• Early recognition and treatment of CF exacerbations is one of the cornerstones of modern CF care
• Diagnosis is essentially clinical, based largely on patient symptoms
• Anything other than very mild exacerbations requires intravenous antibiotics, typically for 10–21 days
• Choice of antibiotics should be based upon known antimicrobial sensitivities
• Monotherapy should be avoided in Pseudomonas infections
• In patients colonized with Pseudomonas, treatment usually involves a combination of a β-lactam antibiotic and an aminoglycoside
• Treatment can be delivered at home but requires the same assessment as for inpatients, and close monitoring
• Treatment is multidisciplinary and also involves attention to physiotherapy, nutrition and glucose homeostasis
• Antibiotic hypersensitivities are common, particularly in those with repeated courses of treatment. Antibiotic desensitization can be attempted for each course if necessary.
5.1 Presentation and assessment
CF lung disease is characterized by recurrent episodes of increased pulmonary symptoms, termed exacerbations. These episodes are important events in the natural history of CF, with a significant impact on lung function, quality of life and mortality. Early resort to intravenous (IV) antibiotic therapy to treat new respiratory symptoms is one of the most important features of modern management of CF.
Little is known about the underlying pathophysiology of these events, which appear to be largely a result of increased endobronchial bacterial burden, rather than to the acquisition of new bacterial strains. Alterations in host defences (e.g. secondary to preceding viral infections) may also play a role. There is a spectrum of severity, from mild exacerbations with little objective evidence of inflammation, to severe and life threatening pulmonary sepsis. In the majority of cases however, the inflammatory response is largely restricted to the lung, with an increase in sputum inflammatory mediators but relatively little systemic inflammation.
Prevention and early treatment of pulmonary exacerbations is one of the key aims of effective management of CF. In order to reduce morbidity and mortality, this requires early recognition of a change in symptoms and aggressive management, usually with intravenous antibiotics, airway clearance and nutritional support.
Despite the central role of exacerbations in the clinical course CF, there is no universally agreed definition of what constitutes an exacerbation. In research studies, a number of different scoring systems have been devised that combine patient symptoms with clinical evaluation and data from laboratory and lung function assessments.
The symptoms and signs most predictive of an exacerbation are increased cough, change in sputum volume or consistency (i.e. darker or thicker), decreased appetite or weight, and change in respiratory examination or rate. Ultimately, in the absence of an agreed definition, the diagnosis remains essentially clinical, and typically relies on the presence of three or more of the signs or symptoms listed in Table 5.1. Of these, symptoms are the most important, and isolated changes in lung function, radiology, or laboratory findings should prompt further evaluation to identify the cause. In young children, who do not typically produce sputum and cannot perform spirometry, exacerbations are much harder to diagnose and may be indicated by new onset cough, a decrease in weight-for-age percentile, or development of new respiratory signs.
Table 5.1 Signs and symptoms associated with pulmonary exacerbation
Pulmonary signs and symptoms (new or increased)
Upper respiratory tract symptoms
Constitutional signs and symptoms
Those indicated by a * are those most strongly associated with a diagnosis of exacerbation.
Adapted from Ferkol et al. (2006).
5.1.3 Mild exacerbations
There is a wide range of clinical severity, and some well patients with mild or minimal symptoms will only require outpatient treatment with oral antibiotics. The presence of constitutional upset, or changes in clinical examination or radiology, necessitates intravenous therapy. Some patients will present with upper respiratory tract symptoms alone (e.g. coryza and cough), but these viral infections can perturb host defences and progress to more severe respiratory symptoms if untreated. These can usually be treated as mild exacerbations with an antibiotic that will cover both Staphylococcus aureus (SA) and Haemophilus influenzae (HI) (e.g. oral co-amoxiclav), after sending appropriate microbiological samples.
5.1.4 Epidemiology of exacerbations
Frequency of exacerbations increases with age and deteriorating lung function, from 23% patients/year for children under 6 years to 63% for those aged 18 years and over. Other factors associated with an increased frequency of exacerbations include infection with Pseudomonas aeruginosa (PsA), reactive airway disease, viral infections, lower socioeconomic status and air pollution.
