Cystic fibrosis: Treatment of acute pulmonary exacerbations

INTRODUCTION — Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic variants in the CFTR gene (cystic fibrosis transmembrane conductance regulator), located on chromosome 7 [1-3]. (See "Cystic fibrosis: Genetics and pathogenesis".)

Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF [4]. Infection is one of the major drivers of CF lung disease [5,6]. Treatment of acute pulmonary exacerbations in CF is multifaceted, involving antibiotics, chest physiotherapy, inhaled medications to promote secretion clearance, and antiinflammatory agents. Improved treatment of lung disease, improved nutrition, and the introduction of CFTR modulators are likely responsible for the increased survival that has occurred in patients with CF (figure 1).

The treatment of acute pulmonary exacerbations in CF will be reviewed here. Treatment of chronic pulmonary infection and other aspects of pulmonary disease in CF are discussed in separate topic reviews:

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately. (See "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Genetics and pathogenesis" and "Cystic fibrosis: Nutritional issues" and "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis: Overview of gastrointestinal disease" and "Cystic fibrosis: Hepatobiliary disease".)

PULMONARY EXACERBATIONS IN CYSTIC FIBROSIS

Definition — The clinical course of most patients with CF is punctuated by acute episodes of worsening pulmonary status that are referred to as "pulmonary exacerbations" [7,8]. The CF field has not developed a consensus on criteria to define a pulmonary exacerbation for the purposes of patient care or clinical research [9,10]. Symptoms that are commonly present during pulmonary exacerbations include:

●New or increased cough

●New or increased sputum production or chest congestion

●Decreased exercise tolerance or new or increased dyspnea with exertion

●Increased fatigue

●Decreased appetite

●Increased respiratory rate or dyspnea at rest

●Change in sputum appearance

●Fever (present in a minority of patients)

●Increased nasal congestion or drainage

Reductions in pulmonary function as measured by forced expiratory volume in one second (FEV₁) are often present during pulmonary exacerbations, but chest radiographs may not show significant changes over baseline and are not routinely done. A decrease in arterial hemoglobin oxygen saturation may occur but is not required to diagnose an exacerbation.

Of note, diagnosis of an acute exacerbation is based on changes from an individual patient's recent baseline health status [11]. There are no absolute thresholds that must be crossed to qualify for a pulmonary exacerbation designation. For example, a patient who is asymptomatic at baseline is typically considered to have a pulmonary exacerbation if there is a new cough with sputum production, fatigue, and decreased appetite, even though FEV₁ may remain in normal range [12].

Severity grading — Although there are no published protocols for grading the severity of pulmonary exacerbations [13], CF clinicians routinely distinguish mild from severe exacerbations when planning treatment [14,15]. A common approach is to consider the degree of worsening from baseline of each of the patient's signs and symptoms and arrive at a global assessment of the extent of decline. The designation is not based on reaching a specific level of impairment but rather on relative change from baseline. For example, a patient with near-normal baseline pulmonary status would be said to have a severe exacerbation if the acute illness was characterized by the onset of a productive cough and a large decline in FEV₁ (eg, greater than 10 percent). A patient with severe pulmonary disease would be considered to have a mild exacerbation if the cough, sputum production, exercise tolerance, and FEV₁ worsened minimally but perceptibly from prior baseline status.

Incidence and consequences — The Cystic Fibrosis Foundation Patient Registry reported that 12.1 percent of patients had at least one pulmonary exacerbation severe enough to be treated with intravenous (IV) antibiotics in 2021, down from 31.6 percent in 2019 [4,16]. The availability of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators has decreased the rate of pulmonary exacerbations, especially following the US Food and Drug Administration approval of elexacaftor-tezacaftor-ivacaftor, which brings highly effective treatment to approximately 92 percent of patients >6 years of age (see "Cystic fibrosis: Treatment with CFTR modulators"). It is also likely that social distancing and mask wearing recommended during the coronavirus disease 2019 (COVID-19) pandemic contributed to the reduction in pulmonary exacerbations by limiting exposure of CF patients to respiratory viruses [17].

The consequence of each episode of pulmonary exacerbation can be considerable. Between 12 and 35 percent of patients who have a pulmonary exacerbation fail to recover to at least 90 percent of their baseline FEV₁ [18-20]. Given the adverse effects of exacerbations, many of the chronic treatments for CF pulmonary disease are recommended, in part because they have been shown to reduce exacerbation frequency. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection" and "Cystic fibrosis: Treatment with CFTR modulators".)

PATHOGENESIS

Viruses — Viruses are detected in many cases of acute exacerbations in children with CF, and there is some evidence that they are important contributors to declining pulmonary function. This was shown in a prospective study in which viruses were detected by a molecular method in 60 percent of children with CF presenting with an exacerbation during winter months [21]. The pathogens were coxsackie/echovirus, rhinovirus, respiratory syncytial virus, parainfluenza, adenovirus, and influenza. A somewhat lower frequency of viral detection was reported in a study in adults, in whom viruses were detected in 10 to 25 percent of those with acute exacerbations, with rhinovirus, coronaviruses, and influenza being detected most frequently [22,23]. Patients in whom viruses were associated with their acute exacerbations were less likely to recover to baseline forced expiratory volume in one second (FEV₁) compared with those in whom viruses were not detected [23].

Bacteria — Most patients with CF have chronic bacterial infection of the airways, as demonstrated by sputum cultures (table 1); the prevalence of each bacterial type varies with the age of the patient (figure 2). (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)

Important pathogens include:

●Pseudomonas aeruginosa

●Staphylococcus aureus (methicillin-sensitive or methicillin-resistant species)

●Burkholderia cepacia complex

●Nontypeable Haemophilus influenzae

●Stenotrophomonas maltophilia

●Achromobacter species

●Nontuberculous mycobacteria

Anaerobic bacteria are frequently identified, but their role in pulmonary exacerbations is uncertain [24-26]. Nonculture-based assays to identify bacteria have shown that the number of species present in respiratory secretions from CF patients is often considerably higher than what is revealed by culture-based methods, with substantial variation among patients [27].

It is generally accepted that bacteria are involved in the pathophysiology of pulmonary exacerbations in CF, but how they do so is uncertain [28-31]. Most exacerbations are not associated with the appearance of bacterial species or strains that are new to the patient. Furthermore, there is no consistent pattern of change in bacterial communities leading up to pulmonary exacerbations [27].

Noninfectious causes — The CF airway is characterized by chronic neutrophil-rich inflammation (see "Cystic fibrosis: Clinical manifestations of pulmonary disease"). Inflammatory markers in serum and airway secretions increase during pulmonary exacerbations [32,33]. Although pulmonary infection is probably a major contributor to the airway inflammation, there is some evidence that cystic fibrosis transmembrane conductance regulator (CFTR) deficiency itself can cause inflammation in the absence of infection [34]. In any case, the inflammatory processes associated with the bacterial infection appear to exceed the level that is required to limit systemic spread of infection and results in excessive damage to the lung. As a result, some antiinflammatory strategies are effective at limiting lung damage. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Antiinflammatory therapy'.)

TREATMENT: NONANTIMICROBIAL

Continuation of the chronic treatment regimen — Nonantimicrobial treatments are an important component of managing an acute pulmonary exacerbation, in combination with antibiotics and antiviral agents. (See 'Treatment: Antibiotics' below and 'Treatment: Antivirals' below.)

