Pulmonary infection in CF can be classified into 3 phases1:

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  Initial colonization (primary colonization). Detection of the first positive PA culture in which non-mucoid, antibiotic-sensitive strains are usually isolated. A negative culture after the first positive culture can indicate an aborted initial colonization, cryptic colonization, or eradication of PA following antibiotic therapy. PA is considered eradicated when negative results are obtained from at least 2 cultures: 1 taken 1–2 weeks following completion of treatment and another 2–4 weeks later.51

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  Intermittent colonization. This is indicated by intermittent positive and negative results from consecutive cultures after an initial infection. It can indicate permanent low-grade colonization, sample heterogeneity (different origins), or apparently transient eradication with colonization persisting in the sinuses, causing intermittent reinfection.3,52 Different strains are isolated, including mucoid morphotypes.

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  Chronic infection. Common in CR patients with advanced disease. Mucoid colonies with a variety of other morphotypes are found as a result of specialization and adaptation of PA to the endobronchial environment. The causes of exacerbations are still unclear, but they usually coincide with increases in bacterial load or the emergence of antigenic variants.

Table 3 shows the patterns of infection defined in 20051 and updated according to the Leeds criteria and correlated with clinical parameters (II-A).53,54

There is no evidence to support the effectiveness of administering antibiotics before initial PA colonization, nor of PA vaccination, so these strategies are not recommended (I-A).73,74

Early treatment of primary PA colonization slows the development of chronic colonization (I-A). Treatment should be started as soon as the bacterium is isolated, as the eradication rates are very high (63%–100%).42,75–81 There are various eradication protocols, none of which have been shown to be clearly superior (I-A).3,55,82 Differences in design, in the definition of eradication, and in antibiotic treatment, make it difficult to compare studies published to date.79 Primary colonization is usually asymptomatic; however, if it debuts as an exacerbation, standard treatment regimens are recommended (III-A).

Twice-daily colistimethate sodium, taken together with oral ciprofloxacin for periods ranging from 3 weeks to 3 months,83,84 was the first antibiotic to have a significant effect on chronic infection. In Spain, this drug is marketed under the brand names GES® (Genéricos Españoles Laboratorio) and Promixin® (Praxis Pharmaceutical).

Inhaled tobramycin (300mg/5ml/12h) (TNS, TOBI®, Novartis) is also a safe and effective therapy for eradication of PA, and can even be used in children aged from 6 months to 6 years.78,80,85,86 The ELITE80 study compared the safety and efficacy of TNS (300mg/5ml) for 28 and 56 days following the first PA-positive culture, finding both strategies to be similar. Over 90% of patients tested negative for PA after 1 month of treatment, and most (69%) remained infection-free at 27 months follow-up. These and other studies suggest that short-duration (1–3 months) inhaled antimicrobials should be the treatment of choice (II-A).79,84–86

In the EPIC85 study, patients (aged from 1 to 12 years) were randomized to different treatment regimens for 18 months: combined TNS and oral ciprofloxacin cyclically every 3 months or placebo, or combined TNS plus oral ciprofloxacin or placebo only when 3-monthly sputum culture was positive for PA. TNS (300mg/5ml) was given in 28 days on/28 days off cycles for 18 months, and ciprofloxacin or placebo was administered for 14 days. No significant differences were observed between groups, suggesting that the addition of oral ciprofloxacin does not improve the efficacy of inhaled TNS.

Taccetti et al. in a study comparing TNS (300mg/5ml or 300mg/4ml) with inhaled colistin (2 MU/12h) for 28 days, both in combination with oral ciprofloxacin, found that neither regimen was clearly superior.79

Recently, the ALPINE study of aztreonam lysine for inhalation (AZLI, Cayston®, Gilead), 75mg/8h for 28 days, to treat primary colonization in patients aged between 3 months and 18 years showed that 89.1% of patients were negative for PA at the end of treatment, and that 75.2% and 58.2% remained free of infection at 28 days and 6 months, respectively, after the end of treatment.87

In the light of these studies, inhaled antibiotic treatment with colistimethate sodium (0.5–2 MU, 2 or 3×day) should be given for 1 month (I-A), or TNS (300mg/12h) for 28 days (I-A), or AZLI (75mg/8h) (II-A), either as monotherapy or in combination with oral ciprofloxacin (15–20mg/kg/12h) (maximum 2g/day), for 2–3 weeks (Table 5). Based on the analysis of microbiological tests, combination therapy with ciprofloxacin improves antibiotic action.89

A follow-up culture should be taken 1–2 weeks after the end of the eradication therapy.52,88,90–92 If the culture is negative, TNS or AZLI should be prolonged for between 1 and 3 on/off (28-day) cycles (maximum 3–6 months), or 3–6 months uninterrupted colistimethate (II-A). If the culture is positive, the original regimen should be repeated, or a new regimen (ciprofloxacin in combination with an inhaled antibiotic not previously used) should be ordered (III-A). Cultures should be repeated at the end of the second cycle. If positive, the chronic infection protocol should be applied (I-A), with at least 1 follow-up culture every 3 months (III-A).

There is no conclusive data defining the number of times eradication cycles should be repeated following initial treatment failure. If PA persists after the second eradication attempt, an alternative strategy, such as combination inhaled and intravenous antibiotics (I-B) or the chronic infection protocol (I-A), could be used.3 The appearance of a positive culture after 1 year of negative cultures should be treated as a new initial colonization event (III-A).

Long-term antibiotic therapy has been shown to be effective against chronic PA colonization (I-A),92 inhalation being the route of choice (I-A).10,93 Comparative studies in inhaled antibiotics are limited insofar as they do not usually include patients not previously treated with the study drugs.

