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 super-infection 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 antibiotic related diarrhoea in other patient groups is less critical. Most patients should be prescribed at least two antibacterial agents in combination. These may be given ally, intravenously in combination. The al route is usually acceptable where available and absption not a concern. Several of the agents are only available parenterally and patients will nmally be trained to self-administer, often using a Totally Implantible Intravenous Access Device (TIVAD). In patients colonised by multiple pathogens often a third ( me) antibiotic may be required. Specialist advice is required in complex cases. 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. Treatment regimens should be tailed to maximise individual patient needs in der to maximise 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 may require a dose reduction Doses may need to be reduced in renal impairment Histy of allergic reactions intolerances is me common in the CF population Treatment is usually initiated based on assessment of lung function including spirometry results, chest radiograph, signs of infection, respiraty symptoms and changes in volume colour of sputum. Courses are generally given f two weeks. Response to treatment should be assessed at the end of the course earlier if required (e.g. adverse effect wsening symptoms). A third week of treatment may be considered if there has been a partial response. Po response requires review of treatment. Local practice is to withhold nebulised antibiotics during a course of Intravenous IV antibiotics to avoid toxicity. Long-term azithromycin should usually be continued during a course of antimicrobial treatment unless there are any specific interactions. 1

Infusions of beta-lactam antibiotics There is emerging evidence that suggests administration of beta-lactam antimicrobials by infusion is me efficacious than giving by bolus injection. It is thought this is because giving slowly results in a much better pharmacokinetic profile. F bacteriostatic drugs such as betalactams constant levels are me desirable than high peaks and low troughs. Consideration should be given to dering beta-lactam infusion on the in-patient drug chart f patients on the respiraty ward who are considered to be seriously ill and not suitable f home. Bolus injections are still appropriate f home IV administration. 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] The group will carry out surveillance and audit of new acquisitions of SABs, MRSA, C. difficile, Pseudomonas aeruginosa (PA). This will include moniting incidence, contamination of samples, patterns of infection, resistance and audit of infection control policies, PA and MRSA eradication outcomes. These guidelines will be regularly updated and reviewed in line with emerging evidence, change in practice and results of surveillance and audits. Members of the Adult CF Microbiology wking group as below. Dr Ian Laurenson, Consultant Microbiologist Profess Andrew Greening, Consultant Physician Dr Alastair Innes, Consultant Physician Dr Helen Rodgers, Clinical Direct of Adult CF Service Catriona McMullen, Cystic fibrosis nurse specialist Douglas McCabe, Pharmacist, Cystic Fibrosis Ratified by: Antimicrobial Team and LUHD Drug and Therapeutics Committee Date written: June 2011 Date updated: September 2013 (Version 2) Review date: September 2015 2

Table of contents Antibiotic guideline in Adult Cystic Fibrosis... 1 Table of contents... 3 1. Common gram-positive infections... 4 2. Methicillin resistant Staphylococcus aureus (MRSA)... 5 3. Pseudomonas aeruginosa... 7 4. Other gram-negative infections... 10 5. Fungal infections... 13 6. Non-tuberculous mycobacteria... 14 7. TIVAD infection... 14 8. Oral Antimicrobials Dosing... 15 9. Intravenous Antimicrobials Dosing... 16 10. Diluents and flushes... 17 11. Desensitisation... 18 12. Recommended doses in renal impairment... 20 13. Cost of commonly prescribed antimicrobials and serum concentration assays... 23 14. Summary of antimicrobial choices in adult CF... 24 3

1. Common gram-positive infections Two agents should be used guided by patients individual tolerances and susceptibility results. See notes above f further advice. Colonising ganisms Recommended therapy Notes Haemophilus influenzae and Staphylococcus aureus Mild symptoms Co-amoxiclav 625mg every 8 ally Plus Ciprofloxacin 500mg every 8 ally Penicillin allergy: Doxycycline 100mg every 12 ally Clarithromycin 500mg every 12 ally Plus Ciprofloxacin 750mg every 12 ally Co-amoxiclav covers both H influenzae and S aureus. Ciprofloxacin covers H influenzae and P aeruginosa which is useful where P aeruginosa is grown intermittently and to reduce the risk of P aeruginosa super-infection 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 IV Plus Ciprofloxacin 500mg every 8 ally Cefriaxone IV may be useful f patients self-administering at home as it can be given as 2g once daily (as 2 x 1g bolus injections). However, it does not have as good Staph. aureus cover as cefuroxime. 4

