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New Uses for Old Agents BSAC Spring Meeting 2013 Thursday 14 th March, Royal College of Physicians, London Dr Kieran Hand PhD MRPharmS Consultant Pharmacist.

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Presentation on theme: "New Uses for Old Agents BSAC Spring Meeting 2013 Thursday 14 th March, Royal College of Physicians, London Dr Kieran Hand PhD MRPharmS Consultant Pharmacist."— Presentation transcript:

1 New Uses for Old Agents BSAC Spring Meeting 2013 Thursday 14 th March, Royal College of Physicians, London Dr Kieran Hand PhD MRPharmS Consultant Pharmacist Anti-Infectives, University Hospital Southampton NHS Foundation Trust Post-doctoral Clinical Academic Fellow, Faculty of Health Sciences, University of Southampton

2 Scene-setting

3 Clostridium difficile risk & antibiotics: new world order? 2010/11 CDRN Report. 7,026 faecal samples (90% culture-positive) from 152 healthcare facilities. 73% reported patient exposure to antibiotics. CMO Report Volume 2, 11 March 2013

4 Running out of options Health Protection Report, June 2011 (n=333 isolates in 2010) CMO Report Volume 2, 11 March 2013

5 Older agents

6 Excellent inventory of potentially useful antibiotics not currently marketed in all countries (n=21) Drugs not routinely available in the UK include: –Fosfomycin –Pristinamycin –Synercid –Cefepime, Cefoperazone-sulbactam, Cefoxitin Focus of this presentation: colistin, co-trimoxazole, beta- lactam infusions 6 Clinical Infectious Diseases 2012;54(2):268-74

7 Colistin

8 Colistin Dosing Recommendations Patient categoryDose* to target average serum level 2 mg/L Loading dose All patientsBW** (kg) / 7.5 (MU, max 10 MU) Maintenance total daily dose Not on renal replacement(CrCl (mL/min)/10)MU +2MU (given in 2-3 divided doses) 1 st dose 24 h after loading dose Intermittent hemodialysis2 MU (in two doses) + 30% on the day of hemodialysis after session Continuous renal replacement 12 MU In 2-3 divided doses *1 million IU of CMS ~ 30 mg of CBA ~ 80 mg of CMS **Lower of ideal or actual body weight in kg Garonzik SM et al. AAC 2011 (modified) Acknowledgement: Dr David Wareham

9 Clinical Infectious Diseases 2012;54(12):1720–6 Prospective, observational, cohort study in a 16-bed general ICU in Italy All critically ill patients with sepsis due to MDR organism and prescribed colistin salvage therapy were enrolled (Aug10-Jun11) Colistin (Colomycin, Forest Labs, UK) –Loading dose 9MU in 100mL saline over 30mins –Maintenance doses CrCl >50mL/min: 4.5MU 12-hourly CrCl 20-50mL/min: 4.5MU 24-hourly CrCl < 20mL/min: 4.5MU 48-hourly

10 28 adult patients enrolled –16 with severe sepsis, 12 with septic shock –18/28 bloodstream infections; 10/28 VAP –Pathogens: A. baumannii 13/28; K. pneumoniae 13/28; P. aeruginosa 2/28 –Colistin monotherapy 14/28, + aminoglycoside 10/28, + carbapenem 4/28 –Median treatment duration 12 days (22 patients at full dose 9MU/day) Clinical cure 82% Renal toxicity –No renal dysfunction in 82% (23/28 patients) –AKI in 5 patients, developed within median 4 days and SCr returned to normal within median of 10 days after stopping

11 Wareham DW et al, JAC 2011 Colistin-glycopeptide synergy vs. MDR Acinetobacter baumannii

12 Co-trimoxazole (Septrin ® )

13 Staphylococcal infection: Clinical trial evidence of efficacy of Septrin in skin and soft tissue infections and osteomyelitis –Euba G, Murillo O, Fernandez-Sabe N et al. Long-term follow-up trial of oral rifampin–cotrimoxazole combination versus intravenous cloxacillin in treatment of chronic staphylococcal osteomyelitis. Antimicrob Agents Chemother 2009; 53: 2672–2676. –Cenizal MJ, Skiest D, Luber S et al. Prospective randomized trial of empiric therapy with trimethoprim–sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2007; 51: 2628–2630 –Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim–sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med 1992; 117: 390–398 13 Clin Microbiol Infect 2012;18:8-17

