When are combinations of

antibiotics really clinically useful?

Gavin Barlow

Clinical Senior Lecturer in Infection

Consultant Physician

@gavin_barlow

Centre for Immunology and Infection

Spectrumof

microbial cover(CAP)

Synergy(Endocarditis)

Immuno-modulatory(Severe group A Strep.)

Prevent resistance

(TB, CF) ‘Capture’ β-lactamase inhibitorIncrease PBPs covered

(Theoretical)

Reduce adverse effects

(Theoretical)

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

Why combination

therapy?

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Meropenem Gentamicin Ciprofloxacin Tigecycline Colistin Ceftazidime/Avibactam

Ceftolozane/tazobactam

Aztreonam Temocillin Piperacillin/Tazobactam

≤ 0.5 Synergy > 0.5 and ≤ 1.0 Additive > 1.0 and ≤ 4.0 Indifferent > 4.0 Antagonism

Non-cell wall acting agents

Synergy Additive Indifference Antagonism

Cell wall acting agentsCWA

Fosfomycin in combination with other antibiotics in-vitro

versus Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa bacteraemia isolates (N = 30)

Fractional Inhibitory Concentration Index

But why worry about it..!Look at what’s happening in Greece…

Klebsiellabloodstream

infections

53%resistant to

carbapenemsThe last line of

defence

Carbapenem-resistantGram-negative

infections

>8000Mostly:PneumoniaBloodstreamUrinary

Vulnerable patients

52% ICUBM transplant>>

immunocompetent

Adverse effects of antibioticsJAMA Intern Med. 2017 Sep 1;177(9):1308-1315

J Gen Intern Med. 2018 Apr 20.

USA: 14% of drug

related visits to ED

145,490 per year

due to antibiotics

Hospitalised patients

prescribed antibiotics

1 in 5 will develop a

clinically important

adverse event

What do we use antibiotics for?Antibiotic 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 recommendationsCommunity-acquired pneumonia

• Low severity:

Amoxcillin (Macrolide or Tetracycline)

• Moderate-severity:

Amoxicillin + 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-pseudomonalantibiotic 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 flucloxacillin plus penicillin?

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 1Paul 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?

42.5% 45%

What about combinations for highly resistant Gram-negatives?

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 Cefiderocol Ceftazidime-avibactam

Meropenem-vaborbactam

Aztreonam PBP3(Permeability; Efflux)

PBP 1a/b, 2, 3 (Synergy described; MBL stable)

PBP 2, 3, 4(MBL stable)

Cefiderocol PBP3(Permeability; Efflux)

PBP 1a/b, 2, 3(Permeability; Efflux)

PBP 2, 3, 4(Permeability; Efflux)

Ceftazidime-avibactam

PBP 1a/b, 2, 3 (Synergy described; MBL stable)

PBP 1a/b, 2, 3(Permeability; Efflux)

PBP 1a/b, 2, 3, 4

Meropenem-vaborbactam

PBP 2, 3, 4(MBL stable)

PBP 2, 3, 4(MBL stable)

PBP 1a/b, 2, 3, 4

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 aureusbacteraemia (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?