2. Methicillin resistant Staphylococcus aureus (MRSA) Eradication should include a combination of systemic (2a), topical therapy (2b) and environmental decontamination from the start. Two agents should be used guided by patients individual tolerances and susceptibility results. See notes above f further advice. 2a. MRSA Eradication 1 st line: 6 weeks al therapy. 2 nd line: 6 weeks al therapy Recommended therapy Doxycycline 100mg every 12 ally Plus Trimethoprim 200mg every 12 ally Rifampicin [dose per kg, see table 8] ally Sodium fusidate 500mg every 12 ally Rifampicin + sodium fusidate, if sensitive. TWO agents based on sensitivities. Notes Choice should be based on full sensitivities (call microbiology if full rept not available). 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 but this combination can be poly tolerated. Up to 3 to 6 months can be given f treatment resistant cases. Anti-emetic cover may be useful. *Remember to check interactions and monit LFTs with rifampicin and sodium fusidate. 2b. MRSA decolonisation and suppression: Topical Therapy 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 5

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. If samples become negative, regard patients as potential carriers f at least 6 months. At least 3 negative screens over 6 months required to confirm successful eradication. Screening should be as per current NHS Lothian Infection Control Manual. 2.c MRSA Treatment Oral treatment Intravenous treatment Recommended therapy Doxycycline 100mg every 12 ally Plus Trimethoprim 200mg every 12 ally Rifampicin [based on body weight, [see Table 8] ally Sodium fusidate 500mg every 12 ally Include an al agent from above and Vancomycin IV f 2 weeks [see guideline] Notes 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 symptoms of visual impairment immediately as risk of optic neuropathy. Interactions should also be checked. NB. linezolid is an alert antibiotic and is not currently approved f any indication. An alert antibiotic fm, approved by a microbiologist and non-fmulary fm (signed by consultant and pharmacist) are required to obtain supply. Some centres have repted success with nebulised vancomycin. This is currently an experimental option. Teicoplanin 10mg/kg to nearest 200mg (max. 800mg) 12 hourly f 3 doses then every 24 IV f 2 weeks 6 Teicoplanin is given by IV bolus, so is suitable f Home IV Antimicrobial Treatment. Doses > 800mg should be given by sequential boluses over at least 10 minutes. Determination of teicoplanin serum concentrations are recommended in CF; suggested target is >20mg/L (contact microbiology lab to arrange).

3. Pseudomonas aeruginosa Two agents should be used guided by patients individual tolerances and susceptibility results. See notes above f further advice. 3a. Pseudomonas aeruginosa eradication Recommended therapy 1 st choice Ciprofloxacin 750mg every 12 ally Plus Tobramycin 300mg every 12 nebulised f 4 weeks 2 nd choice Ciprofloxacin 750mg every 12 ally Plus Colistimethate sodium 2MU every 12 nebulised f 6 weeks Continue f a further 6 weeks if sputum remains positive. 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. After two failed attempts at eradication, give two weeks of suitable intravenous antimicrobial therapy followed by a further course of eradication therapy including nebulised tobramycin. After multiple failures, patient is likely to be colonised. See table 3c f long term suppressive therapy. Failure of eradication current exacerbation Intravenous antibiotics f 2 weeks Then Ciprofloxacin 750mg every 12 ally Plus Tobramycin 300mg every 12 nebulised f 4 weeks 7

