Antibiotic guideline in Adult Cystic Fibrosis

Antibiotic guideline in Adult Cystic Fibrosis Choice of antibiotics in cystic fibrosis is based on several facts including ganism sensitivity, histy of adverse reactions allergy and severity of symptoms. In most cases, at least two antibiotics are prescribed together in der to limit the emergence of superinfection with resistant strains pathogens which may be present in sputum but not consistently present on culture. The incidence of Closdtridium difficile in CF is low, so the restriction on use of drugs which commonly cause C. difficile. diarrhoea in other patient groups is less critical. In patients colonised by multiple pathogens often a third ( me) antibiotic may be required. Specialist advice is required in complex cases. Individual antibiotic regimens should be based on sputum sensitivity results, however a response is often observed despite in vitro resistance. Synergy testing may be useful to guide antimicrobial choice where multi-resistant ganisms are cultured. Where possible treatment regimens are designed to maximise patient adherence and minimise adverse effects. This is a guideline only and individual patient facts should be considered when selecting treatment, including: Interactions should be checked, especially in post-transplant patients who will be taking immunosuppressant drugs Low body weight patients under 50kg a dose reduction be required Doses may need to be reduced in renal impairment Histy of allergic reactions documented intolerances Courses are generally given f two weeks. Response to treatment should be assessed at end of the first and second weeks. A third week of treatment should be considered if there has been a partial response. Po response requires review of treatment. Several drugs also can cause photosensitivity on exposure to sunlight (e.g. quinilones and tetracyclines) and patients should be warned about this and how to avoid it. - 1 -

These guidelines have been produced by a wking group including the Scottish Adult Cystic Fibrosis team, pharmacy and microbiology departments. They are intended to be used along side national guidance such as Antibiotic Treatment f Cystic Fibrosis, 3 rd Edition, May 2009, Cystic Fibrosis Trust and local expertise. [http://www.cftrust.g.uk/aboutcf/publications/consensusdoc/antibiotic_treatment_f_cystic_fibrosis.pdf] It is the intention of the group to carry out ongoing surveillance and regular audit of critical areas such as C difficile incidence, contamination of samples, patterns of infection and resistance and MRSA acquisition/colonisation/eradication and treatment outcomes. These guidelines will be regularly updated and reviewed in line with emerging evidence, change in practice and results of surveillance and audits. Date written: 08 June 2011 Written by: Approved by: Douglas McCabe, Pharmacist, Cystic Fibrosis Dr Ian Laurenson, Consultant Microbiologist Dr Helen Rodgers, Clinical Direct of Adult CF Service Profess Andrew Greening, Consultant Physician Dr Alastair Innes, Consultant Physician - 2 -

Table of contents Table Title Page 1 Common gram-positive infections Haemophilus influenzae, Staphylococcus aureus, 2 2a 2b 3 3a 3b 3c 4 4a 4b 4c 5 5a 5b MRSA Eradication Exacerbation Pseudomonas aeruginosa Eradication Exacerbation Chronic infection Other gram-negative infections Burkholeria cepacia complex, Stenotrophomonas maltophillia, Achromobacter (Alcaligenes) xylosoxidans Fungal infections Oral candidiasis ABPA 6 Non-tuberculous mycobacteria 12 7 Totally implantable intravenous access device (TIVAD) infections 12 8 Oral antimicrobials dosing 13 9 Intravenous antimicrobials dosing 14 10 Diluents and flushes 15 11 Desensitisation 16 12 Renal doses 17 13 Cost of commonly prescribed antimicrobials 20 14 Summary chart of antimicrobial choices 21 4 5 7 9 11-3 -

1. Common gram-positive infections Colonising ganisms Recommended therapy Notes Haemophilus influenzae and Staphylococcus aureus Mild symptoms Co-amoxiclav 625mg every 8 hours ally +/- Ciprofloxacin 500mg every 8 hours ally Penicillin allergy: Doxycycline 100mg every 12 hours ally Clarithromycin 500mg every 12 hours ally +/- Ciprofloxacin 750mg every 12 hours ally Co-amoxiclav covers both H influenzae and S aureus. Flucloxacillin 1g QDS can be used in place of co-amoxiclav. Ciprofloxacin covers H influenzae and P aeruginosa which is useful where P aeruginosa is grown intermittently and to reduce the risk of P aeruginosa superinfection which can be unmasked by treatment with a single anti-staphylococcal agent. Ciprofloxacin may not be required in mild exacerbations where there is little no risk previous histy of P aeruginosa infection. Moderate severe symptoms, failure of first line therapy Cefuroxime 1.5g every 8 hours IV Plus Ciprofloxacin 500mg every 8 hours ally - 4 -

