New Uses for Old Agents

BSAC Spring Meeting 2013

Thursday 14th March, Royal College of Physicians, London

Dr Kieran Hand PhD MRPharmS Consultant Pharmacist Anti-Infectives, University Hospital Southampton NHS Foundation TrustPost-doctoral Clinical Academic Fellow, Faculty of Health Sciences, University of Southampton

Scene-setting

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

Running out of options

Health Protection Report, June 2011 (n=333 isolates in 2010)

CMO Report Volume 2, 11 March 2013

Older agents

• 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

6Clinical Infectious Diseases 2012;54(2):268-74

Colistin

Colistin Dosing RecommendationsPatient category Dose* to target average serum level 2 mg/L

Loading dose

All patients BW** (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)

1st dose 24 h after loading dose

Intermittent hemodialysis

2 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

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

• 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

Wareham DW et al, JAC 2011

Colistin-glycopeptide synergy vs. MDR Acinetobacter baumannii

Co-trimoxazole (Septrin®)

• 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

13Clin Microbiol Infect 2012;18:8-17

Co-trimoxazole: MRSA skin infection?Community-acquired MRSA

Outcome Septrin 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 failure

26% 25%

Microbiological failure

13% 15%

Required additional inpatient intervention

6% 5%

Required outpatient intervention

20% 20%

Data presented for patients undergoing incision & drainage.No statistically-significant differences reported.

14Frei CR et al, J Am Board Fam Med 2010;23:714-719

Co-trimoxazole: not adding much for UTI?ECO-SENS Antibiotic E. 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

Trimethoprim 14.9%

Co-trimoxazole 14.4%

Co-amoxiclav 2%

(Piv)mecillinam 1%

Ciprofloxacin 0.5%

Gentamicin 0.5%

Cefotaxime 0.5%

Fosfomycin 0.5%

Nitrofurantoin 0%15Kahlmeter G et al, IJAA

2012;39:45-51

• 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)

16Clinical Infectious Diseases 2012;143-14951(2):

• 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

Beta-lactam infusions

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

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)

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 4C followed by 24hr at 37C

• Can deliver 240mL over 24h

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

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 arithmetic23

Masterton RG, JAC 2005; 55: 71–77

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!