5.2 Treatment of an exacerbation
5.2.1 Principles of treatment
There are few randomized clinical trials to guide choice of therapy but the following principles are generally applied:
• There should be a low threshold for starting IV antibiotics
• The selected antibiotics should have different modes of action, e.g. a β-lactam and an aminoglycoside, in order to improve response by antibacterial synergy
• Treatment typically lasts 10–21 days, and decision to finish the course is guided by clinical response. Shorter courses may be insufficient to treat the infection effectively but reduce the burden for the patient, increase compliance, and reduce risk of toxicity
• Antibiotic choice should be guided by antimicrobial sensitivity testing of a recent sputum sample. If none are available, choice should be based upon knowledge of the usual susceptibilities of the colonizing organisms, or previously effective treatments. In vivo response is often poorly predicted by in vitro testing, and demonstration of resistance in the lab does not necessarily mean that antibiotic will be ineffective when given to the patient, especially if they have responded to it previously. There is insufficient evidence to determine the effects of combined antimicrobial sensitivity testing on clinical outcome (i.e. testing the effects of more than one antibiotic on bacterial cultures) and this is not widely available.
5.2.2 Elective versus symptomatic treatment
Some units apply a policy of regular (elective) antibiotic treatment, usually every 3 months, irrespective of clinical condition. The rationale is that this reduces the bacteriological burden in the lung, and reduces exacerbations and need for unplanned therapy. There is a theoretical risk of increased resistance if antibiotics are given more frequently. Studies on this are limited, but there is no evidence of a difference in clinical outcomes between elective and symptomatic antibiotics. In the absence of evidence, the decision to employ the elective approach is down to patient preference, and may be useful in those with frequent exacerbations or complex social circumstances.
An alternative use of elective antibiotics is immediately before events that are important to the patient (e.g. holidays, exams). This helps to avoid untimely therapy and ensure that they remain well for the event.
5.2.3 Routes of delivery
Antibiotics can be given orally, intravenously and/or nebulized. Oral antibiotics alone are reserved for mild infections, and significant exacerbations are typically treated using intravenous antibiotics. Nebulized antibiotics are used as maintenance therapy in patients chronically infected with PsA, and as part of the eradication regimen for PsA when first isolated (see Chapter 4). Their role in the treatment of acute exacerbations is less clear, but they are not usually employed in this role. Regular nebulized antibiotics should be continued whilst on IV antibiotics, unless the nebulized drug is also prescribed for IV treatment (e.g. tobramycin) in which case the nebulized drug is usually discontinued until the IV treatment is completed in order to avoid excess drug accumulation and toxicity.
5.2.4 Home treatment
Home intravenous antibiotic treatment (HIVT) is a practical and effective alternative to inpatient administration. There is an added burden on the patient or parent, who must be taught to administer the antibiotics themselves (typically requiring two or three days of in-patient education and supervision). This is offset by the advantages and freedoms of being at home, and overall there is no difference in QoL, or clinical outcomes, between HIVT and inpatient antibiotics.
To reduce the burden to patients, some units now offer pre-prepared IV medications, delivered to the patient's home.
• Patients undergoing HIVT must be assessed by a doctor or clinical nurse specialist, as for any patient being admitted for treatment, including height, weight and lung function
• Patients/carers must have previously undergone training in HIVT, and be competent to carry this out. If not previously taught, a 2–3 day admission for intensive education and supervision is required
• Administration is either via a totally inplantable venous access device (TIVAD) or a long line (see below)
• The first dose is given under supervision in the unit. If a patient has not previously being exposed to the antibiotic, the first dose, and often the second, must be given in the unit. The patient should remain for 30–60 minutes after administration to watch for development of an allergic reaction
• Patients/carers should be provided with an anaphylaxis kit, and given clear written instructions in case of adverse reaction
• Patients should be followed up at least every 7 days, ideally with a home visit from a specialist nurse
• Patients may need to attend for serum drug levels and will need to be instructed when to do this. Ensure that contact details are recorded so that advice on subsequent dosing or blood tests can be passed back to the patient
• If the patient fails to improve, or adherence is poor, they should return to the unit for admission
• At the end of treatment, patients will need to return to the unit for assessment (including weight and lung function) to ensure success of treatment and removal of any lines.