Key components of nonantimicrobial treatment include:

●Medications to clear respiratory secretions (eg, inhaled dornase alfa, hypertonic saline, and mannitol) (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Inhaled airway clearance agents')

●Chest physiotherapy (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Chest physiotherapy')

●Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (see "Cystic fibrosis: Treatment with CFTR modulators")

●Antiinflammatory medications (eg, azithromycin, glucocorticoids) (see 'Glucocorticoids' below and "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Antiinflammatory therapy')

●Optimization of nutritional status (see "Cystic fibrosis: Nutritional issues", section on 'Nutrition support')

●Ensuring glucose control for those with CF-related diabetes (see "Cystic fibrosis-related diabetes mellitus", section on 'Treatment')

●Exercise, as tolerated (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Chest physiotherapy')

These therapies are often components of the patient's chronic treatment regimen and are discussed in detail in a separate topic review. (See "Cystic fibrosis: Overview of the treatment of lung disease".)

These treatments should be continued or intensified during an acute exacerbation, as recommended by virtually all guidelines, although high-quality studies are generally lacking to assess this strategy [28]. Many patients have poor adherence to these treatments when they are at their baseline status and require encouragement to increase their use during exacerbations [35]. In addition, Cystic Fibrosis Foundation guidelines recommend increasing the frequency of airway clearance treatments during exacerbations beyond what is prescribed as part of the chronic therapy regimen (eg, increasing to four times per day) [28].

Glucocorticoids — Some CF clinicians administer a brief course of glucocorticoids to selected patients during an acute exacerbation, although the evidence is limited and there is considerable variation in practice [36,37]. Our own practice is to administer only a brief course of prednisone (2 mg/kg/day [maximum 60 mg daily] for five days) to the rare subset of CF patients whose exacerbations have characteristics of an acute asthmatic episode (eg, chest tightness, wheezing, acute symptomatic response to inhaled beta-adrenergic agonists). We use this strategy because glucocorticoids are useful for asthmatic symptoms in patients without CF. (See "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Systemic glucocorticoids'.)

We do not recommend broader use of glucocorticoids (ie, the routine use of glucocorticoids for exacerbations in the absence of asthma-like symptoms). This approach is used by some clinicians, based upon the hypothesis that acute exacerbations in CF are similar to those in adults with chronic obstructive pulmonary disease (COPD), in whom glucocorticoids are generally beneficial (see "COPD exacerbations: Management"). However, there are no definitive studies to evaluate the risks and benefits of this strategy in patients with CF. A small pilot study showed no significant difference in forced expiratory volume in one second (FEV₁) in patients treated for five days with prednisone 2 mg/kg/day (up to 60 mg daily), and hyperglycemia or glucosuria were noted in many prednisone-treated patients [38]. A retrospective study of pediatric patients hospitalized for a pulmonary exacerbation compared 63 admissions (in 42 patients) who received corticosteroids with 43 admissions (in 26 patients) who did not [39]. Propensity scoring identified a subset of matched subjects between the groups. No difference was found in FEV₁ at discharge or follow-up nor in time to next exacerbation. The scarcity of data evaluating glucocorticoids has led a Cystic Fibrosis Foundation guidelines committee to conclude that there is insufficient information to permit a recommendation regarding the use of glucocorticoids in this setting [28]. To help fill this information gap, a clinical trial is underway to determine the efficacy and safety of oral prednisone (NCT03070522).

Respiratory support

●Supplemental oxygen – We administer supplemental oxygen during pulmonary exacerbations, following the same guidelines as used for patients with acute exacerbations of COPD (see "COPD exacerbations: Management"). No CF-specific clinical trials of supplemental oxygen administration have been performed that would modify these COPD recommendations. We administer oxygen to achieve an oxygen hemoglobin saturation by pulse oximetry of 88 to 92 percent or an arterial blood oxygen tension of 60 to 70 mmHg.

●Noninvasive ventilation – We offer patients noninvasive positive-pressure ventilation, using guidelines similar to those for patients who develop acute ventilatory failure during exacerbations of COPD (see "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications"). Appropriate candidates are those with acute elevation of arterial carbon dioxide tension to >45 mmHg or hypercapnic acidosis and who have none of the contraindications (eg, severely impaired consciousness, inability to cooperate, or inability to protect their airway). The noninvasive ventilation regimen must accommodate intermittent treatments for assisting airway secretion clearance.

●Invasive ventilation – The guidelines for endotracheal intubation and mechanical ventilation used for patients with COPD are appropriate for CF patients whose pulmonary exacerbation progresses to acute respiratory failure, if congruent with the patient's goals of care and if noninvasive ventilation fails or is contraindicated (see "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease"). Input from the appropriate transplant center should be sought to ascertain how intubation with mechanical ventilation will affect the patient's listing for transplantation. (See "Cystic fibrosis: Management of advanced lung disease".)

●Extracorporeal membrane oxygenation support (ECMO) – When adequate ventilation and/or oxygenation cannot be supported by assisted ventilation, ECMO has been used to successfully bridge CF patients to lung transplantation [40,41]. The Cystic Fibrosis Foundation Advanced CF Lung Disease Guidelines recommend that those who require invasive ventilation be considered for early institution of ECMO, if congruent with the patient's goals of care and with input from the pertinent transplant center [42]. (See "Extracorporeal membrane oxygenation (ECMO) in adults".)

Intensive care unit treatment — Outcomes for both adult and pediatric CF patients requiring treatment in an intensive care unit (ICU) was previously reported to be uniformly poor [43] but has fortunately improved [44,45]. Patients requiring ICU treatment admission for pneumothorax or hemoptysis have a better prognosis compared with CF patients admitted to the ICU for other indications [46]. In addition, ICU support appears to be useful for those patients who are candidates for lung transplantation and for infants and young children with acute bronchiolitis but without extensive bronchiectasis. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Intensive care unit treatment'.)

An episode of respiratory failure, regardless of age (except for infants and young children with pure bronchiolitis), should prompt discussion of end-of-life care, quality of life, and the possible indications for lung transplantation. Ideally, these discussions should occur when a patient's clinical trajectory suggests increasing risk for respiratory failure but well before ICU care is needed. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplant evaluation'.)

TREATMENT: ANTIVIRALS — Because CF patients are at increased risk for severe consequences from influenza infection, we suggest prophylaxis with oseltamivir and treatment with either oseltamivir or baloxavir. (See "Seasonal influenza in children: Prevention with antiviral drugs" and "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)  

Annual vaccination against viral influenza is also recommended for all CF patients older than six months of age, using an inactivated vaccine delivered by injection. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Prevention of infection'.)

There are no specific treatments for viruses other than influenza that are typically associated with CF exacerbations.

TREATMENT: ANTIBIOTICS

Rationale — Systemic antibiotic treatment of patients with acute pulmonary exacerbations is recommended in virtually all consensus guidelines [28-31]. Although this is a nearly universal practice and reflects widespread expert opinion, it is based primarily on clinical experience and indirect evidence.

Only a few small controlled trials have specifically evaluated the benefit of antibiotics in treating pulmonary exacerbations [47-49]. These have shown that subjects treated with antipseudomonal antibiotics are more likely to have improvements in pulmonary function tests lasting up to four months, as well as reduction in sputum bacterial density, compared with subjects given placebo with chest physiotherapy and bronchodilators [47] or those treated with antibiotics with no antipseudomonal activity [48]. Additional evidence comes from observational data that suggest that the burden of bacteria (particularly P. aeruginosa) is correlated with pulmonary symptoms of CF patients [6] and that bacterial density and inflammatory markers decrease after antibiotic treatment of pulmonary exacerbations [50]. Finally, data from large observational studies show that the frequency and severity of pulmonary exacerbations are associated with long-term decline in pulmonary function, worse quality of life, and decreased survival [51-53].

Most recommendations regarding antibiotic use are based on expert opinion with few high-quality studies to support what is done. This results in considerable variation in antibiotic-prescribing practices among CF clinicians [54]. In an effort to standardize care, the CF community has adopted guidelines that will be described here. Some of these practices are being actively challenged and are being assessed by clinical trials. Regardless, the combination of practices that are commonly used are likely effective since they have been associated with marked improvements in life expectancy and quality of life over many decades (figure 1). Therefore, abandonment of past practices should be done cautiously and ideally should be driven by high-quality clinical research.

