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When are combinations of really clinically useful?

Gavin Barlow Clinical Senior Lecturer in Infection Consultant Physician @gavin_barlow

Centre for Immunology and Infection Why do we use a combination antibiotics? 11% of all patients and 36% of patients on antibiotics in my hospital

Spectrum of microbial cover (CAP) Immuno-modulatory (Severe group A Strep.) Synergy (Endocarditis)

Why combination therapy?

Reduce adverse Prevent effects resistance (Theoretical) (TB, CF) ‘Capture’ β-lactamase inhibitor Increase PBPs covered (Theoretical) in combination with other antibiotics in-vitro versus , and bacteraemia isolates (N = 30)

CWA Non- acting agents Cell wall acting agents

100%

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0% Gentamicin Ciprofloxacin Tigecycline / Ceftolozane/ Temocillin / Tazobactam Synergy Additive Indifference Antagonism ≤ 0.5 Synergy > 0.5 and ≤ 1.0 Additive > 1.0 and ≤ 4.0 Indifferent > 4.0 Antagonism Fractional Inhibitory Concentration Index But why worry about it..! Look at what’s happening in Greece…

Klebsiella -resistant bloodstream Gram-negative infections infections 53% resistant to >8000 Mostly: The last line of defence Pneumonia Bloodstream Urinary Vulnerable patients 52% ICU BM transplant>> immunocompetent

Adverse effects of antibiotics JAMA Intern Med. 2017 Sep 1;177(9):1308-1315 J Gen Intern Med. 2018 Apr 20.

USA: 14% of drug Hospitalised patients related visits to ED prescribed antibiotics 145,490 1 in 5 per year will develop a due to antibiotics clinically important adverse event

What do we use antibiotics for? ward round data, Hull & East Yorkshire Hospitals

Diagnosis % of patients with Main pathogens

1. Respiratory 28.5% Strep. pneumoniae, viruses, MSSA, Gram negatives 2. Urinary 17% E. coli, other Gram negs

3. Skin or soft tissue 11% Group A/C/G strep, MSSA

4. Bloodstream infections 6% E. coli, MSSA

5. Bone and joint infections 4% MSSA, CoNStaph, Gram negs

6. Clostridium difficile 4% C. difficile

7. Surgical prophylaxis 3% Depends on operation

8. Unclear indication 2.5% - NICE CG191 recommendations Community-acquired pneumonia

• Low severity: Amoxcillin (Macrolide or Tetracycline) • Moderate-severity: + Macrolide • High-severity: -lactamase stable -lactam + Macrolide

Macrolide = atypical pathogen cover; possibly immuno-modulatory • N = 2011 from 5 trials • Mild to moderate hospitalised CAP • Only one trial compared dual versus monotherapy • Only one trial was industry funded 22% 26% NNT = 25 • N = 36,318 from 2 open RCTs, 1 non-RCT intervention study and 11 observational studies • Median PSI = 4 in most of the studies (~9% mortality) • Quality of observational studies considered good

Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis Elphick H, Scott A. Cochrane Database of Systematic Reviews 1st Dec 2016

• Eight trials; N = 356; all pre-1999

• 7 comparisons of a β-lactam to β -lactam/ aminoglycoside combination; 3 comparisons of aminoglycoside to a β -lactam/aminoglycoside

• No clinical outcome benefits

• Adverse effects similar, but poorly studied

• No effect on bacterial density or Pseudomonas spp. resistance In cellulitis… Do you need plus ?

Intervention

• ‘Standard’ limb cellulitis treated in GP, ED or inpatients (N = 410)

• Control: Flucloxacillin, at a minimum of 500mg 4 times per day for 5 days IV/oral

• Intervention: Above with clindamycin 300 mg 4 times per day for 2 days given orally

So when should you add Clindamycin (or Linezolid) to beta-lactam therapy in Group A streptococcal infection

• Sepsis (new definition) and/or admission to critical care – E.g. GAStrep pneumonia in critical care setting (more common in flu’ seasons)

• Limb- or eye- threatening infections – E.g. Necrotising fasciitis

• Consider in extensive (e.g. whole limb) cellulitis with systemic features, especially if rapid progression

• Stop as soon as patient is clinically stable So what about UTI and Gram-negative infections? The evidence is not convincing! Beta-lactam antibiotic monotherapy versus beta-lactam-aminoglycoside combination for sepsis Cochrane Database of Systematic Reviews 2014, Issue 1 Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L.

• 69 trials, N = 7863 (mean 114 per trial); evidence quality poor • No mortality/bacterial eradication benefit (including in Gram negative infections, endocarditis and Pseudomonas spp.) • Bacterial superinfections less with monotherapy (N = 3135) • No difference in development of resistance (N = 1370) • Nephrotoxicity less with monotherapy Impact of combination therapy on ascertaining required cover?

• 17% (N = 616) received initial antibiotic therapy that was not active in-vitro

• Resistance to co-amoxiclav = 36% (most commonly used antibiotic [32%])

• Using dual therapy (usually with aminoglycoside) decreased likelihood of in- vitro inactivity – 27% to 2% for co-amoxiclav – 15% to 6% for piperacillin/tazobactam

• Inappropriate therapy, however, not associated with outcome Key antimicrobial stewardship question for Gram-negative infections Is a

Beta-lactam + aminoglycoside (Or other combination regimens)

‘better’ than

Monotherapy

for susceptible bacteria? What about combinations for highly resistant Gram-negatives?

42.5% 45% New and old Gram-negative antibiotic combinations and penicillin binding protein avidities (Adapted from: Exploiting antibiotic combinations to overcome resistance. Barlow G. Infectious Diseases Hub, Nov. 2018) Antibiotic Aztreonam Ceftazidime- Meropenem- avibactam

Aztreonam PBP3 PBP 1a/b, 2, 3 PBP 2, 3, 4 (Permeability; (Synergy (MBL stable) Efflux) described; MBL stable) Cefiderocol PBP3 PBP 1a/b, 2, 3 PBP 2, 3, 4 (Permeability; (Permeability; (Permeability; Efflux) Efflux) Efflux)

Ceftazidime- PBP 1a/b, 2, 3 PBP 1a/b, 2, 3 PBP 1a/b, 2, 3, 4 avibactam (Synergy (Permeability; described; MBL Efflux) stable)

Meropenem- PBP 2, 3, 4 PBP 2, 3, 4 PBP 1a/b, 2, 3, 4 vaborbactam (MBL stable) (MBL stable) What about Staph. aureus bacteraemia? Intervention

• N = 758

• Control: Standard of care ‘backbone’ therapy for the Staph. aureus bloodstream infection

• Intervention: Above with 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous)

‘Backbone’ therapy was most commonly flucloxacillin

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): a multi-centre, randomised, blinded, placebo controlled trial The Lancet, in press; ECCMID 2017

• 17.0% rifampicin vs 10% placebo had antibiotic/trial-drug-modifying adverse events (p=0.007) [Renal]

• 6.5% rifampicin versus 1.5% had drug-interactions (p=0.0005)

• 0.5% rifampicin developed new rifampicin-resistant S. aureus BSI 7 and 42 days after randomisation Summary – Antibiotic Combinations

• Reasonable to continue current NICE approach to CAP • Combinations should not routinely be used in cellulitis • In Gram-negative bacteraemia, decrease risk of non- susceptibility, but no efficacy benefit except perhaps in extensive resistance • No benefit of rifampicin combinations in Staph. aureus bacteraemia • Combinations increase the risk of adverse effects and no resistance prevention benefit (outside of tuberculosis) • When using, always ask: What am I trying to achieve?