5.2.5 IV access devices
1. Long lines
Long lines are inserted into a large peripheral vein, usually in the antecubital fossa. The catheter is long enough to access the larger, more proximal veins. They are usually left in for the duration of treatment, and can remain in place for up to 4 weeks, unlike small peripheral cannulae which typically require re-insertion every few days. They should be considered in those starting IV antibiotics who do not possess a TIVAD (see below). They should be flushed with heparinized saline after use. PICC lines (peripherally inserted central catheters) are similar, though longer, in order to access central veins. PICC line insertion requires special training and radiological confirmation of position.
2. Totally implantable vascular access device (TIVAD)
TIVADs, or ‘ports’, facilitate long term IV access, avoiding repeated peripheral venous cannula insertion and the irritant effect of infusions on small peripheral veins. A TIVAD consists of a silicone membrane, mounted in a titanium chamber, and inserted subcutaneously, usually on the chest wall (see Figure 5.1). The chamber is connected to a catheter tunnelled into a central vein. The device is inserted as a day case procedure, usually under local anaesthetic, by a vascular surgeon or anaesthetist. Venous access is achieved via a Huber (or ‘gripper’) needle inserted into the chamber through the skin and underlying silicone membrane. The Huber needle remains in place throughout the course of treatment, allowing repeated administration of IV therapies, whilst permitting almost unlimited physical activity.
TIVADS are generally well received by patients, but complications can develop and the mean survival of an individual port is around 3–5yrs. Complications occur in around 40%, most commonly catheter occlusion (20% of all TIVADs). Other complications include infection (9%, requiring removal in 80% cases), vascular thrombosis (5%), and catheter displacement (3%) or dis-insertion (2%). Blood sampling via the TIVAD is convenient for patients, but increases risk of thrombosis (relative risk 2.2). Occlusion or thrombosis can be diagnosed by injecting contrast dye during X-ray screening (a “line-o-gram”). Incomplete thrombotic occlusion can sometimes be relieved by urokinase infusion.
• TIVAD should be considered in patients requiring IV antibiotics on a regular basis (i.e. more than 3 times per year), or those with difficult IV access
• Devices must be flushed every 4 weeks with heparin solution (5ml of 100iu/ml)
• Patients should be warned to seek advice if their TIVAD becomes slow to flush
• If possible, venepuncture should ideally be from a separate, peripheral, vein. In children, this is rarely possible
• Antibiotic levels must never be taken from a TIVAD.
5.3 Antibiotic selection
5.3.1 Pitfalls of antibiotic use in CF
Metabolism and clearance of some antibiotics is altered in CF, and the doses required to achieve therapeutic plasma levels are different from non-CF patients (see Chapter 3). Repeated dosing can lead to cumulative toxic effects (e.g. renal function and hearing impairment with aminoglycosides), and to the development of hypersensitivity. Gentamicin is no longer recommended in CF because of its association with renal failure, and tobramycin is the preferred aminoglycoside. This must be balanced against evidence showing that more aggressive and early use of antibiotics results in better preservation of lung function.
There is uncertainty as to the optimal antibiotic regimen at different stages of CF lung disease, and local guidelines may differ. The primary aims are to select the most effective and least toxic regimen, and the secondary aims are to choose the most cost-effective treatment and avoid the development of antibiotic resistance. Table 5.2 shows the typical antibiotic sensitivities of the common infecting organisms in CF. The choice of antibiotics will depend on the known, and likely, infecting organisms, and the clinical severity of the infection.
Table 5.2 Antibiotic spectrum of activity
SA Staphylococcus aureus (not MRSA)
HI Haemophilus influenzae
PsA Pseudomonas aeruginosa
BCC Burkholderia cepacia complex
Dark shaded boxes indicate usually good antibiotic cover, and pale boxes indicate some activity against the organism. Unfilled boxes indicate no useful antibacterial activity. This is intended only as a general guide and should be checked against local and individual antibiotic sensitivities.
