA approved for this use. Colistin-resistant to P. aeruginosa has been rarely reported. The dose used for inhalation therapy is 150 mg in 2-4 ml of normal saline twice a day, cycled every other 28 days. The disadvantage of colistin is the lack of a preservative-free form for nebulization, thus the IV solution is used. Some patients may dislike the foamy, sticky nature of the solution when reconstituted; the solution may be irritating to the airway. Colistin must be reconstituted immediately before use in the nebulizer. In 2007, the death of a patient with CF was linked to the use of premixed colimycin, prepared and dispensed by a pharmacy as a ready-to-use liquid. A break-down product in the colimycin solution was determined to be the cause of toxicity and respiratory failure in the CF patient (Communication from CF Foundation: www.cff.org).

Other antimicrobial agents, using the IV solutions of the drugs, have been attempted with limited success (i.e. gentamicin, ceftazidime) for inhalation. Again preservative-free forms are not available, with very limited data available on proper dosing and safety or efficacy in the lung. Bioavailability of the antimicrobial from the aerosolized route of administration is unknown for the off-label use of these agents. The major drawback to use of inhaled ceftazidime is the very offensive taste and smell when this drug in placed into a nebulizer for inhalation.

Two new products are in Phase 2/3 studies for inhalation in patients with CF: a dry powder form of tobramycin (tobramycin inhaled powder or TIP, Novartis) for inhalation (25) and aztreonam (Gilead) in a pulmonary solution (27), are still in clinical trials. Both drugs are intended for long-term intermittent suppressive treatment of P. aeruginosa infection in CF patients.

Non-CF patients requiring tracheotomy tubes and chronic mechanical ventilation are frequently colonized with P. aeruginosa, making intermittent use of TOBI® a reasonable consideration. No published studies are available for use in the non-CF population. The dose of 300 mg twice a day is the same regardless of age or size. Tobramycin levels are not recommended.

Azithromycin

Macrolide antibiotics have been recognized to have a stabilizing effect on patients with chronic P. aeruginosainfection. Recent clinical trails in CF patients have demonstrated a benefit of chronic therapy with azithromycin or clarithromycin by maintaining or improving pulmonary function, improving weight gain, and diminishing need for oral or parenteral antibiotics in adolescent patients with CF over a 48-week period of long-term therapy. The benefit of the longer acting macrolide, azithromycin, as compared to erythromycin and clarithromycin, is less GI-toxicity, and ease of dosing. For patients with CF the recommended dose is 250 mg (weight <40kg) or 500 mg (weight > 40 kg) of oral azithromycin, administered orally 3 times a week (7,18,51,52,62,64). Efficacy data for children under 13 years of age is currently not available. The effect of azithromycin may be the inhibition of alginate production, blockage of quorum sensing, and increased sensitivity to hydrogen peroxide and the complement system (29).

Chronic azithromycin therapy improves outcome in patients with bronchiolitis obliterans organizing pneumonia, now called cryptogenic organizing pneumonia, and radiation-related bronchiolitis obliterans organizing pneumonia. Macrolides may have anti-inflammatory effects in patients with these syndromes although the mechanism of action is not completely understood (56). Long-term azithromycin in a study is being given to CF children without chronic P. aeruginosa infection to determine the safety and impact on pulmonary function and time to acquisition of P. aeruginosa infection (Therapeutics Development Network- CF Foundation).

Role of non-P. aeruginosa Bacteria in Pulmonary Exacerbation

Many other bacterial are known pathogens in the cystic fibrosis lung. Staphylococcous aureous (S. aureus), both methicillin-sensitive and methicillin-resistant, and Haemophilus influenzae are often present in young children, in adults with non-classic CF, as well as adults with classic CF pulmonary disease. Other non-Pseudomonal gram-negative bacteria are isolated in 5-7% of CF patients, which include the Burkholderia cepacia (B. cepacia)complex, Achromobacter/Alcaligenes xylosoxidans, and Stenotrophomonas maltophilia. Atypical nontuberculous mycobacteria can be a cause of chronic infection in CF adolescents and young adults as well (12).