2. Meticillin resistant Staphylococcus aureus MRSA Eradication should include a combination of systemic and topical therapy from the start. 2a. MRSA Eradication and Treatment: Systemic Therapy 1 st line: 6 weeks al therapy. 2 nd line: 6 weeks al therapy 3 rd line current exacerbation: 2 weeks IV therapy followed by 4 weeks al therapy. Recommended therapy Doxycycline* 100mg every 12 hours ally Plus ONE other agent based on sensitivities from list: Trimethoprim 200mg every 12 hours ally Rifampicin* 300mg every 12 hours ally Sodium fusidate 500mg every 8-12 hours ally Two al agents from above based on sensitivities. Use a combination of rifampicin + sodium fusidate, if sensitive. Vancomycin IV 2 weeks Teicoplanin IV 2 weeks then 4 weeks of second line therapy (2 agents) Linezolid 600mg every 12 hours ally f 4 weeks Plus - 5 - Notes Sensitivities should be checked befe starting eradication. *Check interactions. Monit LFTs with rifampicin and sodium fusidate. Repeat MRSA screening as per NHS Lothian Infection Control Policy. If MRSA persists, proceed to 2 nd line treatment. Most evidence f combination of rifampicin + sodium fusidate f 3-6 months, but can be poly tolerated. Anti-emetic cover may be useful. If MRSA persists, proceed to 3 rd line treatment. See LUHD Antimicrobial Prescribing Guideline on intranet f dosage calculation and moniting requirements f IV vancomycin: http://intranet.lothian.scot.nhs.uk/nhslothian/healthcare/a- Z/amt/AntimicrobialGuidelines/Pages/vancomycin.aspx Determination of teicoplanin serum concentrations are recommended in CF; suggested target is >20mg/L. Doses up to 800mg can be given by IV bolus at home. Doses > 800mg can be split 12 hourly. The role of linezolid remains unclear. It is costly and there are concerns about toxicity with prolonged treatment. FBC should be monited weekly to check f bone marrow suppression; and a maximum of 4 weeks is recommended; check interactions; counsel patient to rept any

One other agent based on sensitivities. symptoms of visual impairment immediately as risk of optic neuropathy. Outcomes with this agent should be audited prospectively. There is some evidence f 6 months rifampicin + sodium fusidate nebulised vancomycin. Both these approaches require further investigation but can be considered in difficult cases. 2b. MRSA decolonisation and suppression: Topical Therapy If samples become negative, regard patients as potential carriers f at least 6 months. Minimum of 3 negative screens over 6 months required to confirm successful eradication. Screening should be as per current NHS Lothian Infection Control Manual. Determine mupirocin sensitivity BEFORE starting treatment (check with microbiology). At each step decolonisation should be prescribed as per currently NHS Lothian Infection Control Policy. This includes: 5 days topical treatment of nose, throat and body. Environmental decontamination. Screening close contacts in the household Change nebuliser equipment and disinfect equipment as per manufacturer guidelines at start of treatment. See current LUHD Infection Control Manual MRSA Decolonisation / Suppression Regimen on intranet f details: http://intranet.lothian.scot.nhs.uk/nhslothian/healthcare/a-z/infectioncontrol/icm/pages/cp0020.aspx MRSA treatment and outcomes should be audited on an ongoing basis and guidance updated as new evidence emerges. - 6 -