* These agents should not be used in severe exacerbations
+ Not suitable as monotherapy
For children who have never cultured PsA, or who have had repeated negative cultures for over 12 months following PsA eradication therapy, a suggested approach to antibiotic selection is given in Figure 5.2.
1: Alternatives include clarithromycin and erythromycin.
2: If tobramycin or other aminoglycosides can no longer be used due to bacterial resistance or intolerable side effects, IV colistin is a suitable alternative.
3: Cefaclor or cefixime if penicillin allergic. Cephradine and cefalexin not suitable. Doxycyline is another alternative if patient over 12yrs.>
The presence of PsA should be suspected in children who have failed to respond well to two courses of non-PsA therapy, or in whom there has been a recent clinical deterioration. A concerted effort to obtain relevant airway cultures is necessary in these cases, either by induced sputum or bronchoalveolar lavage. A suggested approach to antibiotic selection in children with confirmed PsA colonization is illustrated in Figure 5.3.
PsA infection is common in older children and adults, and the use of monotherapy for intravenous medicines in these patients may encourage resistance and permit a selective bias, allowing the organisms to become established. Adult patients therefore are usually treated with antibiotics that also provide cover against PsA. A suggested approach is illustrated in Figure 5.4.
Other antibiotics may be prescribed on occasion, depending on microbial sensitivities and patient allergies.
If Burkholderia cepacia or Stenotrophomonas maltophilia are cultured from a patient's sputum, the above flowchart does not apply.
1: If tobramycin or other aminoglycosides can no longer be used due to bacterial resistance or intolerable side effects, IV colistin is a suitable alternative.
2: Oral ciprofloxacin is included in regimens where SA is the predominant organism in order to discourage the selection and enhancement of early cryptic PsA colonisation in these patients
5.3.2 Identification of infecting organism
It is important to have up to date microbiological culture of respiratory tract samples in order to guide appropriate antibiotic selection and to monitor for the development of new infecting organisms. Few young children, and not all adult patients, can produce sputum spontaneously, even during an exacerbation. Alternative methods of sampling the respiratory tract include:
• Cough swab or plate
• Laryngeal or nasopharyngeal aspirate
• Bronchoalveolar lavage
• Induced sputum.
The following section is intended as a quick reference guide. For full details on dosing and side effects, please refer to a local or national formulary.
5.4.1 Exacerbations caused by S.aureus alone
• Dose: Child 50mg/kg 6hrly IV
Adult 2–3g 6hrly IV
• Type: β-lactam penicillin (inhibits synthesis of bacterial cell walls)
• Side effects: GI upset, hypersensitivity
• Spectrum of action: Main use is against SA.
5.4.2 Exacerbations caused by H. influenzae
• Amoxicillin/clavulanic acid (co-amoxiclav)
• Dose: Child 25mg/kg amoxicillin IV tds or qds
Adult 1.2g IV tds
• Type: Penicllin (amoxicillin) combined with a beta-lactamase inhibitor (clavulanic acid)
• Side effects: Hypersensitivity, GI upset, hepatitis, cholestatic jaundice
• Spectrum of action: Active against SA and HI.
• Dose: Child 50mg/kg (max 1.5g) 6–8hrly IV
Adult 750–1.5g 6hrly IV
• Type: 2nd generation cephalosporin (inhibits bacterial cell wall synthesis)
• Side effects: Diarrhoea, Clostridium difficile infection in adults, nausea, vomiting, headache, allergic reactions and blood dyscrasias.
• Dose: Child 50mg/kg 6–8hrly IV (max 12g/d)
Adult 2g 8hrly IV (max 12g/d)
• Type: 3rd generation cephalosporin
• Side effects: see cefuroxime.
• Spectrum of action: Should not be given as monotherapy – combine with aminoglycoside. Little activity against SA.
