Old and new antibiotics for S. aureus bacteraemia

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Old and new antibiotics for S. aureus bacteraemia
Guy Thwaites Reader in Infectious
Diseases/Honorary Consultant in Infectious
Diseases and Microbiology Centre for Diagnostics
and Clinical Infection Research Kings College
London/Guys and St. Thomas Hospital
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My delight may be conceived when there were
revealed to me beautiful tangles, tufts and
chains of round organisms in great numbers, which
stood out clear and distinct among the pus cells
and debris...

• Once established the micrococci are hard to kill
• the only thing I found effective was
  cauterisation with a strong solution of chloride
  of zinc
• Alexander Ogston.1844-1929

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Treatment of staphylococcal septicemia with
sulfamethylthiazole and sulfathiazole. A report
of 12 cases. Hamburger and Ruegsegger Ann Int
Med. 141137. 1941
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Reserve Constable Albert Alexander John Radcliffe
Hospital. Dec 1940. First recipient of IV
penicillin for purulent staphylcoccal infection
of head and neck one eye enucleated. Produced by
Florey, Chain and Heatley in Oxford
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PENICILLIN ITS ANTIBACTERIAL EFFECT IN WHOLE
BLOOD AND SERUM FOR THE HEMOLYTIC
STREPTOCOCCUS AND STAPHYLOCOCCUS AUREUS CHARLES
H. RAMMELKAMP AND CHESTER S. KEEFER
In patients with staphylococcal bacteremia
or localized infections caused by
Staphylococcus aureus, the blood or local lesion
may not be sterilized for several days after the
institution of penicillin therapy
J Clin Invest.22(5)649657. 1943
California and Western Medicine. 63 (5) 1945
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• 55 cases (64 endocarditis)
• Mortality 71
• No single drug regimen can be confidently
  recommended.but various combinations, in pairs,
  of penicillin, tetracycline, chloramphenicol and
  erythromycin are suggested. and should be
  administered for at least 6 weeks.

Wilson and Hamburger. Am J Med. 22 (3) 437. 1957
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What more do we know now?
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The management of S. aureus bacteraemia in 2009/10
The Management of Staphylococcus aureus
Bacteremia in the United Kingdom and Vietnam A
Multi-Centre Evaluation. UKCIRG. PLOS One Dec
2010
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What does the current literature tell us?
March 2011

• Mortality 25
• 12,000 cases. UK
• 16 RCT anti-microbial therapy
• lt1500 patients enrolled
• Majority of evidence from uncontrolled
  observational studies

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What do we know in 2012?

• Rapid identification and removal of the focus
  (pus) improves outcome
• Prolonged antimicrobial treatment is required for
  cure
• Glycopeptides arent as good as beta-lactams

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What dont we know?

• Are some beta-lactams better than others?
• Best dose?
• Best mode of delivery?
• Optimal duration of therapy?
• Are combinations better than single agents?
• What role should the new agents linezolid,
  daptomycin, tigecycline play?

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Rapid identification and removal of the focus
(pus) improves outcome
Copenhagen, Denmark
Duke Medical Centre, USA 244 patients with
SAB 13 relapsed 16 died Death 6.5X more
likely if IV catheter not removed
Persistent focus associated with death OR 6.7
(2.1-21.0)
Fowler V, CID. 274781998
Detroit, USA 284 adults with SAB 33 died 8
relapse 16X more likely to relapse or die If
focus not removed
Jensen A. Arch Int Med. 162252002
Johnson L, Scand J ID. 35782. 2003
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In-hospital outcome in 630 adults with SAB 549
UK, 80 Vietnam
UKCIRG. PLOS One. Dec 2010
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Prolonged antimicrobial treatment is required for
cure

• 1 RCT. 11 adults with SAB. 2 vs 4 weeks
• Rest of evidence is observational (gt20 studies)
• Thomas and Morris, Int Med J. 2005.
• Prospective study of 276 cases of
  catheter-associated SAB
• 9 mortality 4 metastatic disease
• 33 given lt10 days of antibiotics
• No relationship between duration and outcome

235 patients 46 IV catheter related
Fowler and Cosgrove. Clin Infect Dis. 46
S386-S393. 2008
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Glycopeptides arent as good as beta-lactams

• RCT evidence Beta-lactam vs GP
• 2 trials 47 IVDU with Right sided S. aureus
  endocarditis
• 68 failed in GP arm vs 5 in Beta-Lactam arm