Antibiotic selection

Sputum cultures — Virtually all guidelines for treatment of pulmonary exacerbations recommend selecting antibiotics based on the bacteria identified by culture of respiratory secretions [28-31,55]. We suggest performing cultures of expectorated sputum or throat swabs every three months during routine clinic visits, consistent with guidelines from the Cystic Fibrosis Foundation [30,56,57]. Since CF patients often carry the same bacteria for long periods of time, these cultures are relatively predictive of what will be found in specimens obtained at the start of a pulmonary exacerbation. If a routine culture has not been performed within the few weeks prior to the start of an exacerbation, we usually obtain one at that time (see "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Periodic surveillance cultures'). However, we use the new culture results to alter the initially selected antibiotic regimen only if the clinical response is inadequate. (See 'General strategies' below.)

Antibiotic susceptibility testing — Conventional practice has been to use antibiotic susceptibility testing to select antibiotics to treat CF pulmonary exacerbations [28,29,31], but accumulating evidence has shown that selecting antibiotics for P. aeruginosa based on susceptibility testing may not improve outcomes [58]. This has led some CF centers to decrease the frequency of routine antibiotic susceptibility testing to once a year for P. aeruginosa. A group of experts was assembled by the Cystic Fibrosis Foundation to use a Delphi approach to generate a list of best clinical practices regarding selection of antibiotics [55]. No consensus could be reached regarding the use of antibiotic susceptibility test results to guide antibiotic selection for treatment of P. aeruginosa during acute exacerbations. To improve the utility of susceptibility testing, alternate strategies have been evaluated, including culturing bacteria under conditions that induce biofilm formation and performing antibiotic synergy tests, but the results so far do not support their clinical use.

●Conventional in vitro susceptibility testing – Selection of antibiotics has traditionally been based on in vitro antibiotic susceptibility testing. Special laboratory procedures are necessary to test the Gram-negative bacilli isolated from CF patients because these tend to grow slowly on standard media [5]. Many laboratories test multiple morphotypes of the same species. (See "Sputum cultures for the evaluation of bacterial pneumonia".)

However, the benefit of susceptibility testing is uncertain, particularly for P. aeruginosa:

•A systematic review of the literature identified studies whose results could be used to assess whether the clinical response to antimicrobial treatment for pulmonary exacerbations was predictable by antibiotic susceptibility test results [58]. Of the 13 studies identified, 11 failed to show that susceptibility results predicted clinical response. One of the studies that did show a correlation found it for only one of two treatment regimens being evaluated [59]. In the second study, the reported correlation between drug resistance and treatment failure was lost when multivariable logistic regression analysis showed that the correlation could be explained by imbalances in other risk factors known to influence treatment outcomes [60].

•Most of the studies identified in the systematic review evaluated patients infected with P. aeruginosa. The data needed to assess the value of antibiotic susceptibility testing for other CF bacteria are insufficient to reach conclusions. Until such data become available, we continue to use susceptibility test results to aid in antibiotic selection for these other bacteria.

•Subsequent to the systematic review [58], a single-center retrospective study of 2390 pulmonary exacerbations in 413 patients reported that improvements in forced expiratory volume in one second (FEV₁) and body weight were no different between groups whose antibiotic selection fully covered, partially covered, or left uncovered the P. aeruginosa bacteria that were isolated [61].

•Another study evaluated outcomes from a single center where the protocol changed from testing antibiotic susceptibility of P. aeruginosa in respiratory secretions from every three months to once a year unless a morphologically different strain was detected [62]. Comparing data from the two years before the protocol change with that of two years after, they found no difference in number of pulmonary exacerbations and hospitalizations, duration of treatment, or pulmonary function test results.

●Limitations of antibiotic susceptibility testing – There are multiple reasons to explain the problems with antibiotic susceptibility testing as performed in clinical microbiology laboratories:

•Studies of the reproducibility of antibiotic susceptibility test results found considerable variation when the same morphotype was tested multiple times and when a single isolate was tested by multiple laboratories [63].

•The same bacteria species obtained from different airway segments of the same patient can have different phenotypes, including antibiotic-resistance profiles [64].

•Culture conditions used by clinical microbiology laboratories do not duplicate the CF airway environment. Bacteria may be susceptible to a given antibiotic in one environment but not the other [65].

•Microbiome studies have demonstrated that the spectrum of bacteria present in the CF airway is much broader than what is identified by culture techniques [27]. The role of the previously unrecognized bacteria in pulmonary exacerbations is unknown.

●Testing bacteria grown as biofilms – To address the limitations of conventional susceptibility testing, some laboratories have applied the technique to bacteria cultured under conditions that induce them to form biofilms in vitro. The rationale is that bacteria grown as biofilms may more closely mimic the properties of bacteria in the airways of CF patients, a proportion of which grow in self-generated biofilms. This type of testing is more likely to report antibiotic resistance because bacteria grown as biofilms are less susceptible to antibiotics compared with the same isolates grown under standard clinical laboratory conditions [66].

Unfortunately, susceptibility testing of the biofilms grown using current laboratory techniques does not appear to have a clinical advantage over conventional susceptibility testing. Two randomized studies found no differences in clinical outcomes or bacterial density for patients whose antibiotic regimens were chosen based upon susceptibility results from biofilms versus conventional cultures [67,68], as outlined in a systematic review [69].

●Antibiotic synergy testing – Combinations of antibiotics have been tested to determine whether their combined effects are greater than the sum of their individual activities. The rationale is that multidrug-resistant bacteria that are often encountered in patients with CF may be susceptible to combinations of antibiotics, although they are resistant to each drug when tested separately. Indeed, studies have described in vitro synergistic effects of various combinations of antibiotics for many isolates of multidrug-resistant P. aeruginosa [70] and B. cepacia complex [71]. But, unfortunately, a large randomized trial showed no difference in clinical outcome when antibiotics were selected based on synergy testing compared with standard susceptibility testing [72].

General strategies

●Initial antibiotic selection – Virtually all guidelines recommend selecting antibiotics that have activity against the pathogenic bacteria identified in the patient's recent respiratory secretion cultures (table 2). Our practice is to prescribe the same antibiotic regimen that was previously successful, unless the bacteria identified in respiratory secretions have changed since the last episode.

The traditional practice of using susceptibility test results to guide selection is being questioned and actively reexamined (see 'Antibiotic susceptibility testing' above). In particular, we assign secondary importance to the results of susceptibility testing for P. aeruginosa, based on the accumulating data that question the value of testing susceptibility for this bacterium (see 'Antibiotics for specific bacteria' below). Until studies are done to assess the value of test results for other bacteria, we are continuing the traditional practice of selecting antibiotics based on susceptibility test results.

●Double antibiotic coverage – CF guidelines recommend at least one antibiotic to cover each pathogenic bacteria that is cultured from respiratory secretions and two antibiotics for P. aeruginosa infections [28]. The evidence supporting double coverage of Pseudomonas is lacking [73], but it has been the standard of care for many years. In the published CF guidelines cited above, there was considerable discussion regarding the pros and cons of double coverage [28]. In the end, the guidelines committee concluded that the practice should be continued until definitive data become available that support single coverage. Subsequent to the writing of these guidelines, a retrospective study was completed that linked data from the Cystic Fibrosis Foundation Patient Registry with the Pediatric Health Information System [74]. No differences in improvement in FEV₁ or time to next pulmonary exacerbation were found when comparing 455 pulmonary exacerbations treated with one antipseudomonal intravenous (IV) antibiotic with the 2123 exacerbations treated with two.