3. Pseudomonas aeruginosa 3a. Pseudomonas aeruginosa eradication Step 1: Step 2: Failure of eradication current exacerbation Step 3: Recommended therapy Ciprofloxacin 750mg every 12 hours ally Plus Colistin 2MU every 12 hours nebulised* Repeat step 1. Intravenous antibiotics f 2 weeks Then Ciprofloxacin 750mg every 12 hours ally Plus Tobramycin 300mg every 12 hours nebulised Notes Recheck sputum at 6 weeks. Stop treatment if negative. Continue f 3 months if remains positive. 3 negative samples required, over 6 months to confirm successful eradication. Test dose of nebulised antibiotics required befe commencing treatment. *Nebulised tobramycin is alternative where colistin is not tolerated. After two failed attempts at eradication, give two weeks of suitable intravenous antimicrobial therapy followed by a further 3 months of eradication therapy including nebulised tobramycin. 3b. Pseudomonas aeruginosa exacerbation After multiple failures, patient is likely to be colonised. See table 3c f long term suppressive therapy. Mild symptoms: Moderate to severe symptoms: (See table 9 on page 14 f details of dosing IV antimicrobials.) Co-amoxiclav 625mg every 8 hours ally Plus Ciprofloxacin 500mg every 8 hours ally Ceftazidime IV Piperacillin/tazobactam IV Aztreonam IV Meropenem IV Plus either - 7 - Co-amoxiclav covers Haemophilus influenzae and Staphylococcus aureus which will also be present. Levofloxacin can be considered as an alternative quinolone where ciprofloxacin is not tolerated [currently non-fmulary]. Combination of beta-lactam with tobramycin colistin is synergistic. *Initial tobramycin dose should be based on the current Tobramycin Dosing Guideline f adult CF the dosage regimen that was previously identified as suitable f the patient. Determination of serum concentrations is required - see guideline f details. Avoid prolonged regular courses of tobramycin due to risk of accumulation in the inner ear.

Tobramycin* IV Colistin** IV 3c. Pseudomonas aeruginosa chronic infection **Consider prescribing colistin on alternate courses where regular IV tobramycin is required in der to limit ototoxicity if sensitivities allow. Note colistin is also renally toxic and neurotoxic (usually dose related). There is some evidence that a combination of ceftazidime + meropenem are effective where both tobramycin and colistin are not suitable e.g. due to renal toxicity. Step 1 Step 2 Azithromycin 500mg THREE times weekly ally Add: Colistin 2mu every 12 hours nebulised Tobramycin 300mg every 12 hours nebulised alternate months Check LFT s befe starting treatment and every 6 months. Avoid where non-tuberculous mycobacteria is also present in sputum. Test dose of nebulised antibiotics required befe commencing treatment. Withhold nebulised antibiotic during courses of intravenous antibiotics to limit risk of cumulative toxicity. Minimum recommended gap between each dose of nebuliser = 6 hours. - 8 -

4. Other gram-negative infections 4a. Burkholderia cepacia Mild symptoms: Moderate to severe symptoms: (See table 9 on page 14 f details of dosing IV antimicrobials.) Recommended therapy Co-trimoxazole 960mg every 12 hours ally Plus Minocycline 100mg every 12 hours ally Or Chlamphenicol* 500mg every 6 hours ally (Trimethoprim 200mg every 12 hours, may be a suitable alternative where cotrimoxazole is not tolerated. Desensitisation may be considered where rash has occurred.) Ceftazidime IV Piperacillin/tazobactam IV Meropenem IV Temocillin IV Plus Another agent based on sensitivities and other ganisms present in sputum. Notes B. cepacia species is inherently resistant to most anti-pseudomonal penicillins, aminoglycosides and colistin. Typing required samples sent to reference lab. Synergy testing may be useful in individual cases where resistance and/ adverse reactions limit choices. *Oral chlamphenicol is expensive and requires moniting of FBC f bone marrow toxicity. Irreversible aplastic anaemia repted. Prolonged repeated courses should be avoided. Co-infection with P. aeruginosa: Regimen should include at least 2 active agents to cover both P. aeruginosa and B. cepacia if possible usually including a combination of a beta-lactam plus tobramycin colistin and one other agent. - 9 -