3b. Pseudomonas aeruginosa exacerbation Oral treatment Recommended therapy Co-amoxiclav 625mg every 8 ally Plus Ciprofloxacin 500mg every 8 ally Notes Co-amoxiclav covers Haemophilus influenzae and Staphylococcus aureus which will also be present. Levofloxacin is approved as an alternative quinolone where ciprofloxacin is not tolerated. Intravenous treatment Ceftazidime [based on weight, see Table 9] IV Piperacillin/tazobactam 4.5g every 8 30min IV infusion as in-patient; IV bolus f home patients Aztreonam 2g every 8 IV Meropenem 2g every 8 IV Plus either Tobramycin [see guideline] IV Colistimethate sodium 2MU every 8 IV Combination of beta-lactam with tobramycin colistimethate sodium 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. Consider prescribing colistimethate sodium on alternate courses where regular IV tobramycin is required in der to limit ototoxicity if sensitivities allow. Note colistimethate sodium 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 colistimethate sodium are not suitable e.g. due to renal toxicity. Multiple allergies multiresistant PA Fosfomycin 4g every 8 IV infusion Add as replacement f either a beta-lactam, tobramycin colistimethate sodium as a third agent where multiple allergies and/ multi-resistant Pseudomonas are a problem. Pseudomonas are usually resistant, so synergy testing should be used to confirm activity with another drug. It may be particularly useful f Liverpool strain, which has inherent resistance to most usual options. This is an unlicensed medicine, ask pharmacist f further advice 8445. 8

3c. Pseudomonas aeruginosa chronic infection Step 1 Step 2 Recommended therapy Azithromycin 500mg THREE times weekly ally Colistimethate sodium every 12 nebulised inhaled Tobramycin every 12 nebulised inhaled alternate months Notes Check LFT s befe starting treatment and every 6 months. Avoid single macrolide in presence of non-tuberculous mycobacteria to reduce the risk of resistance. Test dose of inhaled antibiotics is required befe commencing treatment. Withhold nebulised antibiotic during courses of intravenous antibiotics to limit risk of cumulative toxicity. Both colistimethate sodium and tobramycin are available as dry powder inhalers and nebulised treatment. Dry powder inhalers are generally me convenient f patients and do not require equipment and cleaning. Please follow shared care protocols available on the Lothian Joint Fmulary website: www.ljf.g.uk 9

4. Other gram-negative infections Two agents should be used guided by patients individual tolerances and susceptibility results. See notes above f further advice. When Pseuodomonas a. is also present 3 agents may be required to cover multiple pathogens. Seek advice if required. 4a. Burkholderia cepacia complex Oral treatment Recommended therapy Co-trimoxazole 960mg every 12 ally plus Minocycline 100mg every 12 ally Chlamphenicol 500mg every 6 ally Intravenous treatment Ceftazidime [based on weight, see table 9] IV Piperacillin/tazobactam 4.5g every 8 30min IV infusion as in-patient; IV bolus f home patients Meropenem 2g every 8 IV Temocillin 2g every 12 IV Notes B. cepacia species is inherently resistant to most anti-pseudomonal penicillins, aminoglycosides and colistimethate sodium. Typing required samples sent to reference lab. Synergy should be checked once a year. Oral chlamphenicol is expensive and requires moniting of FBC f bone marrow toxicity. Irreversible aplastic anaemia repted. Prolonged repeated courses should be avoided. Trimethoprim 200mg every 12, may be a suitable alternative where co-trimoxazole is not tolerated. Desensitisation may be considered where rash has occurred. Co-infection with P. aeruginosa: Regimen should include at least 2 active agents to cover both P. aeruginosa and B. cepacia (3 me agents may be required). This usually includes a combination of a beta-lactam plus tobramycin colistimethate sodium and one other agent (which can be given ally). 10