Our practice has been to follow the double-coverage guideline, but it is tempered by the limited evidence on which the recommendation is based, the toxicity incurred by the second antibiotic, and other patient factors, such as the severity of the exacerbation and response to therapy during past exacerbations (see 'Patient-specific considerations' below). We generally avoid using two beta-lactam antibiotics simultaneously, but some CF clinicians are not as reluctant, particularly when other regimens have failed. Our decision is based upon in vitro studies showing that the antimicrobial effect of adding the second beta-lactam is unpredictable and can sometimes be antagonistic to the first [70,75]. CF guidelines do not recommend double antibiotic coverage for other Gram-negative organisms, such as the Achromobacter species, B. complex species, or S. maltophilia.

●Coverage of multiple bacteria – It is not unusual for CF patients to have multiple bacterial species identified in their respiratory secretions. Selecting an antibiotic combination that covers all of the isolates is occasionally difficult without resorting to an impractically large number of antibiotics. Unfortunately, little information is available to determine the priority of the different pathogens when only a subgroup can be reasonably covered.

●Antibiotic-resistant bacteria – When in vitro testing can identify no antibiotic to which a bacterium is susceptible, our practice is to select from a list of antibiotics that would otherwise be chosen empirically for that pathogen (table 2). Retrospective studies indicate that many patients will improve clinically under these circumstances [58,76]. Furthermore, the lack of correlation between susceptibility test results and clinical outcomes for P. aeruginosa indicate that clinicians should not be hesitant to choose antipseudomonal antibiotics that the laboratory reports as resistant. (See 'Antibiotic susceptibility testing' above.)

If a patient is clinically improving following initiation of antibiotics, we continue the regimen regardless of the resistance pattern reported from a sample obtained at the start of treatment. A retrospective study of 6451 pulmonary exacerbations in pediatric patients reported that antibiotic switching during treatment was more frequent when new susceptibility tests were performed but without evidence of improved outcomes [15,77].

●Response to a failing regimen – If a patient does not show clinical improvement within approximately five days of starting treatment, we alter the antibiotic regimen. We choose the new regimen either empirically or by adjusting the regimen if new culture results reveal a bacteria species not covered by the initial regimen (see 'Pseudomonas aeruginosa' below). Failure to improve should also prompt a reassessment of contributing factors (eg, an asthma component to the exacerbation or the presence of a new pathogenic organism [virus, fungus, or mycobacterium]), which may not have been cultured or detected on initial sputum testing.

●Managing the chronically prescribed antibiotics

•Chronic azithromycin – We continue administering oral azithromycin during the acute exacerbation if it is a component of the chronic pulmonary regimen, with some important exceptions (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'). We temporarily stop it if continuation might cause adverse interactions with the antibiotics added to treat the exacerbation (eg, risk for QTc prolongation when used with fluoroquinolones) but recognizing that the half-life of azithromycin is long. Accumulating evidence indicates that patients with acute pulmonary exacerbations may respond less favorably to tobramycin if they are receiving chronic azithromycin therapy [78,79]. A proposed mechanism is the induction of bacterial efflux pumps by azithromycin that reduces bacterial tobramycin levels [80]. There is no consensus within the CF community on how to respond to this provocative, but as yet inconclusive, information [81]. Options include discontinuing chronic azithromycin for patients who are likely to be prescribed tobramycin in the near future, continuing azithromycin but selecting antibiotics other than tobramycin to treat pulmonary exacerbations, or continuing the current practice of prescribing both azithromycin and tobramycin while waiting for more definitive data.

•Chronic inhaled antibiotics – There is insufficient information to recommend whether to continue an inhaled antibiotic during an acute exacerbation when it is part of a patient's chronic pulmonary regimen. Our local practice is to suspend the inhaled medication. Others would continue the inhaled medication during an acute exacerbation but generally not as a substitute for one of the two-drug IV regimens for P. aeruginosa outlined in the table (table 2). A guidelines committee of the Cystic Fibrosis Foundation could not reach a conclusion regarding the risks and benefits of administering the same antibiotic by both IV and inhaled routes [28]. Of note, if both inhaled and IV tobramycin are used, one needs to be aware that the inhaled drug can cause a modest increase in serum levels, possibly interfering with pharmacokinetic analyses and causing errors in dosing [28]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Inhaled tobramycin'.)

Patient-specific considerations — Although antibiotic selection starts with the principles outlined above, there are a number of factors that typically modify final choices based on an assessment of benefits versus risks.

●Severity of exacerbation – A severe exacerbation (see 'Severity grading' above) generally warrants rapid initiation of aggressive therapy, under the assumption that doing so will increase the chances of returning to baseline status. S. aureus should be covered with a first-line drug, and P. aeruginosa should be covered with two systemic antibiotics (table 2). Aggressive treatment is warranted because the risk of permanent loss of lung function if the infection persists is thought to outweigh the risks of adverse effects from drug toxicity and the burden and complications of IV access.

For milder exacerbations, many clinicians will initiate treatment with an oral antibiotic regimen that minimizes the risk for adverse effects associated with IV treatment yet has a reasonable likelihood of success [14,15]. Evidence shows that this approach leads to clinical improvement [82], but the extent may not be as great compared with using more aggressive therapy such as regimens that include hospitalization and/or IV antibiotics [11,83-85]. If a less aggressive approach is used, patients should be monitored closely and treatment escalated to a more aggressive regimen if they do not return to their baseline level of function.

●Drug allergy and toxicity considerations – Allergies to antibiotics are common in patients with CF [86] and influence the choice among the antibiotic options suggested by the culture results [86]. If acceptable alternatives are not available, desensitization protocols can be used for antibiotics that previously caused immediate hypersensitivity reactions (see "Rapid drug desensitization for immediate hypersensitivity reactions"). Any significant adverse effects that occurred during previous courses of antibiotics (eg, renal or ototoxicity from aminoglycosides) influence drug selection.

●Efficacy of past antibiotic regimens – Because of the uncertain value of using susceptibility testing to guide antibiotic selection, particularly for P. aeruginosa, our practice has been to consider the response to past treatments, as measured by changes in symptoms and pulmonary function tests. If the same bacterial species are identified in recent cultures, we tend to select a regimen that was previously successful.

●Patient preferences – Although the treatment options we present to a patient are derived from the above considerations, patient preferences can influence the final decisions. For example, a number of patients have strong opinions about when they are willing to use IV antibiotics or be hospitalized in given situations. After a discussion of the benefits and risks of the different options, we incorporate the patient's preferences when forming the treatment plan.

Route of administration — The route by which an antibiotic is administered does not determine its effectiveness but rather its bioavailability. Ciprofloxacin and linezolid are highly effective antibiotics that achieve therapeutic levels when administered orally, thus obviating the need for IV delivery. Most other antibiotics that are effective for moderate or severe acute exacerbations must be administered IV because they are not absorbed when given orally.

●Oral – It is common practice to initiate treatment with oral antibiotics for mild exacerbations [14,15] (see 'Patient-specific considerations' above). However, if the initially chosen regimen does not achieve the desired goals, the regimen should be altered. (See 'General strategies' above.)

●IV – The following situations require use of IV antibiotics:

•Severe exacerbations for which optimal systemic treatment requires at least one antibiotic that can be administered by IV route only

•Failure of oral antibiotic therapy to resolve the exacerbation

•Resistance of bacteria (other than P. aeruginosa) to orally administered antibiotics

•Drug allergy or intolerance to the otherwise appropriate oral antibiotics

●Inhaled – Practice varies among clinicians regarding use of inhaled antibiotics as a component of the treatment for an acute pulmonary exacerbation, in conjunction with oral and/or IV antibiotics [14]. A systematic review found insufficient information to guide when to use inhaled antibiotics during exacerbations [87]. Based in part on our concern that the distribution of inhaled medications to the lungs of CF patients can be very inhomogeneous [88], we do not consider an inhaled antibiotic to be an equivalent substitute when systemic antibiotics would otherwise be used as recommended, as shown in the table (table 2). When a beta-lactam and/or either an aminoglycoside or colistimethate are indicated, we deliver them parenterally and do not rely on their inhaled versions.