Lack of Response to IV Therapy

A difficult scenario facing the CF caregiver is when there is lack of response to the antimicrobial agents used to treat a CF patient. Lack of adherence to the triad of therapy (antimicrobial agents, chest-physiotherapy, and rest and nutrition) may be the likely reason for a lack of improvement. Consideration of the following should be evaluated for a non-improving CF patient:

• Focal or worsening pulmonary infection

  • Evaluate by high-resolution chest computerized tomography (CT) scan

• Unrecognized sinus disease

  • Evaluate by sinus CT scan

• Other bacterial pathogens inadequately treated (i.e. Staphylococcus aureus)

• Infection by nontuberculous mycobacteria

  • Mycobacterial culture and AFB smears

• Allergic Broncho-Pulmonary Aspergillous (ABPA)

  • Check IgE

  • CBC for eosinophilia

  • Chest radiograph for fungal consolidation

  • Fungal sputum culture

  • Wheezing on chest exam

  • Serum aspergillous precipitans.

• Chest Physiotherapy (CPT)

  • Improperly implemented

  • Non-Adherence

  • Poor pain control (unable to tolerate coughing, as well as CPT)

• Antimicrobial choices:

  • Minimum inhibitory concentration (MIC) of. P aeruginosa isolate at top range of sensitivity (may be a cause of failure to piperacillin-tazobactam)

  • Aminoglycoside peak inadequate for maximal killing if high MIC of  P aeruginosa isolate

• Pneumothorax

• Severe fat/ protein malnutrition with weakened respiratory musculature

• CF-related diabetes mellitus poorly controlled or not recognized:

  • Hyperglycemia 2-hours post-prandial is not normal

  • Fasting glucose may still be normal

  • Unrestricted caloric intake, esp. fat & protein

• New illness (i.e. viral, pertussis)

• Gastroesophageal reflux

  • No tipping during manual CPT

• End-stage lung disease with respiratory failure

Role of Yeast/Fungus in CF Lung

Many CF patients will grow Candida or Aspergillous species from sputum cultures (2,9). These fungi are considered colonizers of the upper airway, especially with repeated courses of antimicrobial agents. In two scenarios, consideration of treatment of the yeast/mold/ fungus is:

• Listing for lung transplant: oral prophylaxis directed at the organism;

• Allergic Broncho-Pulmonary Aspergillous (ABPA): Treatment may include an oral antifungal and corticosteroid therapy. 

  • Guidance with an allergist may be helpful if non-aspergillus mold/ fungus species are suspected as a contributor to reactive-airway disease.

INFECTION CONTROL

In general Pseudomonas aeruginosa bacteria are ubiquitous, i.e. being present commonly in the home, clinic and hospital environments. In a hospital room occupied by a CF patient with a known infection from P. aeruginosa, within a matter of days, the same strain of the bacteria can be found in the sink drain and faucet, the shower stall, toilet and on surfaces in the hospital room. Bars of soap can become contaminated with P. aeruginosa, as can refillable containers of liquid soap, containers of distilled water, and multi-use vials of respiratory medication.

Infection control practices within the home, the clinic and the hospital are important during the routine, daily care of patients with CF. Continuous education of patients, families, and caregivers is important to minimize spread of bacteria, viruses, molds, etc.

 Patients with infections with P. aeruginosa should receive Standard Transmission Precautions in the clinic and hospital setting, with Contact Isolation for a patient with MDR- P. aeruginosa infection. Recommendations for good infection control practices for P. aeruginosa include (but are not limited to) the following (53):

• Perform proper hand hygiene.

• Use hand soap from non-reusable containers; no bar soap.

• Limit fingernail length, and artificial fingernails or nail extenders in medical/ hospital personnel.

• Place all CF patients in a private room that does not share common facilities (i.e. bathroom or shower).

• Avoid direct contact between CF-patients in the hospital unless they are co-habitants at home.

• Follow published recommendations for sterilization and disinfection of patient care equipment.

• Use sterile or 0.2 micron filtered (not distilled or tap) water for rinsing disposable devises after they have been chemically disinfected; avoid the practice of rinsing equipment in tap water which may contaminate a devise.  Dry this equipment after rinsing.