4b. Stenotrophomonas maltophilia Mild-Moderate symptoms: Main pathogenic ganism use 2 active agents Severe symptoms no al route available: Co-trimoxazole* 960mg every 12 hours ally and/ Minocycline* 100mg every 12 hours ally 1 st line: Co-trimoxazole** 1440mg every 12 hours IV *Include one active agent with anti-pseudomonal agent where present in sputum in addition to P aeruginosa. Choice of agent should be based on sensitivity testing. Synergy testing may be useful in individual cases where resistance and/ adverse reactions limit choices. Combinations of ceftazidime + tobramycin ciprofloxacin piperacillin/tazobactam + co-trimoxazole may be active. **Seek seni advice** (See table 9 on page 14 f details of dosing IV antimicrobials.) 2 nd line: Ticarcillin/clavulinic acid** IV Tigecycline** IV 4c. Achromobacter (Alcaligenes) xylosoxidans ** given by infusion. There is little experience with 2 nd line agents but they may be useful to consider if the al route is not available, where other agents are not tolerated IV therapy is justified. Both 2 nd line agents are non-fmulary drugs and tigecycline is an ALERT ANTIBIOTIC, so approval is required by the CF pharmacist (8445) and a CF consultant. Mild-Moderate symptoms: Main pathogenic ganism use 2 active agents Co-trimoxazole* 960mg every 12 hours ally and/ Minocycline* 100mg every 12 hours ally and/ Chlamphenicol 500mg every 6 hours ally *Include one active agent with anti-pseudomonal agents where present in sputum in addition to P aeruginosa. A. xylosoxidans is inherently resistant to most anti-pseudomonal penicillins, cephalospins, aminoglycosides and quinilones. Choice of agent should be based on sensitivity testing. Synergy testing may be useful in individual cases where resistance and/ adverse reactions limit choices. - 10 -

Severe symptoms: **Seek seni advice** (See table 9 on page 13 f details of dosing IV antimicrobials.) Piperacillin/tazobactam IV Meropenem IV Imipenem IV Temocillin IV 5. Fungal infections 5a. Oral candidiasis Likely ganisms Recommended therapy Notes Candida albicans 5b. ABPA (Aspergillis sp.) Presence in sputum alone does not require treatment. Consider treatment where diagnostic criteria met: acute clinical deteriation; total IgE >500-1000 IU/ml; precipitins IgE antibody to A.fumigatus; new abnmalities on chest X-ray CT not 1 st line: Nystatin 100,000MU 1ml every 6 hours ally 2 nd line: Fluconazole 50mg every 24 hours f 7 days ally Prednisolone 0.5mg/kg every 24 hours ally f 1-2 weeks. Taper dose over 2-3 months based on clinical progress. Po response as steroid-sparing agent: Add Itraconazole liquid ally 3-6 months (See table 8 on page 13 f dosing advice.) - 11 - Commonly occurs with systemic steroids and/ broad spectrum antibiotics. Oral fluconazole will also cover vaginal candida. Persistent recurrent canidiasis may respond to regular antifungal treatment weekly f 4 weeks. Treatment failure recurrence should be investigated further by confirmation of ganism and sensitivities. Check interactions befe starting antifungal treatment. Monit LFTs during treatment. The liquid preparation of itraconazole is better absbed than the capsules and should be taken on an empty stomach. The capsule should be taken after food. PPI s and H2 antagonists itraconazole reduce absption. Patients taking acid suppressive therapy should be advised to take itraconazole with a cola drink, as it is better absbed in an acid environment. Determination of itraconazole concentrations should be considered where there is an inadequate response concern about drug absption interactions patient compliance. Steady state is achieved after 2 weeks. A trough samples should be taken pre-dose. Infm microbiology befe sending samples so they can send to Bristol.

cleared by standard antibiotics physiotherapy. Raised eosinophils 5c. Invasive aspergillosis Seek expert advice including microbiology. Viconazole is an alternative antifungal which is better absbed and therefe may be considered where serum concentrations of itraconazole are inadequate despite increased dose if itraconazole is not tolerated is contra-indicated. Individual patient treatment request required see CF pharmacist. 6. Non-tuberculous mycobacteria Likely ganisms Mycobacterium avium complex and Mycobacterium absessus. Notes Seek expert advice, including Scottish Mycobacteria Reference Labaty, telephone 26016, Dr Ian Laurenson Dr Ewan Olson. 7. TIVAD infection Likely ganisms Recommended therapy Notes S. aureus fungal. Treat based on blood culture. May require removal of line. Seek advice. - 12 -