4b. Stenotrophomonas maltophilia Oral treatment Intravenous treatment **Seek seni advice** Recommended therapy Co-trimoxazole 960mg every 12 ally Minocycline 100mg every 12 ally Levofloxacin 500mg every 12 ally Co-trimoxazole 1440mg every 12 IV infusion Ticarcillin/clavulinic acid 3.2g every 6-8 IV infusion Notes Inherently resistant to most anti-pseudomonal penicillins, aminoglycosides and colistimethate sodium. Synergy should be checked once a year. Combinations of ceftazidime + tobramycin ciprofloxacin piperacillin/tazobactam + co-trimoxazole may be active. Co-trimoxazole and ticarcillin/clavulinic acid are given by infusion, see IV guidelines f details. Ticarcillin/clavulinic acid is currently not approved, non-fmulary fm required, infm pharmacist. 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 e.g. severe symptoms and/ hospitalised. Tigecycline IV may be useful where an IV tetracycline is required. It is an alert antibiotic and is not approved f this indication. Relevant fms are required to obtain supply. Contact pharmacy f advice 8445. 11

4c. Achromobacter (Alcaligenes) xylosoxidans Oral treatment Intravenous treatment **Seek seni advice** Recommended therapy Co-trimoxazole 960mg every 12 ally and Minocycline 100mg every 12 ally Chlamphenicol 500mg every 6 ally Piperacillin/tazobactam 4.5g every 8 30min IV infusion as in-patient; IV bolus f home patients Meropenem 2g every 8 IV Temocillin 2g every 12 IV Notes A. xylosoxidans is inherently resistant to most anti-pseudomonal penicillins, cephalospins, aminoglycosides and quinilones. Synergy should be checked once a year. Imipenem may be useful where meropenem can not be used if it is the preferred carbapenem on synergy tests. It is not currently approved in Lothian, the non-fmulary procedure should be followed. It is given by IV infusion, usually as an in-patient. Contact pharmacist f advice. 12

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 cleared by standard antibiotics physiotherapy. Raised eosinophils 1 st line: Nystatin 100,000MU 1ml every 6 ally f 7 days 2 nd line: Fluconazole 50mg every 24 f 7 days ally Prednisolone 0.5mg/kg every 24 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 23 f dosing advice.) 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 and LFT s befe starting antifungal treatment. Check LFTs after one month and throughout treatment. Caution in patients who are taking other hepatotoxic drugs, who have a histy of hepatotoxicity with other drugs who have pre-existing liver disease. The liquid preparation of itraconazole is better absbed than the capsules and should be taken on an empty stomach. PPI s and H2 antagonists reduce itraconazole absption significantly. Patients taking acid suppressive therapy should be advised to take itraconazole with a cola drink to provide and acid environment. Capsules may be considered where the al solution is not tolerated and should be taken after food to improve absption. 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. Trough samples should be taken pre-dose. Infm microbiology befe sending samples so they can arrange transpt to reference lab. 13

5c. Invasive aspergillosis Seek expert advice including microbiology. 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. 14

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; Ciprofloxacin Up to 1g four times daily in severe infections. 500mg three times daily 750mg twice daily 15 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. Clarithromycin 500mg twice daily Co-amoxiclav 625mg three times daily Co-trimoxazole 960mg twice daily 1440mg twice daily in severe infections especially if larger body weight. Doxycycline 100mg twice daily Flucloxacillin Treatment: 1g four times daily Prophylaxis: 1000mg twice daily Itraconazole liquid 5mg/kg daily See notes above. <40kg 100mg twice daily Consider checking serum concentration if po 40-59kg 150mg twice daily response absption issue e.g. on PPI. >60kg 200mg twice daily Check interactions and monit liver function. 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

9. Intravenous Antimicrobials Dosing Drug f Route Dose Max Dose Notes Reconstitution Aztreonam IV bolus 2g every 8 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. 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 resistant to 40-60kg 3g 2g antiemetics. >60kg 4g 2-3g Ceftriaxone IV bolus 2g every 24 Cefuroxime IV bolus 1.5g every 8 1.5g every 6 Colistimethate sodium (Colomycin) IV bolus < 40kg 40-60kg 1 MU every 8 1.5 MU every 8 2 MU every 8 Consider dose reduction f mild, transient adverse effects. > 60kg 2 MU every 8 Fosfomycin IV 4g every 8 4g every 6 Dilute in 250ml infusion fluid and give over 60 infusion minutes. Meropenem IV bolus <40kg 1.5g every 8 2g TDS >40kg 2g every 8 Piperacillin/tazobactam IV bolus 4.5g every 8 4.5g every 6 Teicoplanin IV bolus 10mg/kg every 12 f 3 doses, then 10mg/kg every 24 Doses > 800mg can be given as 2 separate bolus injections. 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 2g every 8 Ticarcillin/clavulinic acid IV infusion 3.2g every 8 3.2g every 6 Dilute in 100mls glucose 5% water f injections and give over 30 mins. Tobramycin IV bolus 120mg/m 2 every 12 - [see guideline]. Serum concentration moniting required. Vancomycin IV infusion see guideline - 16