Colistimethate sodium with no antibiotic-free rest periods has been shown to be effective (III-A).2,94 The usual dose in adults is 0.5–2MU, 2–3×day, and in children 1MU, 2–3×day. However, this dose can be halved with some nebulizers. In a trial comparing TNS vs colistimethate sodium, most patients had previously received colistimethate. In both groups, the PA colony count fell significantly, although only the TNS group showed significant improvement in lung function.95

Colistimethate in dry powder (Colobreathe®, Forest Laboratories) (125mg/12h) is indicated in patients aged over 6 years with chronic PA colonization,72 and has been shown to be safe and equally effective as TNS. TNS (300mg/5ml/12h) in 28-day on/off cycles significantly improves FEV1, and reduces PA density in sputum, the number of hospitalizations, need for intravenous antibiotics and number of exacerbations (I-A),57,96 even in patients with mild-moderate lung infection.96 It also improves quality of life. A recent study has suggested that it can reduce mortality in patients with chronic infection.97 Tobramycin is also available in a new, more concentrated nebulized formulation (Bramitob®, Chiesi) with the same posology (300mg/4ml), thereby effectively reducing nebulization time.98

A dry powder formulation of tobramycin has recently been approved (TIP™, TOBI® Podhaler®, Novartis). The efficacy and tolerability of the powder form are similar to that of TNS, although a higher incidence of coughing has been reported.99,100 It is available in 112mg doses (4/28mg capsules/12h), in 28-day on/off cycles.

AZLI (75mg/8h in 28-day on/off cycles) has recently been introduced for patients aged 6 years or more (I-A).58,101 AZLI was shown to be superior to TNS (300mg/5ml) for a number of different parameters.102 Treatment was followed by an open-label extension period in which patients received 3 courses of AZLI. Improvements were comparable to those obtained during the initial 6-month trial.

In conclusion, several different therapeutic options for treating chronic bronchial infection are available, including continuous inhaled colistimethate sodium, or 28-day on/off cycles of TNS or AZLI (Table 5). Evidence that most of the benefits obtained during the treatment phase are not maintained during rest periods57,58,102 has led to the development of other regimens, including continuous inhaled antibiotics, alternating or rotating regimens, or even shortened cycles (for example, 14-day on/off cycles) (III-A).103 Combinations have been shown to be effective both in vitro and in animal models104 and are currently at the clinical trial stage; it is hoped they will limit the development of drug resistance.

Inhaled antibiotics should preferably be administered using the same nebulizers as tested in the clinical trials (III-A). The most common side effect is bronchospasm, so a fast-acting bronchodilator should be administered prior to inhalation. Patients receiving ototoxic or nephrotoxic inhaled antibiotics should be monitored once a year for kidney and auditory function.

Exacerbations increase the risk of mortality and are associated with a decline in respiratory function and quality of life. Despite its importance, no definition of exacerbation in CF has yet been agreed.105,106 It is generally accepted that a patient presenting 2 or more of the signs and symptoms indicated in Table 2 should receive antimicrobial treatment (III-A).1,105,107 Symptoms can be less evident in infants and preschool children.

Although the choice of empirical treatment is usually based on a sensitivity analysis of the most recent respiratory sample, in vitro sensitivity does not always correlate with response to treatment (III-A). Traditionally, 2 antimicrobials with different mechanisms of action have been used to enhance antibiotic action and restrict the selection of resistant mutants. Guidelines recommend, albeit on the basis of insufficient evidence, the use of dual therapy in severe exacerbations and in patients with more severe pulmonary infection1,4 (III-C). In mild to moderate exacerbations, treatment should start with oral ciprofloxacin (15–20mg/kg/12h, 2–3 weeks) (III-B).106 In the case of severe exacerbations, or when oral therapy has failed, a combination of an antipseudomonal beta-lactam (piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem or doripenem) and an aminoglycoside (usually tobramycin) or a fluoroquinolone is usually recommended (II-B).105,106 These drugs should be used in high doses due to their limited ability to penetrate respiratory secretions, and because the renal clearance of some antimicrobials, particularly aminoglycosides, is particularly rapid in CF patients.60,64,108

Intravenous colistimethate sodium has also been shown to be effective (III-A)2,108 although kidney function must be monitored. This antibiotic is usually reserved for multi-drug resistant strains, or when the usual treatment options have failed. There is insufficient evidence to recommend withdrawal or continuation of inhaled antibiotics in patients receiving the same antibiotic intravenously,4 although the risk of increased toxicity must be considered (III-C). Exacerbations should not be treated solely with inhaled antibiotics (III-D).

There is insufficient evidence to recommend continuous infusion of beta-lactams; therefore, intermittent cycles should be the norm (II-C).4 In the case of children, once-daily aminoglycosides should be given (B-II) to reduce the risk of kidney damage.109 There is no evidence to define the dosage regimen in adults. When receiving these drugs, patients must be monitored for serum levels and kidney function (III-A). Patients receiving frequent cycles of aminoglycosides should be monitored for auditory function (III-A).

Although there is insufficient evidence to determine the duration of exacerbation therapy,110 it should be continued until symptoms resolve and lung function returns to previous levels (III-C). This usually occurs within 2 weeks,111 except in the case of multi-drug resistant PA or severe pulmonary infection, where prolonged treatment is required.

Home intravenous therapy improves quality of life and can be more cost-effective (III-A); it should be chosen on the basis of the patient's circumstances and the resources available.112 Chest physiotherapy should be stepped up during exacerbations, and existing chronic therapies should be maintained (III-A).4