123 haemodialysis patients with MSSA
bacteraemia Treated with cefazolin (46) or
vancomycin (77)
Stryjiewski M, CID 2007.
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What is the role of new antibiotics?LinezolidDa
ptomycinTigecycline
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Linezolid
Linezolid versus vancomycin for the treatment of
infections caused by methicillin-resistant
Staphylococcus aureus in Japan.
Linezolid versus teicoplanin in the treatment of
Gram-positive infections in the critically ill a
randomized, double-blind, multicentre study
J Antimicrob Chemother. 2007 Dec60(6)1361-9
J Antimicrob Chemother. 2004 Feb53(2)345-55
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cSSTI
Efficacy and safety of linezolid in
methicillin-resistant Staphylococcus aureus
(MRSA) complicated skin and soft tissue infection
(cSSTI) a meta-analysis.
Curr Med Res Opin. 2010 Feb 26(2)407-21
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Linezolid versus vancomycin for Staphylococcus
aureus bacteraemia pooled analysis of randomized
studies

• N 99
• Cure in 28 (55) of 51 linezolid recipients
  and 25 (52) of 48 vancomycin recipients
• Odds ratio for cure with linezolid versus
  vancomycin 1.12 (95 CI, 0.51-2.47)

J Antimicrob Chemother. 2005 Nov56(5)923-9
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Linezolid for HAP?
Linezolid vs glycopeptide antibiotics for the
treatment of suspected methicillin-resistant
Staphylococcus aureus nosocomial pneumonia a
meta-analysis of randomized controlled trials.
Linezolid versus vancomycin or teicoplanin for
nosocomial pneumonia a systematic review and
meta-analysis.
Crit Care Med. 2010 Sep38(9)1802-8.
Chest. 2011 May139(5)1148-55
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Daptomycin
Daptomycin versus standard therapy for
bacteremia and endocarditis caused by
Staphylococcus aureus
246 patients with S. aureus bacteremia with or
without endocarditis 6 mg/Kg of Daptomycin vs
initial low-dose gentamicin antistaphylococcal
penicillin or vancomycin.
42 days later modified ITT, successful
outcome Daptomycin 53/120 (44.2) Standard
48/115 (41.7) Absolute difference 2.4
percent 95 percent confidence interval, -10.2 to
15.1 percent).
Note Clinically significant renal dysfunction
occurred in 11.0 who received daptomycin and in
26.3 who received standard therapy (P0.004).
N Engl J Med. 2006 Aug 17355(7)653-65
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Daptomycin exposure and the probability of
elevations in the creatine phosphokinase level
data from a randomized trial of patients with
bacteremia and endocarditis.
Clin Infect Dis. 2010 Jun 1550(12)1568-74.
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Tigecycline

• Safety and efficacy of intravenous tigecycline in
  subjects with secondary bacteremia pooled
  results from 8 phase III clinical trials
• 170 patients with cSSI, cIAI, or CAP
• Cure rates for bacteraemia
• MSSA/MRSA 16/20 (80)
• MRSA 5/6 (83)

Efficacy and safety of tigecycline compared with
vancomycin or linezolid for treatment of serious
infections with methicillin-resistant
Staphylococcus aureus or vancomycin-resistant
enterococci a Phase 3, multicentre,
double-blind, randomized study.
Cure for MRSA disease Tigecycline 70/86 81.4
(71.689.0) Vancomycin 26/31 83.9 (66.394.5)
Clin Infect Dis. 2010 Jan 1550(2)229-38
J Antimicrob Chemother. 2008 Sep62 Suppl
1i17-28
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Why is S. aureus bacteraemia so difficult to
treat?
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Persistent bacteraemia is an independent
predictor of metastatic spread of S. aureus

• Detroit, USA
• Prospective study of 245 adults with SAB
• BC gt3 days in 38 (MRSAMSSA)
• Rapid extinction complications in 5
• Persistent bactereamia (gt3 days) complications
  in 40

Fowler V et al. Arch Int Med. 163(7)2066 2003
Khatib Scand J ID. 387 2006
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Why does S. aureus persist in the bloodstream
despite active antibiotics?
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Rogers D, J Exp Med. 103 (6)713. 1957
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Neutropenia and invasive human S. aureus disease
Comparative study of clinical characteristics of
neutropenic and non-neutropenic adult cancer
patients with bloodstream infections
399 consecutive blood-stream infections S.
aureus 12 in neutropenic vs 35 if
non-neutropenic (p0.02)
S. aureus bacteraemia in patients With
haematological malignancies
Velasco. J Clin Micro Infect Dis. 25. 1. 2006