As exceptions, we might include an inhaled antibiotic in the following situations:

•For a relatively mild pulmonary exacerbation, when an inhaled antibiotic can be added to an oral medication (eg, a fluoroquinolone)

•When the inhaled antibiotic provides coverage for a particular bacterial isolate that is not otherwise covered by the chosen systemic regimen

Antibiotics for specific bacteria — We select antibiotics based on the bacteria identified in the most recent respiratory secretion cultures, as outlined in the table (table 2). For mild exacerbations, we often begin with an oral regimen (see 'Route of administration' above). For moderate or severe exacerbations or if the response to the initial oral regimen is suboptimal, we use a regimen that usually includes antibiotics that require IV administration.

Pseudomonas aeruginosa

●For mild exacerbations, we treat with an oral fluoroquinolone, either ciprofloxacin or levofloxacin, even if the clinical laboratory reports resistance, as long as the patient responded well in the recent past. Based on published pharmacokinetic studies, children with CF generally require higher doses of ciprofloxacin than other children (see 'Ciprofloxacin' below). For patients using an inhaled antipseudomonal antibiotic as part of their chronic treatment, we recommend that they continue it or start a new course if they are in their "off" period.

●For moderate or severe exacerbations, or if the above oral/inhaled regimen fails, we treat with an antibiotic combination that includes a beta-lactam such as piperacillin-tazobactam, cefepime, ceftazidime, imipenem with cilastatin, or meropenem (or ticarcillin-clavulanate, where available) plus one of the following: a fluoroquinolone (eg, ciprofloxacin or levofloxacin) or tobramycin if recent use of a fluoroquinolone has failed. Tobramycin, rather than gentamicin, is selected because it usually has greater in vitro activity against P. aeruginosa. We use IV rather than inhaled tobramycin for this purpose. (See 'General strategies' above and 'Route of administration' above.)

If the clinical response is suboptimal after approximately five days, we will alter the regimen, usually by changing to a different beta-lactam. For a failing regimen, the fluoroquinolone can be changed to tobramycin. If already on tobramycin, it can be changed to amikacin or colistimethate. Unfortunately, there are few data on which to base a strategy for choosing which of these options to follow. Notwithstanding the problem of poor correlation between susceptibility testing of P. aeruginosa and clinical outcome, in the absence of other guiding factors such as drug allergies or past adverse drug effects, we will use minimal inhibitory concentrations reported by the microbiology laboratory to select the replacement beta-lactam and/or to decide whether to use amikacin or colistimethate in place of tobramycin.

For patients with newly acquired P. aeruginosa, sputum cultures should be obtained following successful treatment of the exacerbation to determine if the strain has been eradicated. If not, an "early eradication" protocol should be used. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Prevention and eradication'.)

Methicillin-sensitive Staphylococcus aureus (MSSA)

●For mild exacerbations, we treat with trimethoprim-sulfamethoxazole, doxycycline, or amoxicillin-clavulanate when in vitro testing shows susceptibility. Based on published pharmacokinetic studies, children with CF generally require higher doses of trimethoprim-sulfamethoxazole than other children. (See 'Sulfonamides' below.)

●For moderate or severe exacerbations, or if the above oral regimen fails, we treat with nafcillin or cefazolin.

Methicillin-resistant Staphylococcus aureus (MRSA)

●For mild exacerbations, we treat with trimethoprim-sulfamethoxazole or doxycycline, if in vitro testing shows susceptibility to these drugs.

●For moderate or severe exacerbations, or if the above oral regimen fails, we treat with oral linezolid, IV vancomycin, or IV ceftaroline [89].

Of note, S. aureus resistance to macrolides is increasing in patients treated chronically with azithromycin, causing macrolides to be less reliable for the treatment of S. aureus infections [90]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'.)

Pseudomonas aeruginosa with MSSA or MRSA

●For mild exacerbations, we treat with an oral fluoroquinolone, either ciprofloxacin or levofloxacin, for the P. aeruginosa plus a second oral antibiotic selected depending on whether MSSA or MRSA is identified, as detailed above.

●For moderate or severe pulmonary exacerbations, or if the above oral regimen fails:

•When MSSA accompanies the P. aeruginosa, we treat with a combination that includes piperacillin-tazobactam, cefepime, imipenem with cilastatin, meropenem, or ticarcillin-clavulanate plus one of the following: an oral fluoroquinolone or IV tobramycin, amikacin, or colistin, as discussed above.

•When MRSA accompanies the P. aeruginosa, we treat with vancomycin or linezolid plus the same antibiotic combination as for P. aeruginosa alone (three antibiotics total). Although ceftaroline has good activity against MRSA, it is not effective for P. aeruginosa. Because we usually include an antipseudomonal beta-lactam to treat pulmonary exacerbations involving P. aeruginosa, we try to avoid ceftaroline for the MRSA out of concern for using two beta-lactams simultaneously, but we will resort to using two beta-lactams if there are no better options. (See 'General strategies' above.)

Burkholderia cepacia — B. cepacia complex bacteria (which includes Burkholderia multivorans and Burkholderia cenocepacia) are often highly resistant to multiple antibiotics. Antibiotic selection should be guided by in vitro susceptibility testing, when possible. Treatment options are often limited, but some isolates show susceptibility to trimethoprim-sulfamethoxazole, doxycycline, ceftazidime, and/or meropenem. When no single antibiotic is effective, combinations of two or more antibiotics sometimes show in vitro susceptibility [71]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Burkholderia cepacia complex'.)

Achromobacter species — We treat Achromobacter species if present because there is evidence that some isolates can be particularly inflammatory in nature and are associated with an increased rate of FEV₁ deterioration, similar to that induced by P. aeruginosa [91,92].

Stenotrophomonas maltophilia — We attempt to treat S. maltophilia when this organism is identified in patients with pulmonary exacerbations but recognize that there is uncertainty regarding the importance of targeting this organism [93]. Because S. maltophilia is acquired more frequently in patients with existing advanced lung disease, they on average have worse pulmonary function test results and more frequent pulmonary exacerbations than those without it [94-96]. However, acquisition of S. maltophilia may not affect subsequent disease progression; the rate of FEV₁ decrease following new acquisition of S. maltophilia is no different from matched control patients [94,96]. But, of relevance, we have occasionally seen patients with a deteriorating clinical course in whom S. maltophilia is the only cultured pathogen, and, in these cases, we select antibiotics to target it.

Aspergillus — The prevalence of Aspergillus species in respiratory secretions has been reported to be between 12 and 35 percent [97,98]. Although there remains conflicting information whether Aspergillus contributes to the progression of CF lung disease (see "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Aspergillus species'), there is no definitive evidence that Aspergillus causes pulmonary exacerbations. As such, we do not initiate antifungal therapy for pulmonary exacerbations when Aspergillus is identified.

Antibiotic dosing — Dosing recommendations for antibiotics are summarized in the table (table 2) and detailed below. For many of the antibiotics, we agree with the doses recommended in a comprehensive review of antipseudomonal antibiotics in CF [99]. For a few of the antibiotics (piperacillin-tazobactam, ceftazidime, and ticarcillin-clavulanate), the review recommends much higher doses for CF patients than are used for patients without CF. These are based primarily on pharmacokinetic/pharmacodynamic considerations, but clinical trial data for these very high doses are sparse [100]. Therefore, we suggest intermediate doses for these drugs, as shown in the table. Higher doses or prolonged infusions (ie, either continuous or extended intermittent infusions) may be considered on a case-by-case basis. (See "Prolonged infusions of beta-lactam antibiotics".)