• Use a one-step process and an EPA-registered hospital grade disinfectant/detergent designed for housekeeping environmental surfaces. (HICPAC Guidelines: http://www.cdc.gov/ncidod/dhqp/hicpac.html).

• Cohort patients in the clinic setting by pathogen (i.e. a separate B. cepacia clinic, newborns not mixed into a clinic with chronic P. aeruginosa infection);

• Limit broad spectrum antibiotic usage, if possible (4,33,34).

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28. Han EE, Beringer PM, Falck P, Louie S, Rao P, Shapiro B, Gill M. Pilot study of continuous infusion cefepime in adult patients with cystic fibrosis J Antimicrob Chemother. 2006 May;57(5):1017-9. Epub 2006 Mar 13. [PubMed]

29. Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, Givskov M, Høiby N. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice.Antimicrob Agents Chemother. 2007 Oct;51. [PubMed]

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31. Johansen HK, Norregaard L, Gotzsche PC, Pressler T, Koch C, Hoiby N. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success?--A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection. Pediatr Pulmonol. 2004 May;37(5):427-32. [PubMed]

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33. Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, Green CG, Collins J, Farrell PM. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001 Oct;32(4):277-87. [PubMed]

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35. Lam W, Tjon J, Seto W, Dekker A, Wong C, Atenafu E, Bitnun A, Waters V, Yau Y, Solomon M, Ratjen F. Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients. J Antimicrob Chemother. 2007 Jun;59(6):1135-40. Epub 2007 Apr 19. [PubMed]

36. Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, Collins J, Rock MJ, Splaingard ML. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA. 2005 Feb 2;293(5):581-8. [PubMed]

37. LiPuma JJ, VanDevanter DR. Unique aspects of chronic airways infection. Commentaries on Chronic Airways Infection 2007;1(1):1-6.

38. Massie J, Cranswick N. Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis. J Paediatr Child Health. 2006 Oct;42(10):601-5. [PubMed]

39. Mouton JW, Jacobs N, Tiddens H, Horrevorts AM. Pharmacodynamics of tobramycin in patients with cystic fibrosis. Diagn Microbiol Infect Dis. 2005 Jun;52(2):123-7. [PubMed]

40. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, Grimwood K. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr. 2001 May;138(5):699-704. [PubMed]

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43. Ramsey BW, Pepe MS, Quan JM, et al. Chronic intermittent administration of inhaled tobramycin in patients with cystic fibrosis. New Engl J Med 340:23-30, 1999. [PubMed]

44. Ramsey BW, Wentz KR, Smith AL, Richardson M, Williams-Warren J, Hedges DL, Gibson R, Redding GJ, Lent K, Harris K. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis. 1991 Aug;144(2):331-7. [PubMed]

45. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 141:914-921, 1990. [PubMed]

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47. Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, Ramsey B. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 2001 Sep;139(3):359-65. [PubMed]

48. Saiman L. Microbiology of early CF lung disease. Paediatr Respir Rev. 2004;5 Suppl A:S367-9. [PubMed]

49. Saiman L, Burns JL, Whittier S, Krzewinski J, Marshall SA, Jones RN. Evaluation of reference dilution test methods for antimicrobial susceptibility testing of Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis. J Clin Microbiol 37:2987-2991, 1999. [PubMed]

50. Saiman L, Chen Y, Gabriel PS, Knirsch C. Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. Antimicrob Agents Chemother. 2002 Apr;46(4):1105-7. [PubMed]

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Table 1: Maintenance Therapy of  Pseudomonas  aeruginosa Chronic Infection

	Therapy	Frequency
Chest Physiotherapy	Hand, Vest, Flutter, Acapella, (Exercise)	BID+
Nebulized:
-Βeta-2 agonist	Albuterol* (may mix with hypertonic saline)	BID+
-Hypertonic saline	7% HyperSal® solution*	BID
-Mucolytic	Pulmozyme*	q day – BID
-Inhaled Antibiotics	Tobi®* colimycin	BID for 28 days qo month
Macrolides	azithromycin	250mg (<40kg) 500mg (>40kg) po q M, W, F
Infection Control	Disinfection, sterilization nebulizer sets Hand washing	Each use

*When available use only single-use vials of pre-mixed medications to avoid contamination.