10. Diluents and flushes Drug Diluent Volume of diluent per vial Aztreonam 1g and 2g vials Water f injection 10ml Ceftazidime 1g and 2g vials Water f injection 10ml Cefriaxone 1g vials Water f injection 10ml Cefuroxime 1.5g vials Water f injection 15ml Colistimethate sodium (Colomycin) 1MU and 2MU Sodium chlide 0.9% TIVAD/Long-line: 10ml Venflon: 20-40ml Fosfomycin 4g vials Water f injection Sodium chlide 0.9% Sodium chlide 0.9% 20mls 250mls 50ml f flushing giving set Meropenem 1g vials Water f injection 20ml per 1g vial 40ml f 2g dose Piperacillin/tazobactam 4.5g vials Water f injection 20ml Temocillin 1g vials Water f injection 10ml each vial 20ml f 2g dose Teicoplanin 200mg and 400mg vials Water f injection 3mls provided with each vial Ticarcillin/clavulinic acid (Timentin ) 3.2g vials Water f injection Glucose 5% Glucose 5% Tobramycin ampoules Already in solution N/A 10mls 100mls 50ml f flushing giving set The IV line must always be flushed befe each antibiotic to avoid any interaction when drugs are mixed together. Specifically aminoglycosides and betalactams can precipitate leading to inactivation befe the drugs reach the systemic circulation, risking treatment failure. 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 Jext f use in case of anaphylaxis and be counselled on how to use it. This should be prescribed if necessary. 17

11. Desensitisation 11.1 Ceftazidime and aztreonam 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 11.3 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 1000mg in 40ml 0.9% sodium chlide 2-3 minutes [made on ward] 18

Patients who require desensitisation should be admitted to the ward f the procedure. At least 24 notice is required f pharmacy to prepare syringes. PRE-MEDICATION: IV hydroctisone 100-200 mg IV chlpheniramine 5 mg IV ranitidine 50 mg may be useful to prevent urticarial rash [unlicensed indication] Desensitisation is required f each subsequent course on antibiotics including the problem drug and after missing me than 1-2 doses. 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 (BP, pulse, temperature) must be carried out every 15 minutes and treatment stopped if there is any sign of a reaction. ANAPHYLAXIS Adrenaline 1 in 1000 IM (follow UK resuscitation council guidelines f treatment of anaphylaxis, 0.5mls f adults, repeated at 5 minute intervals as required and tolerated), Chlpheniramine 10mg IM IV Salbutamol 5mg nebulised, f wheeze IV hydroctisone sodium succinate 200mg delayed onset of action, but can prevent further deteriation in severe cases Oxygen f hypoxia if required Mild urticaria may be successfully treated with al antihistamines and steroids which can allow treatment to continue. CONTRA-INDICATIONS Severe non-ige mediated reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatitis haemolytic anaemia. CONTINUED DESENSITISATION AND FURTHER COURSES If desensitisation is successful, the next dose of antibiotic should be given within 8-12 and must be continued regularly at full dose to ensure maintenance of desensitisation status. 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 without any missed doses. 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. 19