Care must be taken to dose and adjust antimicrobials to achieve lung penetration and maximize the bactericidal efficacy of each agent [89,99]. The goals differ with the class of drug. With beta-lactam antibiotics, efficient bacterial clearance requires prolonged tissue concentrations above the minimum inhibitory concentration through much of the dosing interval. By contrast, for aminoglycosides and fluoroquinolones, bactericidal effect is proportional to the peak antimicrobial tissue concentrations and there is a post-antibiotic effect.

The pharmacokinetics of many antibiotics differ in patients with CF as compared with the general population [101]. In general, higher and/or more frequent dosing is required for many CF patients [102,103]. This is because the volume of distribution and total body clearance is increased for hydrophilic drugs (such as aminoglycosides, penicillins, and cephalosporins), in part because CF patients are generally undernourished and have decreased adipose tissue [104,105]. Although there are few studies that show a link between extended infusion times and improved clinical outcomes for beta-lactam antibiotics in CF [59], the pharmacokinetic data and theoretical argument for prolonging infusion times has led many CF centers to adopt the practice [106-108].

Aminoglycosides — In patients with CF receiving aminoglycosides, the volume of distribution is increased, and renal clearance rate is considerably accelerated as compared with patients without CF. Therefore, starting doses of aminoglycosides for CF patients should be approximately 30 to 35 percent larger than those recommended for individuals without CF [102]. The dose and frequency from a previous course of treatment may be used initially if serum concentrations were in the target range and creatinine clearance is not substantially changed, but drug levels should still be monitored.

Careful monitoring of aminoglycoside levels is necessary to limit the risks of renal injury and ototoxicity [109-112]. The renal damage can be manifested by elevation in creatinine. Patients receiving multiple courses of aminoglycosides may develop a syndrome of magnesium wasting without azotemia [113]. These adverse effects can be limited but not prevented by adjusting antibiotic dose and interval to avoid exceeding target serum levels, as described below. When clinically significant renal damage or ototoxicity is noted, efforts should be made to minimize subsequent aminoglycoside use.

Once-daily dosing — We suggest dosing aminoglycosides once daily (known as "consolidated dosing" or "extended-interval dosing") in CF patients with normal renal function. This approach is consistent with the guidelines endorsed by the Cystic Fibrosis Foundation [28] and is supported by a Cochrane systematic review [114]. This practice has been adopted by the majority of CF centers, including pediatric programs [115]. The starting dose for tobramycin is 10 mg/kg/24 hours for children and adults without renal insufficiency (table 2).

Once-daily administration is supported by a randomized trial in 244 patients greater than five years of age with acute CF exacerbations who were treated with a 14-day course of IV tobramycin either once daily or divided three times daily, with dose adjustments to maintain antibiotic concentrations in a target range [116]. The treatments were equally effective in improving pulmonary function (for change in FEV₁, adjusted mean difference 0.4 percent, 95% CI -3.3 to 4.1). Once-daily therapy was associated with a decreased incidence of nephrotoxicity (mean percent change in creatinine -4.5 [once daily] versus +3.7 [three times daily]). Of note, most of the data assessing efficacy and safety of once-daily tobramycin dosing are derived from studies of patients greater than five years of age. Extended-interval dosing in populations without CF is discussed separately. (See "Dosing and administration of parenteral aminoglycosides", section on 'Comparing extended-interval and traditional intermittent dosing'.)

●Initial dose adjustment – We do not use published tables or nomograms for selecting and adjusting aminoglycoside doses and intervals in patients with CF, because the pharmacokinetics differ from those in non-CF patients and may result in suboptimal aminoglycoside concentrations [117,118].

Instead, we measure serum levels twice following the first dose (eg, at 2 and 10 hours after the dose) and use pharmacokinetic analysis to calculate the peak serum level and to extrapolate forward to determine serum levels approximately 18 hours after the dose. Consultation with a clinical pharmacist skilled in pharmacokinetic-based drug management may be helpful and is suggested. The targets are:

•Calculated peak serum level between 20 and 30 mcg/mL for tobramycin and between 80 and 120 mg/L for amikacin [99,116]. Note that this is the estimated peak level calculated from a pharmacokinetic analysis and not the measured level from blood samples drawn early after antibiotic infusion. Samples taken less than two hours postinfusion are still within the drug distribution phase, so calculations based on them would yield incorrect estimates of peak antibiotic concentrations and clearance rates leading to inappropriate dosing regimens [119].

•Calculated serum level ≤0.5 mcg/mL at 18 hours, so that there is at least a six-hour period prior to the next dose when the patient will have low serum levels, to minimize toxicity. Slightly higher 18-hour levels (eg, ≤1.0 mcg/mL) are also acceptable, provided that the patient's renal function and clinical status are stable and the 18-hour level will be rechecked within three to four days.

If a dose that achieves the target peak level leads to too high a serum level at 18 hours, the dosing strategy is changed to the "conventional" approach to reduce the risk of toxicity. (See 'Conventional dosing' below.)

●Subsequent monitoring – After the initial dose has been established, we measure serum aminoglycoside levels once or twice per week, with each measurement timed for several hours prior to the next dose (ie, at 18 hours following the previous dose). The appropriate frequency of monitoring depends on baseline renal function, the concomitant use of potentially renal toxic drugs, and whether the patient has a history of prior aminoglycoside toxicity. The goal is to ensure that the aminoglycoside level remains relatively low for several hours prior to the next dose (ideally ≤0.5 for tobramycin at 18 hours). An increasing 18-hour level suggests the possibility of renal injury and should prompt dose adjustment. We believe that the 18-hour time point is preferable to a true trough at 24 hours because in CF patients with normal renal function, the drug concentration is frequently below the level of detection at 24 hours, which would prevent early detection of renal impairment as manifested by increasing drug levels. Interpreting these low serum levels can be confounded if the patient is also receiving inhaled tobramycin. As an example, serum levels one hour after inhaling 300 mg tobramycin are 1.05±0.67 mcg/mL (mean±standard deviation) [120].

In addition, we suggest measuring two levels (eg, at 2 and 10 hours after the dose) following any substantial change in dose to allow pharmacokinetic calculations and assure that targeted levels are achieved. Two time point measurements are also recommended if large changes in volume of distribution are likely to have occurred during the course of treatment (eg, sepsis with capillary leak or right-sided heart failure), although these scenarios are uncommon in CF patients having a typical pulmonary exacerbation [117].

To monitor for renal toxicity, blood urea nitrogen (BUN) and creatinine levels are also measured whenever aminoglycoside serum levels are assessed. We also monitor serum magnesium levels in patients who have received multiple aminoglycoside courses within the past year and are therefore at increased risk for isolated tubular damage manifested by magnesium wasting.

Conventional dosing — For patients with renal insufficiency or evidence of delayed aminoglycoside clearance, we do not use once-daily dosing for aminoglycosides. Instead, we use a conventional approach based on peak and trough levels to target drug levels, as follows:

●Peak serum concentration 8 to 12 mcg/mL for tobramycin or 20 to 30 mcg/mL for amikacin (measured 30 to 45 minutes after the dose is given)

●Trough serum concentration ≤2 mcg/mL for tobramycin and <10 mcg/mL for amikacin (measured just before the next planned dose)

These are the targets used for conventional dosing of aminoglycosides, but patients with renal insufficiency will require lower doses and/or longer dosing intervals than are used for patients with normal renal function.

In this situation, the dose and frequency from a previous course of treatment may be used initially if the creatinine clearance is not substantially changed and serum concentrations were within the target range [121]. If there is no reliable historical information, we suggest consulting with an expert pharmacist to guide dosing with a pharmacokinetic analysis. If pharmacist consultation is not available, it is reasonable to use an empiric loading dose of 3.3 mg/kg (if patient is overweight, use ideal body weight or dosing weight) [28,116] and select an initial maintenance dose and dosing interval based upon the patient's creatinine clearance (table 3).