References13, 21, 26, 53, 42, 43, 61

Table 2: Definition of a Pulmonary Exacerbation in Cystic Fibrosis

Subjective features
·          Fatigue ·          Anorexia ·        Dyspnea
Objective features
·          New or increased cough from baseline ·          Weight loss ·          Lower oxygen saturation from baseline ·          Hemoptysis (either a new onset or any increase from baseline) ·          Change in sputum: color (white to yellow/green,) quantity, and tenacity ·          Decline in forced expiratory volume in 1 second (FEV1) of 10% or more from baseline ·          Crackles in the lungs on physical examination* ·          Fever* ·          Infiltrate on Chest radiograph* ·          Elevated White blood cell count (WBC)*

*not always present in a CF exacerbation

References 13, 41, 47, 55, 61

Table 3: Four Characteristics Most Associated with Treatment for Pulmonary Exacerbation in Each Age Group (Age group in years)

< 6years	6-12 years	13-17 years	>=18 years
·        New crackles ·        Increased cough ·        Decline in weight-for-age percentile ·        Increased sputum	·        Decline in FEV1 (% predicted) ·        Increased cough ·        New crackles ·        New P. aeruginosa	·        Decline in FEV1(% predicted) ·        Increased cough ·        New crackles ·        Hemoptysis	·        Decline in FEV1(% predicted) ·        New crackles ·        Hemoptysis ·        Increased cough

Reference 41

Table 4: Monitoring Cystic Fibrosis Patients During Pulmonary Exacerbation with Intravenous (IV) Antibiotics

	Admission	Weekly while on IV’s	Comments
Sputum Culture (CF culture)	X
Acid Fast Bacilli (AFB) culture	if none done in 12 months		Consider if febrile, worsening bronchiectasis, or failure to respond to therapy
Viral Swab RSV/Influenza	if signs/ symptoms
Chest Radiograph	X
Pulmonary Function Testing	if patient able	X	Treat until pulmonary function returns to baseline or plateau in FEV1
High Resolution CT scan chest	As needed
CBC with differential	X	X
Liver function	X	X
BUN/Creatinine	X	X
Glucose	X	If hyperglycemia, monitor 2º post-prandial glucose for CF-related diabetes
PT	if having hemoptysis		Administer Vitamin K, monitor until normalizes
Drug Levels:     vancomycin     tobramycin		X                 X	Aim for tobramycin peak 10 times the  Minimum Inhibitory Concentration (MIC) to P. aeruginosa in mcg/L

 X= recommended for routine care; RSV= Respiratory Syncytial Virus; FEV1= Forced Expiratory Volume at 1 second;

CT+ Computerized tomography; CBC= Complete Blood Count; PT= Prothrombin time

References 13, 21, 26, 42, 61

Table 5: Distinctions between Acute & Chronic Lung Infections

Characteristic	Acute	Chronic
Onset of clinical symptoms	Rapid	Slow
Bacterial population	Clonal	Polyclonal, polyspecies
Growth	Planktonic	Planktonic & biofilm
Antibiotic treatment goal	Eradication	Suppression, palliation
Consequences of antibiotic failure	Death	Accelerated disease progression