12. Recommended doses in renal impairment Use Cockroft-Gault ensure egfr is crected f BSA. Drug Dose if GFR 20-50ml/min Dose if GFR 10-20 ml/min Azithromycin Dose as in nmal Dose as in nmal Aztreonam Dose as in nmal 2g stat, then 1g every 8 Ceftazidime 31-50ml/min 2g every 12 16-30ml/min 2g every 24 Ceftriaxone 1g every 12 Dose as in nmal. Cefuroxime 1.5g every 8 1.5g every 8-12 Cetirizine Chlamphenicol Ciprofloxacin Clarithromycin Co-amoxiclav Colistimethate sodium Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal 1-2 MU every 8 Dose as in nmal Dose as in nmal Dose if GFR < 10 ml/min Dose as in nmal 2g stat, then 500mg every 8 6-15ml/min 1g every 24 Dose as in nmal. 1.5g every 12-24 5-10mg daily Dose as in nmal Dose if on haemodialysis Dose as in nmal renal function Dialysed. Dose as in GFR < 10ml/min. Dialysed. 500mg-1g every 24-48 Dose as in nmal renal function. 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 Dose as in nmal 1MU every 12-18 250mg every 12 375mg tds 1MU every 18-24 Oral: IV: 250-500mg bd 200mg bd Dialysed. Dose as in GFR < 10ml/min Dialysed. Dose as in GFR < 10ml/min. Not dialysed. Dose as in GFR < 10ml/min Notes May increase ciclospin levels, monit levels. <5ml/min 1g every 48 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 Monit closely 20

Drug Co-trimoxazole (al treatment dose) Doxycycline Dose if GFR 20-50ml/min Dose as in nmal Dose as in nmal Dose if GFR 10-20 ml/min Dose if GFR < 10 ml/min Dose if on haemodialysis Notes 480mg bd 480mg bd Dialysed. 480mg bd. Increased risk of nephrotoxicity with ciclospin. Monit clinical response and U+E s. Dose as in nmal Dose as in nmal Not dialysed. Dose as in Possibly increases plasma nmal. ciclospin levels Flucloxacillin Fluconazole Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal Dose as in nmal up to a total daily dose of 4g 50% of nmal dose Not dialysed. Dose as in GFR < 10 ml/min Dialysed. Dose as in GFR < 10ml/min. Give post dialysis. Not dialysed. Dose as in nmal. Not dialysed. Dose as in nmal. Dose as in GFR<10ml/min Fusidic acid Dose as in nmal Dose as in nmal Dose as in nmal Itraconazole Dose as in nmal Dose as in nmal Dose as in nmal Levofloxacin Initial dose 500mg Initial dose 500mg Initial dose 500mg then reduce to then reduce to then reduce to 500mg every 24 250mg every 24 250mg every 48 Linezolid Dose as in nmal Dose as in nmal Dose as in nmal Dialysed. Dose as in GFR< but 10ml/min. monit renal function closely Meropenem 2g every 12 1g every 12 1g every 24 Dialysed. Dose as in GFR< 10ml/min. Rifampicin Dose as in nmal Dose as in nmal 50-100% of nmal Not dialysed. Dose as in dose GFR< 10ml/min. Piperacillin/ Dose as in nmal 4.5g every 8-12 4.5g every 12 Not dialysed. Dose as in tazobactam GFR< 10ml/min. Teicoplanin Dose as in nmal Not dialysed. Dose as in GFR< 10ml/min. Give nmal loading dose, then 10mg/kg every 48 Give nmal loading dose, then 10mg/kg every 72. Increases ciclospin and tacrolimus levels Increases ciclospin and possibly tacrolimus levels Ciclospin half-life increased by 33%, increased risk of nephrotoxicity. Monit FBC, if sign of bone marrow toxicity reduce dose to 600mg once daily. Markedly reduces ciclospin levels. Serum concentration should be monited in der to optimise dose. 21

