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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 Trust
Post-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, betalactam infusions
Clinical Infectious Diseases
2012;54(2):268-74
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Colistin
Colistin Dosing
Recommendations
Patient 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
•
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
Clinical Infectious Diseases
2012;54(12):1720–6
•
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
Colistin-glycopeptide synergy vs. MDR
Acinetobacter baumannii
Wareham DW et al, JAC 2011
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
Clin Microbiol Infect 2012;18:8-17
13
Co-trimoxazole: MRSA skin infection?
Communityacquired MRSA
Outcome
Septrin 960mg Clindamycin
12-hourly
300mg 6-hourly
(n=54)
(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, catheterrelated, 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.
Frei CR et al, J Am Board Fam
Med 2010;23:714-719
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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%
Kahlmeter G et al, IJAA
2012;39:45-51
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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)
Clinical Infectious Diseases
2012;143-14951(2):
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• 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
•
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)
Clinical Infectious Diseases
2013;56(2):236–44
The elastomeric pump device
• Silicone balloon drug
reservoir under pressure
• Rate control device (laserdrilled 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
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
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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
Masterton RG, JAC 2005; 55: 71–77
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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!