8. Oral Antimicrobials Dosing Drug Dose Notes Azithromycin Chronic anti-inflammaty: 500mg once daily three times per week Treatment: 250mg once daily Chlamphenicol 500mg four times daily; Max 1g four times daily in severe infections. Ciprofloxacin Clarithromycin Co-amoxiclav Co-trimoxazole Doxycycline Flucloxacillin 500mg three times daily 750mg twice daily 500mg twice daily 625mg three times daily 960mg twice daily 100mg twice daily Treatment: 1g four times daily Monit FBC during treatment. Avoid in renal hepatic impairment. GI disturbance and optic peripheral neuritis possible. NB high-cost compared to alternatives ( 900-1800 per 2 weeks), so not first line. Prophylaxis: 1000mg twice daily Itraconazole liquid 5mg/kg daily See notes above. Consider checking serum concentration. Check interactions. Split dose twice daily if total daily dose >200mg/day. Levofloxacin 500mg twice daily Linezolid 600mg twice daily Monit FBC if > 28 day treatment. Minocycline 100mg twice daily Rifampicin <50kg: 450mg once daily Check interactions and LFTs. > 50kg: 600mg once daily 300mg twice daily. Sodium fusidate 500mg three times daily Trimethoprim 200mg twice daily - 13 -

9. Intravenous Antimicrobials Dosing Drug f Route Dose Max Dose Notes Reconstitution Aztreonam IV bolus 2g every 8 hours 2g QDS Amikacin IV bolus 30mg/kg ONCE daily, up to maximum Serum concentrations required 1000mg per day initially. Ceftazidime IV bolus 100-150mg/kg daily in 2 3 divided doses. 9g over 24 hours. BD dosing given f convenience. body wt (kg) 12 hourly 8 hourly TDS dosing dose reduction may help if < 40kg: 2-3g 1-2g intolerable nausea occurs which is 40-60kg 3g 2g resistant to antiemetics. >60kg 4g 2-3g Cefuroxime IV bolus 1.5g every 8 hours 1.5g every 6 hours Colistimethate sodium (Colomycin) IV bolus < 40kg 40-60kg 1 MU every 8 hours 1.5 MU every 8 hours 2 MU every 8 hours Consider dose reduction f mild, transient adverse effects. > 60kg 2 MU every 8 hours Co-trimoxazole IV infusion 1440mg every 12 hours Dilute in 500ml infusion fluid and give over 60-90 minutes. Meropenem IV bolus <40kg 1.5g every 8 hours 2g TDS >40kg 2g every 8 hours Piperacillin/tazobactam IV bolus 4.5g every 8 hours 4.5g every 6 hours Teicoplanin IV bolus 10mg/kg every 12 hours f 3 doses, then 10mg/kg every 24 hours 800mg IV bolus. Doses > 800mg can be given by IV infusion. Determination of serum concentrations is useful to confirm dose is therapeutic. Trough concentrations should be > 20mg/l f treatment of MRSA. Temocillin IV bolus 2g every 12 hours 2g every 8 hours Ticarcillin/clavulinic acid IV infusion over 30 mins 3.2g every 6 to 8 hours Dilute in 100mls glucose 5% water f injections Tigecycline IV infusion over 30 mins 100mg loading dose, then, 50mg every 12 hours Dilute in 100mls glucose 5% sodium chlide 0.9% Tobramycin IV bolus 120mg/m 2 every 12 hours See current guideline. Serum concentration moniting required. Vancomycin IV infusion as per current Lothian guideline - 14 -

10. Diluents and flushes Drug Diluent Volume of diluent per vial Aztreonam 1g and 2g vials Water f injection 10ml Amikacin Already in solution N/A Ceftazidime 1g and 2g vials Water f injection 10ml Cefuroxime 1.5g Water f injection 15ml Colistimethate sodium (Colomycin) 1MU and 2MU Sodium chlide 0.9% TIVAD/Long-line: 10ml Venflon: 20-40ml Gentamicin Already in solution N/A Meropenem 1g vials Water f injection 20ml per 1g vial 40ml f 2g dose Piperacillin/tazobactam 4.5g Water f injection 20ml Temocillin 1g Water f injection 10ml each vial 20ml f 2g dose Tobramycin Already in solution N/A Long-line and TIVAD (Pt) Ensure that all patients are prescribed 10ml sodium chlide 0.9% flush and 4ml heparin sodium 100iu/ml to lock the line with every dose of intravenous antibiotics. Peripheral venous catheter (Venflon) Prescribe 10ml sodium chlide 0.9% f flushing with each dose of IV antibiotic. Every patient should also have an in date Epipen f use in case of anaphylaxis and be counselled on how to use it. This should be prescribed if necessary. - 15 -