Drug Ticarcillin/clavulinic acid (Timentin ) Tobramycin Trimethoprim Dose if GFR 20-50ml/min >30ml/min 3.2g every 8 40-70ml/min 2mg/kg then check level Dose as in nmal Dose if GFR 10-20 ml/min 10-30ml/min 1.6g every 8 20-39ml/min 1mg/kg the check level Nmal dose f 3 days, then 50% of dose Dose if GFR < 10 ml/min 1.6g every 12 <20ml/min Avoid 50% of nmal dose every 24 Dose if on haemodialysis Not dialysed. Dose as in GFR<1ml/min. Dialysed. Dose as in GFR< 10ml/min. Dialysed. Give 50% of nmal dose every 24. Notes Risk of accumulation. Monit levels and daily and adjust dose. Monit U+E s and clinical response. 22

13. Cost of commonly prescribed antimicrobials and serum concentration assays IV Antibiotic Cost f 2 weeks Assay Cost Ceftriaxone <50 Itraconazole 120 Vancomycin 75-100 Teicoplanin 120 Ceftazidime 45-160 Tobramycin 40 Piperacillin/tazobactam 100-150 Vancomycin 40 Tobramycin 190-400 Colistimethate sodium 150-250 Ticarcillin/clavulinic acid (Timentin) 250-300* Teicoplanin 300-400 Fosfomycin 600-650* Meropenem 500-750 Aztreonam 900-1000 Tigecycline Temocillin Oral antibiotics 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 capsules 900-1800 Linezolid 600mg tablets 28 day course: > 2500 Itraconazole liquid 200mg BD 28 days: 450 *The cost of 2 weeks of B.Braun Easypumps is approximately 700-750. This is off-set against the cost of an in-patient bed (nearly 3000). 23

14. Summary of antimicrobial choices in adult CF Organism Haemophilus influenzae and Staphylococcus aureus (MSSA) First line ORAL treatment Co-amoxiclav 625mg tds ally +/- Ciprofloxacin $ 500mg tds ally Second line IV treatment Penicillin allergy: Doxycycline $ 100mg bd ally Clarithromycin $ 500mg bd ally +/- Ciprofloxacin $ 750mg bd ally Intravenous treatment: Cefuroxime 1.5g every 8 IV ( ceftriaxone 2g every 24 IV at home) + Ciprofloxacin $ 500mg tds ally Length of treatment 7 14 days Staphylococcus aureus (MRSA) Pseudomonas aeruginosa Doxycycline $ 100mg bd ally Trimethoprim 200mg bd ally Rifampicin $ <50kg 450mg od, >50kg 300mg bd ally Sodium fusidate 500mg bd-tds ally Co-amoxiclav 625mg tds ally +/- Ciprofloxacin $ 500mg tds ally Intravenous treatment: Vancomycin [see guideline] IV Teicoplanin IV Third line: Linezolid $ 600mg bd ally 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 [see guideline] IV Colistimethate sodium 2MU tds IV (<60kg reduce dose to 1.5MU tds) 14 days Check sensitivities at each stage, call lab if not available. 14 days Burkholderia cepacia Stenotrophomonas maltophilia Achromobacter xylosoxidans ABPA (Aspergillus sp.) Co-trimoxazole $ 960mg bd ally + Minocycline $ 100mg bd ally Chlamphenicol 500mg qds ally Co-trimoxazole $ 960mg bd ally Co-trimoxazole $ 960mg bd ally Minocycline $ 100mg bd ally Chlamphenicol 500mg qds ally Prednisolone 0.5mg/kg od >60kg: 30mg 50-59kg: 25mg <50kg: 20mg Taper accding to response over 2-3 months. Alert antibiotic, please fill out Alert Antibiotic Moniting Fm. $ Significant drug interactions, check drug histy befe prescribing. * Given by IV infusion, see main guide f volumes and rates. 3 rd line: Fosfomycin* 4g tds IVI 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 Minocycline $ 100mg bd ally Levofloxacin $ 500mg bd ally Piperacillin/tazobactam* 4.5g every 8 IV Meropenem 2g every 8 IV Temocillin 2g bd tds IV Po response: add Itraconazole $ liquid >60kg: 200mg bd 40-59kg: 150mg bd <40kg: 100mg bd Serum levels can be obtained if po absption is suspected. 14 days 14 days 14 days 3-6 months 24