Once the initial dose and interval are established, we measure peak and trough levels once or twice per week and continue to adjust the dose and interval to ensure that target peak and trough concentrations are achieved and maintained. BUN and creatinine are measured at the same time to monitor for renal toxicity. These steps are detailed in a separate topic review. (See "Dosing and administration of parenteral aminoglycosides".)

Colistin — IV colistin (colistimethate sodium [CMS]) is a useful option for P. aeruginosa strains that fail to respond to aminoglycosides and fluoroquinolones. We usually use it in combination with a beta-lactam antibiotic. It should not be used in combination with IV aminoglycosides, due to their additive renal toxicities.

There is potential for confusion when choosing drug doses due to variability in how the antibiotic is labeled [122,123]. In the United States, each vial of CMS is labeled as containing 150 mg of colistin-base activity (CBA), which is the equivalent of 4,500,000 international units (or 4.5 million units) of CMS. We administer 2.5 to 5 mg/kg per day CBA (approximately 75,000 to 150,000 international units/kg per day CMS) divided into three doses, to a maximum of 300 mg per day CBA (approximately 9,000,000 international units per day CMS) (table 2). Patients with obesity should be dosed by ideal body weight. To convert, 1 mg CBA (United States product) = approximately 30,000 international units CMS (European Union product). Careful attention to the details of the licensed prescribing information is advised. We suggest monitoring of drug levels during treatment for patients with CF. (See "Polymyxins: An overview".)

Vancomycin — The pharmacokinetics of vancomycin do not appear to be altered in patients with CF compared with other patients [124]. When vancomycin is given for a pulmonary exacerbation in a patient with CF, we use the same dose and target blood levels that are used for treating a serious pulmonary infection in a patient without CF.

For patients with normal renal function, we start with a weight-based dose of vancomycin of 45 to 60 mg/kg/day in three divided doses (up to 4 g per day) for adults [125] and 60 mg/kg/day (up to 3.6 g per day) in three or four divided doses for children (table 2). Higher doses may be needed in younger children [126]. Some CF centers use protocols that include loading doses for adult patients. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults" and "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

Of note, a beta-lactam other than piperacillin-tazobactam should be selected when being used in combination with vancomycin and tobramycin to reduce the risk of renal toxicity [127].

●Dose-adjustment strategies – There are two methods of therapeutic monitoring for vancomycin: trough-guided dosing and area under the curve (AUC)-guided dosing, which requires the assistance of a clinical pharmacist (table 4). Our preferred approach is the AUC method, but this may vary from facility to facility. AUC-guided dosing was endorsed in a consensus guideline published jointly by four professional infectious disease and pharmacist societies [126], although the superiority of this approach over trough-guided dosing for children has been questioned [128,129]. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults" and "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

•Trough-directed dosing – Measuring trough levels has been the previous standard method for adjusting vancomycin dose and continues to be so if a clinical pharmacist is not available to perform the calculations for AUC monitoring or when renal function is rapidly changing. It is also the method preferred by some experts for vancomycin dosing in children [128,129]. We usually obtain vancomycin trough concentrations immediately before the third or fourth dose after initiating vancomycin or following a dose change. We aim to achieve trough concentrations of 15 to 20 mcg/mL for adults and 7 to 10 mcg/mL for children. In observational studies in children, trough concentrations ≥15 mcg/mL have been associated with increased risk of acute kidney injury and have not been associated with improved outcomes [130-132]. If trough levels are outside of the target range, the amount of vancomycin administered with each dose can be adjusted, which will proportionally alter trough levels and AUC. Alternatively, the interval between doses can be adjusted, ideally with input from a clinical pharmacist [126].

•AUC-guided dosing – In the AUC-guided approach, the vancomycin dose is adjusted based on the ratio of the AUC over 24 hours to the minimum inhibitory concentration (AUC/MIC) [126]. Clinical pharmacists can use software programs to estimate the AUC/MIC from two serum levels taken at the post-distributional peak (one to two hours after the end of infusion) and within 30 minutes prior to the next infusion. Monitoring should begin within 24 to 48 hours of initiation of treatment. The target AUC/MIC is 400 to 600, assuming a vancomycin MIC of 1 mg/L. Additional details of AUC-guided dosing for children are provided in the consensus guideline [126].

Once the target dosing has been achieved and if renal function is stable, we monitor trough levels every 7 to 10 days. More frequent monitoring is indicated for patients with changing renal function.

Ciprofloxacin — The pharmacokinetics of ciprofloxacin in patients with CF are more variable than in patients without CF and may be altered by disease severity, concurrent drug therapy, and patient age [133-135].

For children with CF, we use oral ciprofloxacin at a dose of 40 mg/kg/day (up to 2 g daily) divided every 12 hours instead of standard doses of ciprofloxacin [135,136]. The IV dose of ciprofloxacin is 30 mg/kg per day (up to 1.2 g daily) in three divided doses. This is because children with CF generally require higher doses of ciprofloxacin than other children. As an example, in a group of children with CF treated for severe pulmonary infection, clearance of ciprofloxacin was two times higher than in children without CF [133].

For adults with CF, we use the standard dosing for ciprofloxacin (750 mg by mouth twice daily) for severe respiratory tract infection. Standard doses are appropriate for this age group because the pharmacokinetics of ciprofloxacin appears to be similar to that of adults without CF [137,138]. Higher dose levels (eg, 1 g twice daily) may also be appropriate based on theoretical considerations of pharmacokinetics and the level of susceptibility of the bacteria [134].

Sulfonamides — The dose of oral trimethoprim-sulfamethoxazole for patients with CF should be increased by approximately 50 percent relative to that used for patients without CF. For example, trimethoprim-sulfamethoxazole (160 mg trimethoprim with 800 mg sulfamethoxazole) should be taken three times daily for an adult with CF rather than twice per day. This is because hepatic clearance of sulfamethoxazole is increased in CF due to accelerated acetylation, and renal clearance of trimethoprim is accelerated by unknown mechanisms [139].

Duration of treatment

●IV antibiotics – For most patients treated with IV antibiotics, we suggest that the duration of therapy be based upon the initial response to treatment, as follows [140]:

•If the response to treatment is rapid (eg, ≥8 point improvement in FEV₁ and improved symptoms within 7 to 10 days of starting antibiotics), stop antibiotics after 10 days

•If the response is slower, complete a 14-day course of antibiotics

A longer course of antibiotics may be warranted for patients requiring intensive care unit (ICU) care and those who experience an acute pulmonary exacerbation despite a recent course of IV antibiotics. In such patients, antibiotics are continued until symptom and FEV₁ improvement have plateaued; typical treatment duration is 14 to 21 days.

For patients with mild to moderate exacerbations who are treated with oral antibiotics, we suggest continuing therapy until FEV₁ and/or symptom improvement has plateaued. The typical practice has been to treat for 14 to 21 days.

Our suggested approach for IV treatment is supported by results from the STOP2 trial, a randomized study of 982 adult patients who were treated with IV antibiotics for a pulmonary exacerbation based on their CF clinicians' clinical assessment [140]. Patients were assessed on day 7 to 10 of treatment and were categorized as having an early "robust" response (ie, increase in FEV₁ by >8 percent predicted and decease in the Chronic Respiratory Infection Symptom Score [CRISS] by >11 points) or a slower response (ie, not meeting the definition of "robust" response). Early robust responders (n = 277) were randomly assigned to stop treatment after either 10 or 14 days; slower responders (n = 705) were randomized to stop treatment after either 14 or 21 days. At two weeks after completing treatment, patients who received shorter antibiotic courses had similar improvements in FEV₁ compared with those who received longer courses. Results were as follows:

•FEV₁ – Among early robust responders, the mean FEV₁ change from baseline was 12.8 percent in the 10-day group versus 13.4 percent in the 14-day group (difference -0.7 percent, 95% CI -3.3 to 2.0). Among slower responders, the mean FEV₁ change from baseline was 3.4 percent in the 14-day group versus 3.3 percent in the 21-day group (difference 0.1 percent, 95% CI -1.1 to 1.3).