11. Desensitisation 11.1 Ceftazidime, aztreonam and meropenem Syringe Dose administered Administration time 1 0.0005 mg in 50ml 0.9% sodium chlide 20 minutes 2 0.005 mg in 50ml 0.9% sodium chlide 20 minutes 3 0.05 mg in 50ml 0.9% sodium chlide 20 minutes 4 0.5 mg in 50ml 0.9% sodium chlide 20 minutes 5 5 mg in 50ml 0.9% sodium chlide 20 minutes 6 50 mg in 50ml 0.9% sodium chlide 20 minutes 7 500 mg in 50ml 0.9% sodium chlide 20 minutes 8 1400 mg in 50ml 0.9% sodium chlide 2-3 minutes 11.2 Piperacillin/tazobactam Syringe Dose administered Administration time 1 0.001125mg in 50ml 0.9% sodium chlide 20 minutes 2 0.01125mg in 50ml 0.9% sodium chlide 20 minutes 3 0.1125mg in 50ml 0.9% sodium chlide 20 minutes 4 1.125mg in 50ml 0.9% sodium chlide 20 minutes 5 11.25mg in 50ml 0.9% sodium chlide 20 minutes 6 112.5mg in 50ml 0.9% sodium chlide 20 minutes 7 1125mg in 50ml 0.9% sodium chlide 20 minutes 8 3150 mg in 50ml 0.9% sodium chlide 2-3 minutes Patients who require desensitisation should be admitted to the ward f the procedure. At least 24 hours notice is required f pharmacy to prepare syringes. Desensitisation is required f each subsequent course on antibiotics including the problem drug. Each syringe except the final one is administered over 20-30 minutes via a syringe pump. The final syringe is given as a slow bolus. Observations must be carried out every 15 minutes and treatment stopped if there is any sign of a reaction. IV hydroctisone 200mg, IM adrenaline 1 in 1000 (follow UK resuscitation council guidelines f treatment of anaphylaxis, 0.5mls f adults, repeated at 5 minute intervals as required and tolerated) and IV chlpheniramine 5-10mg f treatment of allergies anaphylaxis should be readily available throughout the procedure. A mild urticaria may be successfully treated with antihistamines which can allow treatment to continue. Subsequent desensitisation may successfully completed by giving chlpheniramine 10mg IV and hydroctisone 100mg IV befe commencing antibiotic. - 16 -

Desensitisation should not be attempted if the histy indicates a severe non-ige-mediated reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatitis haemolytic anaemia. If desensitisation is successful, the antibiotics should be continued at full dose. Allergic reactions are still possible up to the FOURTH dose. The patient should be warned to rept any signs of a reaction immediately. Continued treatment is required to ensure desensitisation. If me than three consecutive doses in a course are missed, desensitisation must be repeated. References: 1. Khan D and Solensky R. Drug Allergy. J Allergy Clin Immunol 2010;125:S126-37. 2. Burrows J, Toon M, Bell S. Antibiotic desnsitization in adults with cystic fibrosis. Respirology 2003;8:359-364. 3. Moss R, Babin S, Hsu Y et al. Allergy to semisynthetic penicillins in cystic fibrosis. The Journal of Pediatrics 1984;104:460-466. 4. Ghosal S and Tayl C. Intravenous desensitization to ceftazidime in cystic fibrosis patients. J Antimicrob Chemotherapy 1997;39:556-557. 5. Wilson D, Owens R, Zuckerman J. Successful meropenem desensitization in a patient with cystic fibrosis. Ann Pharmacother 2003;37:1424-8. 6. Parmar J, Nasser S. Antibiotic allergy in cystic fibrosis. Thax 2005;60:517-520. - 17 -