5.4.3 Exacerbations caused by P. aeruginosa
• Dose: Child <5yrs 15mg/kg 12hrly PO
Child 5–18yrs 20mg/kg (max 750mg) 12hrly PO
Adult 750mg 12hrly PO, or 400mg 12hrly IV
• Side effects: Nausea, vomiting, joint pain, abdominal pain, headache, rash, dizziness, pruritis and hepatitis. A photosensitive rash is relatively common – avoid exposure to strong sunlight. Use with caution in epileptics
• Spectrum of action: Less effective against gram positive organisms, and high incidence of resistance in SA (should not be used as monotherapy against SA).
• Dose: Child 90mg/kg (max 4.5g) every 6–8hrs IV
Adult 4.5g every 6–8hrs IV
• Type: Extended spectrum beta-lactam antibiotic (piperacillin) combined with a beta-lactamase inhibitor (tazobactam)
• Side effects: Hypersensitivity, GI upset, transient hepatitis, cholestatic jaundice blood dyscrasias
• Spectrum of action: Active against SA, HI and PsA.
• Dose: Child 50mg/kg 8hrly IV (max 6g/d)
Adult 2–3g tds IV (max 9g/d)
• Type: Third generation cephalosporin
• Side effects: Rash, hypersensitivity, GI upset, diarrhoea, headache, dizziness, bad taste
• Spectrum of action: See cefotaxime. No useful activity against SA.
• Dose: Child 50mg/kg (max 2g) 6–8hrly IV
Adult 2g 6hrly IV
• Type: β-lactam antibiotic
• Side effects: GI upset, rash, blood dyscrasias, hepatitis. Lower incidence of anaphylaxis than other β-lactams
• Spectrum of action: Ineffective against gram positive organisms or anaerobes, but effective against PsA and HI.
• Dose: Child 25–40mg/kg (max 2g) 8hrly IV
Adult 2g 8hrly IV
• Type: β-lactamase resistant broad spectrum β-lactam
• Side effects: GI upset, rashes, angioedema, blood dyscrasias, headache
• Dose: Child 25,000 units/kg 8hrly IV
Adult 2,000,000 (2 MU) units 8hrly IV
• Type: Polymixin (binds to LPS in gram negative bacteria and disrupts cell membrane)
• Side effects: Neurotoxicity: sensory and visual disturbances, vasomotor instability, confusion. Do not use with aminoglycosides
• Spectrum of action: Active against PsA and other gram-negative organisms. No action against gram positive bacteria or BCC.
• Dose: Children and adults 10mg/kg/d in 3 divided doses IV
• Administration: Do not mix other antibiotics in same syringe.
• Type: Aminoglycoside (binds ribosomes and prevents mRNA translation)
• Side effects: Nephrotoxicity and ototoxicity. Ensure adequate hydration, and reduce dose in renal impairment
• Monitor blood levels immediately before and 1hr after the third dose, weekly thereafter if satisfactory. Target levels are
— Trough <1mg/L
— Peak 8–12mg/L
• Spectrum of action: Synergistic with β-lactams. Active against PsA, and preferred to gentamicin because of superior bactericidal activity and toxicity profile.
5.4.4 Exacerbations caused by B.cepacia
This should always be discussed with a specialist microbiologist. BCC are intrinsically resistant to β-lactam antibiotics, aminoglycosides and colisitin. Treatment requires combination therapy, usually including meropenem (see Chapter 3)
Antibiotics that have been used to treat cepacia include:
5.4.5 Pregnancy and antibiotics
Lung function can deteriorate during pregnancy (see Chapter 11), and several courses of IV antibiotics may be required.
• Antibiotics generally considered safe in pregnancy include: β-lactams (penicillins, cephalosporins) and oral erythromycin and clindamycin
• Antibiotics that should not be used include ciprofloxacin, chloramphenicol, metronidazole and IV colistin
• Aminoglycosides are probably safe, but levels need close and careful monitoring. Potential for ototoxicity is greatest in the second trimester, and may occur in the foetus independent of signs of toxicity in the mother.