Reference 36

Table 6: Hospital Treatment of Pulmonary Exacerbation

Sputum Culture	Antimicrobial Agents	Chest Physiotherapy (Hold CPT only if massive or submassive hemoptysis)	GI	Infection Control	Other Antimicrobials
P. aeruginosa alone	Anti PA and tobramycin*	·   Increase CPT with albuterol nebulizer treatments to q4-6º	·                   -Optimize nutrition (1.5-2.0 x RDA) ·                   -No limit of calories/fat even if CF-Related diabetes ·                   -Optimize pancreatic enzymes ·                   -ADEK vitamins	Private   Room	-Maintain home TOBI cycle -Continue chronic macrolide therapy - Physical Therapy
P. aeruginosa with methicillin-sensitiveS. aureus	Add nafcillin** (or use piperacillin/ tazobactam or ticarcillin/ clavulenate for Anti PA with tobramycin)	·   Consider increasing pulmozyme to bid		Private   Room
P. aeruginosa with methicillin-resistantS. aureus	Add vanc or linezolid***	·    Hypertonic saline 7% 3 ml by neb bid ·    02 to keep saturation  > 92%		Private   Room   Contact	-Consider corticosteroids if:       -RAD component       -ABPA       -palliation of dyspnea
Multi Drug – Resistant   P. aeruginosa with or without A. xylosoxidans B. cepacia S. maltophilia	Meropenem AND -tobramycin or -doxycycline/ tobramycin or -doxycyline/ trimethoprim/ sulfamethoxazole or -clarithromycin OR Cefepine/tobramycin			Private   Room   Contact	-Consider addition of inhaled Colistin (if sensitive)

*Aim peak tobramycin level to be 10 times minimum inhibitory concentration (MIC) of P. aeruginosa to tobramycin

**Avoid treatment with 2 β-lactam antimicrobials (i.e. cefazolin and ceftazidime)

        *** Consider initiation of anti-staphylococcal for all patients, discontinue if 48-78º when preliminary sputum culture negative for Staph aureus.

        PA= Pseudomonas aeruginosa ; P. aeruginosa = Pseudomonas aeruginosa; S. aureus =Staph aureus; A. Xylosoxidans= Achromobacter (Alcaligenes) xylosoxidans;

        B. cepacia=Burkholderia cepacia; S. maltophilia= Stenotrophomonas maltophilia

        References 3, 21, 26, 42, 43, 61

 

Table 7: Anti Pseudomonal Intravenous (IV) Antimicrobials and Dosing in Cystic Fibrosis Patients

Pick One:	Pediatric Dose	Adult Dose	Comments	Alternative Dosing
-aztreonam -cefepime -ceftazidime -imipenem/cilastin -meroperem -ticar/clav -pip/tazo	50 mg/kg IV q8º	2 g IV q8º	Useful in PCN β-lactam allergy
	50 mg/ kg/dose IV q8º	2 g IV q8º	Continuous Infusion	Load 15 mg/kg then 100 mg/kg/24º
	50mg/kg/dose IV q8º	2 g IV q8º
	15-25 mg/kg IV q6º	0.5-1.0 gm IV q6º
	40 mg/kg IV q8º	2 g IV q8º	Continuous Infusion	125-250 mg/hour for 24º
	100 mg/kg IV q6º	3 g IV q6º
	100mg/kg IV q 6º	3 g IV q6º	Continuous Infusion	3.375 g infused over 4 hrs, q8º
Add Aminoglycoside:
-tobramycin	10-12 mg/kg IV q24º	Same	Aim peak 10 times MIC PA to tobramycin	3-15 mg/kg/dose IV q 8º with peak 10-12 µg/mL; trough < 1-2 µg/mL
-amikacin	7.5 mg/kg IVq8º	Same	Peak 25-30 µg/mL; trough < 5 µg/mL	15 mg/kg IV q24º

Consider addition of:

doxycycline	5 mg/kg/day q12º	300 mg	May be beneficial in combination with TMP/sulfa/ doxy or meropenem/doxy
TMP/sulfa	4-5 mg/ kg of TMP q12º	4-5 mg/ kg of TMP q12º	May be beneficial in combination with TMP/sulfa/ doxy or menopenem/doxy

IV= intravenous; mg=milligrams; kg=kilogram; g=gram; MIC= minimum inhibitory concentration; TMP/sulfa= trimethoprim & sulfamethoxazole

References 13, 21, 26, 28, 34, 35, 38, 39, 42, 59, 61

What's New

Dales L, et al. Combination Antibiotic Susceptibility of Biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa Isolated from Patients with Pulmonary Exacerbations of Cystic Fibrosis. Eur J Clin Microbiol Infect Dis 2009;28:1275-1279.

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