•Symptom scores – Similar improvements were noted in all groups, regardless of treatment duration.

•Treatment failure – The rate of treatment failure (ie, requiring retreatment within 30 days) was similarly low in all groups. Among early robust responders, treatment failure was 1.8 percent in the 10-day group versus 3.7 percent in the 14-day group (difference -1.9 percent, 95% CI -7.5 to 3.3). Among slower responders, treatment failure was 4.5 percent in the 14-day group versus 5.1 percent in the 21-day group (difference -0.6 percent, 95% CI -5.0 to 2.7).

•Adverse effects – An unexpected finding was that the incidence of drug-induced toxicity was not higher in those randomized to the more prolonged treatment groups.

Although this clinical trial did not include pediatric patients, it is reasonable to expect that a shorter course of IV antibiotics would result in similarly comparable outcomes in this population. Thus, we suggest the using the same approach in both children and adults. This clinical trial also did not include patients who require ICU care and those who experience a CF exacerbation despite a recent course of IV antibiotics. A relatively long course of antibiotics (eg, 14 to 21 days) may be appropriate for such patients.

These recommendations may represent a change in clinician prescribing habits and patient expectations at many CF centers. Our experience is that a small but significant number of patients with moderate to severe exacerbations who do not return to their baseline symptom level by 14 days strongly request prolongation of antibiotic treatment. However, the clinical evidence cited above suggests that extending treatment is unlikely to achieve additional benefit.

●Oral antibiotics – Oral antibiotics are usually prescribed for 14 to 21 days [15,141,142]. It is uncertain whether the results of the STOP2 trial [140], which studied patients receiving IV antibiotics, most of whom had some time in hospital, can be extrapolated to patients receiving all oral regimens that are usually delivered at home. Response to outpatient treatment may be slower than inpatient treatment where adequate rest, airway clearance therapy, nutrition, and on-time delivery of medications are likely better.

Of note, following a pulmonary exacerbation, the recovery of lost FEV₁ is often incomplete. A prospective study of 220 patients aged 12 and older reported that only 65 percent recovered to above 90 percent of their prior baseline and only 39 percent had full recovery of FEV₁ to their baseline [20]. In a prospective study of 58 adults with CF, 23 percent of pulmonary exacerbations were associated with ongoing symptoms after 14 days of antibiotics, with further symptomatic improvement when treatment was extended to 21 days [143]. However, continuation of antibiotic treatment was not associated with further improvement in FEV₁ or body mass index.

Home management of exacerbations — Concern over hospital costs as well as the preference of many patients have encouraged home treatment with IV antibiotics for pulmonary exacerbations in CF. Retrospective studies comparing home and hospital treatment have reached conflicting conclusions regarding equivalency of outcomes [84,144-150]. For example, a study that retrospectively analyzed data on 1535 subjects treated for a pulmonary exacerbation found no difference in long-term FEV₁ change or time to next antibiotic treatment for pulmonary exacerbation between patients receiving home therapy as compared with hospital therapy [144]. In contrast, another registry-based study of 4497 pulmonary exacerbations reported that recovery of FEV₁ to ≥90 percent of baseline level was 9.1 percent more likely when all treatment was delivered in-hospital compared with treatment delivered entirely at home [84]. Because this study was not randomized, the characteristics of the two groups likely differed in ways that could affect the analysis, although attempts were made to account for known confounding factors.

When considering home therapy for a pulmonary exacerbation, resources must be available at home to replicate the hospital program including provisions for rest, meals, medications, and physiotherapy [28]. Children require greater assistance than adults to accomplish these goals, and adult supervision is needed even for teenagers. In considering home treatment for children, one must consider the impact of lost work hours, the number of other children in the household, the number and competence of available adult caregivers, and family stress before deciding whether home treatment is preferable to hospitalization.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The clinical course of cystic fibrosis (CF) is frequently complicated by acute pulmonary exacerbations, superimposed on a gradual decline in pulmonary function. It is generally accepted that bacteria are involved in the pathophysiology of most pulmonary exacerbations in CF and that respiratory cultures represent the likely pathogens in an individual patient. Viral pathogens also may play a role. Staphylococcus aureus and Pseudomonas aeruginosa are the most prevalent pathogens in most age groups and are associated with accelerated loss of pulmonary function (figure 2). (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)

●Antibiotic selection – We recommend treating acute pulmonary exacerbations with antibiotics rather than nonantimicrobial treatment alone (Grade 1C). The antibiotics are given either orally or intravenously (IV), depending on the severity of the exacerbation (table 2) (see 'Rationale' above). Common practice is to select at least one antibiotic to cover each bacterial isolate that is cultured from respiratory secretions and two antibiotics for P. aeruginosa infections, if possible. (See 'Antibiotic selection' above.)

•We typically treat P. aeruginosa with piperacillin-tazobactam, ceftazidime, imipenem with cilastatin, meropenem (or ticarcillin-clavulanate, where available) plus one of the following: a fluoroquinolone, tobramycin, amikacin, or colistin. Because results from antibiotic susceptibility testing of P. aeruginosa may not predict clinical outcomes, we base antibiotic selection for P. aeruginosa on the patient's response to prior treatments, with additional considerations based on allergies and past adverse drug effects.

•When methicillin-sensitive S. aureus (MSSA) accompanies the P. aeruginosa, treatment options are piperacillin-tazobactam, cefepime, imipenem with cilastatin, meropenem, or ticarcillin-clavulanate plus one of the following: a fluoroquinolone, tobramycin, amikacin, or colistin.

•When methicillin-resistant S. aureus (MRSA) accompanies the P. aeruginosa, we treat with vancomycin, linezolid, or ceftaroline plus the same antibiotic combination as for P. aeruginosa alone (three antibiotics total).

●Antibiotic dosing

•The pharmacokinetics of many antibiotics differs in patients with CF compared with normal individuals. Patients with CF generally require larger and/or more frequent dosing for penicillins, cephalosporins, sulfonamides, and fluoroquinolones. (See 'Antibiotic dosing' above.)

•For aminoglycosides, starting doses should be larger than those recommended for individuals without CF, but dosing must be adjusted based on pharmacokinetic analysis of serum levels because of considerable interindividual variation in clearance rates. For CF patients with normal renal function, we suggest once-daily dosing ("consolidated dosing") rather than conventional dosing and monitoring, with adjustments of dose and timing based on monitoring of drug levels (Grade 2B). Once-daily dosing has comparable efficacy with conventional dosing and monitoring but has advantages of possibly reducing the risk of nephrotoxicity and simplifying administration and monitoring. (See 'Aminoglycosides' above.)

●Antibiotic duration – We suggest that the duration of IV antibiotic therapy be based upon the initial response to treatment, as follows (see 'Duration of treatment' above):

•For patients with a rapid response to treatment (eg, ≥8 point improvement in forced expiratory volume in one second [FEV₁] and improved symptoms within 7 to 10 days of starting IV antibiotics), we suggest a 10-day course of antibiotics for both adults (Grade 2B) and children (Grade 2C)

•For patients with a slower response, we suggest a 14-day course of antibiotics for both adults (Grade 2B) and children (Grade 2C)

A longer course of IV antibiotics may be warranted for patients requiring intensive care unit (ICU) care and those who experience a CF exacerbation despite a recent course of IV antibiotics. In such patients, antibiotics are continued until symptom and FEV₁ improvement have plateaued (typical duration is 14 to 21 days).

For most patients treated with oral antibiotics, we suggest a 14- to 21-day treatment course (Grade 2C), provided that the patient responds appropriately.