5.5 Non-antibiotic treatments
Physiotherapy is used to assist expectoration during an exacerbation. It is widely applied, and has been shown to improve sputum clearance, though there are no controlled clinical trials on its long term benefits. No specific method of airway clearance has been shown to be superior to any other (see Chapter 4), and the choice is one of patient and physiotherapist preference. If the patient is systemically unwell, they may be less able to achieve effective cough and airway clearance, and may benefit from use of an oscillating resistance device (e.g. Flutter) or positive expiratory pressure delivered via a mask. In patients with more advanced lung disease, vigorous chest physiotherapy may be associated with desaturation during or shortly after therapy. SpO2 should therefore be monitored and supplemental oxygen provided if necessary.
• All patients with an exacerbation should be reviewed early on by a specialist respiratory physiotherapist, and airway clearance assessed. This includes patients considered for HIVT
• Patients may need additional input or devices to assist expectoration when unwell
• SpO2 should be monitored in those with moderate-severe lung disease
• Admission affords a good opportunity to educate and reinforce physiotherapy regimes, and should be provided at least twice per day.
CF patients will often lose weight during an exacerbation, both because of the increased energy demands of the inflammatory response, and because of reduced appetite. Weight loss is one of the signs of an exacerbation, particularly in children and teenagers.
5.5.3 Management of diabetes
Poor glycaemic control, often more apparent during times of systemic illness, results in protein catabolism and weight loss. Insulin requirements usually rise during exacerbations, even if intake is reduced. Patients with impaired glucose tolerance (IGT) who do not normally require insulin may decompensate when unwell, and require the introduction of insulin. Even patients with normal glucose tolerance may have significantly elevated blood glucose (BG) when unwell.
• Blood glucose should be measured in all patients on admission. Consider glucose profile for first 24 hours (i.e. capillary BG before and after meals and 1–2 times overnight)
• With young children, glucose should be checked every time bloods are taken for other assays
• If BG>6mmol/L, known CFRD or IGT, check capillary BG before and after all meals
• Patients on enteral feeds should have capillary BG measured at start, end and at least once during each feed
• Consider starting insulin if BG persistently elevated at any time of day.
Many patients with CF exacerbations also have airway hyper-responsiveness, and an improvement in lung function in hospitalized patients has been shown with regular nebulized salbutamol. Many patients will already be using nebulized or inhaled bronchodilators before physiotherapy, and these should be continued. Patients with known airway hyper-responsiveness or documented wheeze may also benefit from starting these treatments during an exacerbation.
5.5.5 Nebulized saline
Nebulized hypertonic saline (6%) has been shown to improve sputum clearance during an exacerbation. However, it can also cause bronchospasm and other adverse reactions in around 10% patients and should therefore be preceded by inhaled or nebulized bronchodilator. A more tolerable alternative may be 3% or 0.9% (normal) saline, nebulized before physiotherapy, to loosen secretions. These therapies can be trialled on an individual basis if patients are experiencing difficulties with airway clearance.
5.6 Antibiotic desensitization
5.6.1 Drug allergy
Antibiotic hypersensitivity is common in CF because of the repeated high doses and long courses employed. This may place severe limitations on treatment options available to some patients. Most of the antibiotics in use can result in hypersensitivity reactions, but this is most commonly reported for piperacillin (30–50%). Hypersensitivity reactions can range from IgE-mediated immediate anaphylaxis to late onset non-specific features such as rash and fever.
One approach is to desensitize the patient to prevent recurrence of allergic reaction. This involves administration of a 106-times dilution over 20 mins, whilst under observation. This is immediately followed by six 10-fold increases in concentration until the therapeutic dose is reached. The procedure is abandoned if any dose is not tolerated. The whole process, consisting of 7 infusions, takes 2–3 hrs and must be performed as an inpatient, under continuous observation, with resuscitation facilities to hand. If the final dose is tolerated, this is continued to the end of the course. Success rate of desensitization is around 85%.
An alternative approach employed by some units is to use a fixed concentration of antibiotics in a single bag, but to gradually increase the rate of the infusate. This has the advantage that it does not require multiple syringes to be prepared.
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