14 Co-trimoxazole: MRSA skin infection? Community- acquired MRSA OutcomeSeptrin 960mg 12-hourly (n=54) Clindamycin 300mg 6-hourly (n=20) Retrospective cohort review Adult patients with MRSA skin and soft tissue infections managed in outpatient medical clinics in San Antonio, Texas in 2006 Excluded surgical site infection, catheter- related, polymicrobial, diabetic foot Composite failure26%25% Microbiological failure 13%15% Required additional inpatient intervention 6%5% Required outpatient intervention 20% Data presented for patients undergoing incision & drainage. No statistically-significant differences reported. 14 Frei CR et al, J Am Board Fam Med 2010;23:714-719

15 Co-trimoxazole: not adding much for UTI? ECO-SENSAntibioticE. coli % Non-Susceptible European prospective survey of antibiotic susceptibility Non-pregnant females, age 18-65, with symptoms of uncomplicated lower UTI, no abx within 2 wks n =201 from UK in 2007/08 E. coli identified from 74% of +ve cultures Trimethoprim14.9% Co-trimoxazole14.4% Co-amoxiclav2% (Piv)mecillinam1% Ciprofloxacin0.5% Gentamicin0.5% Cefotaxime0.5% Fosfomycin0.5% Nitrofurantoin0% 15 Kahlmeter G et al, IJAA 2012;39:45-51

16 Prospective, randomised, double-blind, double-dummy trial in ICUs of 2 university hospitals in Tunisia Patients with acute exacerbation of COPD requiring mechanical ventilation (45% non-invasive) –Clinical evidence of purulent bronchitis and acute respiratory failure –No antibiotics in previous 10 days and not immunocompromised Oral/NG Septrin 960mg 12-hourly or oral/NG ciprofloxacin 750mg 12-hourly In-hospital death or need for additional antibiotics: 16.4% vs 15.3%, p=0.83 (7/85 deaths in Septrin arm, 8/85 deaths in ciprofloxacin arm) Hospital stay: 12.9 days Septrin arm vs 13.1 days ciprofloxacin arm, p=0.88 Exacerbation-free interval: 83 vs 69 days (p=0.33) 16 Clinical Infectious Diseases 2012;143-14951(2):

17 Is ciprofloxacin a fair comparator? S. pnemoniae isolated from 10/85 patients in Septrin arm and 8/85 patients in ciprofloxacin arm 3 isolates resistant in both groups Clinical Infectious Diseases 2012;143-14951(2): 17

18 Beta-lactam infusions

19 Clinical Infectious Diseases 2013;56(2):236–44 Prospective feasability trial in 1 Hong Kong and 4 Australian hospital ICUs Adult patients with severe sepsis expected to stay on ICU for >48h and prescribed ticarcillin-clavulanate, piperacillin-tazobactam or meropenem Randomised to: –Active infusion with placebo bolus doses –Placebo infusion with active bolus doses –Infusions run over 24 hours for TC and PT and over 8 hours for meropenem (or corresponding placebos) Clinical staff, data collectors and patients all blinded Primary endpoint trough serum levels; secondary endpoint clinical cure

20 Clinical Infectious Diseases 2013;56(2):236–44 60 patients enrolled and 44 completed 4 days treatment Total daily doses for antibiotics: TC 12.4g; PT 13.5g; M 3g Duration of treatment 5 days (2-7) Outcomes –Trough serum level > MIC for 82% of infusion group vs 29% of bolus dosing group (p=0.001) –Clinical cure was higher in the continuous group (70% vs 43%; p = 0.037) –Survival to hospital discharge no significant difference 90% for infusion grou vs 80% for bolus group (p=0.47)

21 The elastomeric pump device Silicone balloon drug reservoir under pressure Rate control device (laser- drilled glass) integrated into giving set Typical fixed flow rate 5mL/hr or 10mL/hr Benzylpenicillin at 8.64g / 240mL in 5% glucose stable for 6 days at 4 C followed by 24hr at 37 C Can deliver 240mL over 24h

22 Continuous infusion penicillin for cardiac device infection 48-year old male with infected cardiac device Streptococcus salivarus isolated from blood cultures; penicillin MIC 0.064mg/L Penicillin G clearance correlated with CrCl [see Bryan CS & Stone WJ, Annals of Internal Medicine 1975 for nomogram] Patient CrCl estimated at 80mL/min = Clpen 300mL/min Infusion of 36mg/mL @ 10mL/hour predicted to achieve steady state serum level of 20mg/L (7mg/L free drug) Patient completed final two weeks of therapy at home with balloon pump without complication 22

23 You can do this at home! Select infection site Select target organisms and MICs Select antibiotics Find PK/PD data in literature Find penetration and protein binding data Do the arithmetic 23 Masterton RG, JAC 2005; 55: 71–77

24 Something for the journey home? Am I recommending adequate doses of colistin? When is the last time I recommended co-trimoxazole for a skin/soft tissue infection or a chest infection? Have we implemented continuous infusions of beta-lactams on our ICU? Thank you for listening!

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