12. Renal doses Use the Cockroft and Gault equation to calculate appropriate dose. Do not rely on egfr. See below. Drug Aztreonam Ceftazidime Dose if GFR 20-50ml/min Dose as in nmal 31-50ml/min 2g every 12 hours Cefuroxime 1.5g every 8 hours Cetirizine Chlamphenicol Ciprofloxacin Clarithromycin Co-amoxiclav Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Colistin 1-2 MU every 8 hours Co-trimoxazole Dose as in nmal (al treatment dose) Dose if GFR 10-20 ml/min 2g stat, then 1g every 8 hours 16-30ml/min 2g every 24 hours 1.5g every 8-12 hours Dose as in nmal renal function Dose as in nmal renal function Dose if GFR < 10 ml/min 2g stat, then 500mg every 8 hours 6-15ml/min 1g every 24 hours 1.5g every 12-24 hours 5-10mg daily Dose as in nmal Dose if on haemodialysis Dialysed. Dose as in GFR < 10ml/min. Dialysed. 500mg-1g every 24-48 hours Dialysed. Dose as in GFR < 10ml/min. Not dialysed. Dose as in GFR < 10ml/min Not dialysed. Dose as in nmal 250-500mg bd 250mg bd Not dialysed. 250-500mg every 12 hours Dose as in nmal renal function 1MU every 12-250mg every 12 hours 375mg tds Oral: IV: 250-500mg bd 200mg bd Dialysed. Dose as in GFR < 10ml/min Dialysed. Dose as in GFR < 10ml/min. Notes <5ml/min 1g every 48 hours Caution with aminoglycosides as can adversely affect renal function Possibly increases ciclospin and tacrolimus levels. Monit serum chlamphenicol levels. Watch very carefully. Increased nephrotoxicity with ciclospin. Anecdotally increases tacrolimus levels. Increases ciclospin and tacrolimus levels 1MU every 18-24 Not dialysed. Dose as in Monit closely 18 hours hours GFR < 10ml/min 480mg bd 480mg bd Dialysed. 480mg bd. Increased risk of nephrotoxicity with ciclospin. Plasma levels recommended - 18 -

Drug Doxycycline Flucloxacillin Fluconazole Fusidic acid Itraconazole Linezolid Dose if GFR 20-50ml/min Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose if GFR 10-20 ml/min Dose as in nmal renal function Dose as in nmal renal function Dose as in nmal renal function Dose as in nmal renal function Dose as in nmal renal function Dose as in nmal renal function Meropenem 2g every 12 hours 1g every 12 hours Rifampicin Dose as in nmal Dose as in nmal renal function Piperacillin/ Dose as in nmal 4.5g every 8- tazobactam Tobramycin Trimethoprim 40-70ml/min 2mg/kg then check level Dose as in nmal 12 hours 20-39ml/min 1mg/kg the check level Nmal dose f 3 days, then 50% of dose Dose if GFR < 10 ml/min Dose as in nmal Dose as in nmal up to a total daily dose of 4g Dose if on haemodialysis Not dialysed. Dose as in nmal. Not dialysed. Dose as in GFR < 10 ml/min 50% of nmal dose Dialysed. Dose as in GFR < 10ml/min. Give post dialysis. Dose as in nmal Dose as in nmal Dose as in nmal but monit closely 1g every 24 hours 50-100% of nmal dose Not dialysed. Dose as in nmal. Not dialysed. Dose as in nmal. Dialysed. Dose as in GFR< 10ml/min. Dialysed. Dose as in GFR< 10ml/min. Not dialysed. Dose as in GFR< 10ml/min. 4.5g every 12 hours Not dialysed. Dose as in GFR< 10ml/min. <20ml/min Dialysed. Dose as in GFR< Avoid 10ml/min. 50% of nmal dose every 24 hours Dialysed. Give 50% of nmal dose every 24 hours. Notes Possibly increases plasma ciclospin levels Increases ciclospin and tacrolimus levels Increases ciclospin and possibly tacrolimus levels Monit FBC, if sign of bone marrow toxicity reduce dose to 600mg once daily. Markedly reduces ciclospin levels. Risk of accumulation. Monit levels and daily and adjust dose. Monit potassium levels. Consider moniting serum levels. - 19 -

Cockcroft and Gault fmula: to calculate creatinine clearance - (140 age) x weight in kg x 1.23(men) 1.04(women) --------------------------------------------------------- serum creatinine This gives the approximate creatinine clearance (GFR) in ml/minute. - 20 -