• Neutropenia associated with
• Less severe signs of sepsis
• Shorter duration of bacteraemia
• Less metastatic complications

Venditti. Haematologica. 88.923. 2003
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Survival of S. aureus within neutrophils is well
documented
Gresham. J Immunol. 164. 3713. 2000
Thwaites and Gant. Nat Rev Micro. 9. 215. 2011
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• S. aureus persists in the bloodstream within
  neutrophils
• Antibiotics with enhanced intracellular activity
  may terminate the bacteraemia
• faster and improve patient outcome

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Combination therapy for SAB?
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Adjunctive gentamicin for SAB/endocarditis
Ceftriaxone gentamicin
Cloxacillin gentamicin
Antimicrob Agents Chemother. 2002
Feb46(2)378-84.
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Initial Low-Dose Gentamicin for Staphylococcus
aureus Bacteremia and Endocarditis Is Nephrotoxic
Clin Infect Dis. 2009 Mar 1548(6)713-21.
Potential individual predictors of clinically
significant decrease in creatinine clearance
Conclusions Initial low-dose gentamicin as part
of therapy for S. aureus bacteremia and native
valve infective endocarditis is nephrotoxic and
should not be used routinely, given the minimal
existing data supporting its benefit.
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Other possible agents

• Fusidic acid anecdotal evidence only hepatic
  toxicity
• Fluoroquinolones 1 RCT (n380) of adjunctive
  levofloxacin no effect except if rifampicin
  used.
• Tetracyclines attractive pharmacological
  properties. No clinical data.

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Rifampicin pros and cons

• Pros pharmacology

• Cons resistance and toxicity

• Excellent oral bioavailability
• Concentrated within cells
• Active within biofilms
• Cheap 73p daily oral dose

• Serious hepatic toxicity lt1
• Drug interactions
• Incidence of rifampicin resistance 0-25

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Clinical evidence 4 RCT (n246 patients)
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Rifampicin meta-analysis of RCT data (246
patients in total)
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Estimated effect sizes

• Bacteraemic patients only (n98)

• All patients with severe S. aureus infection
  (n246)

• Rifampicin reduced infection related death by 55
  (p0.02)
• Rifampicin reduced bacteriolgical failure by 58
  (p0.004)

• Rifampicin reduced infection related death by 54
  (p0.22)
• Rifampicin reduced bacteriological failure by 77
  (p0.17)

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Adjunctive Rifampicin to Reduce Early mortality
from Staphylococcus aureus bacteraemia a
multi-centre, randomised, double blind placebo
controlled trial (the ARREST trial)
Proposal submitted to NIHR/HTA October
2010 Funded November 2011 REC and MHRA
approval May 2012 Start randomising patients in
October 2012
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The UK Clinical Infection Research Group
(UKCIRG) the ARREST Trialists
Middlesbrough
Hull
Liverpool
Sheffield
Cambridge
Birmingham
Royal Free
Bath
UCLH
Exeter
Guys and STH
Plymouth
Kings
St. Georges
Oxford
Brighton
Portsmouth
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Blood taken for culture in adult with signs of
infection
S. aureus grown
Physician decides and initiates standard
antibiotic therapy empirically
lt96hrs antibiotics received, no contraindications
to rifampicin and rifampicin not mandated in
guidelines
RANDOMISE 940CONSENTINGPATIENTS TO
Co-primary endpoint All-cause mortality through
14 days, bacteriological failure/death through 12
weeks
14 days blinded rifampicin
14 days matched placebo
Follow-up day 3, 7, 14 then weekly whilst in
hospital, and at discharge. Final follow-up at 12
weeks.
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Summary

• S. aureus bacteraemia is difficult to treat
• Evidence-base for defining optimal therapy is
  woeful
• Identify and remove the focus (pus)
• Beta-lactams more effective than glycopeptides
  for MSSA
• Newer agents as effective as vancomycin
• Long antibiotic courses required if deep
  undrainable foci
• Combination therapy? Rifampicin?

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Acknowledgements

• All members of the UKCIRG
• Special Trustees for the Hospital for Tropical
  Diseases
• Wellcome Trust UK
• And NIHR HTA for agreeing to fund the trial