13. Cost of commonly prescribed antimicrobials IV Antibiotic Cost f 2 weeks Cefuroxime <50 Ceftazidime 45-160 Piperacillin/tazobactam 100-150 Tobramycin 190-400 Colistin 150-250 Aztreonam 900-1000 Meropenem 500-750 Teicoplanin 300-400 Temocillin 1,700-2000+ Tigecycline 1200 Timentin 400-500 Vancomycin 75-100 Oral antibiotics Cost f 2 weeks Doxycycline 100mg capsules 1.68 Ciprofloxacin 500mg tablets 2.07 Ciprofloxacin 750mg tablets 2.82 Clarithromycin 500mg tablets 4.27 Co-amoxiclav 625mg tablets 4.27 Co-trimoxazole 480mg tablets 10.73 Minocycline 50mg tablets 10.85 Levofloxacin 500mg tablets 80 Chlamphenicol 250mg caps 900-1800 Linezolid 28 day course: 2548 Nebulised Drugs 1 month incl VAT Annual cost Dnase alpha (30) 592 7,110 Colomycin 2MU (+WFI+Saline) 191 2,299 Promixin 1MU BD (+WFI+saline) 283 3,400 Tobi 300mg BD alternate months 1,187 7122 Bramitob 300mg BD alternate months 1,187 7122-21 -

Table 14. Summary of antimicrobial choices in adult CF Organism First line treatment Second line treatment Length of treatment Haemophilus influenzae and Staphylococcus aureus (MSSA) Co-amoxiclav 625mg tds (po) +/- Ciprofloxacin 500mg tds (po) Doxycycline 100mg bd (po) Clarithromycin 500mg bd (po) +/- Ciprofloxacin 500mg bd (po) 7 14 days Staphylococcus aureus (MRSA) Vancomycin* (IV) Teicoplanin* (IV) Severe symptoms failure: Cefuroxime 750mg tds (IV) + Ciprofloxacin 500mg tds (po) Doxycycline 100mg bd (po) Trimethoprim 200mg bd (po) Rifampicin 300mg bd (po) Sodium fusidate 500mg bd-tds (po) 14 days Check sensitivities at each stage, call lab if not available. Pseudomonas aeruginosa Burkholderia cepacia Stenotrophomonas maltophilia Achromobacter xylosoxidans ABPA (Aspergillus sp.) Co-amoxiclav 625mg tds (po) +/- Ciprofloxacin 500mg tds (po) Co-trimoxazole 960mg bd (po) + Minocycline 100mg bd (po) Chlamphenicol 500mg qds (po) Co-trimoxazole 960mg bd (po) + Minocycline 100mg bd (po) Co-trimoxazole 960mg bd (po) + Minocycline 100mg bd (po) Chlamphenicol 500mg qds (po) Prednisolone 0.5mg/kg od +/- Itraconazole* liquid 5mg/kg/daily, spilt bd if dose >200mg Third line: Linezolid** 600mg bd (po) Ceftazidime 2-3g tds 3-4g bd (IV) (use higher dose f >60kg) Piperacillin/tazobactam 4.5g tds (IV) Aztreonam 2g tds (IV) Meropenem 2g tds (IV) Plus Tobramycin* IV Colistin 1.5-2MU tds (IV) (reduce dose f <60kg, see guideline) Ceftazidime 2-3g tds 3-4g bd (IV) (use higher dose f >60kg) Piperacillin/tazobactam 4.5g tds (IV) Meropenem 2g tds (IV) Temocillin 2g bd tds (IV) 2 active agents should be included. Co-trimoxazole 1440mg bd (IV) Third line: Ticarcillin/clavulinic** acid 3.2g qds (IV) Tigecycline** initially 100mg, then 50mg bd (IV) Piperacillin/tazobactam IV Meropenem IV Temocillin** 2g bd tds (IV) 2 active agents should be included. Itraconazole* capsules Third line: Viconazole** 14 days 14 days 14 days 14 days 3-6 months * follow local dosing guidance and monit serum concentrations (where required). **Currently not approved f these indications alert antibiotic, please infm CF pharmacist and consultant to arrange authisation/supply. - 22 -