Pragmatic approaches to better antibiotic stewardship:

Transcription

1 Pragmatic approaches to better antibiotic stewardship: what works? Professor Paul Little

2 Brief Intro/context Outline Systematic review as part of CHAMP Recent studies: Targetting: GRACE, PRISM Delayed prescription cohort: DESCARTE Communication and CRP: GRACE INTRO Analgesics and handwashing: PIPS, PRIMIT

3

4 Context RTIs: the commonest symptoms: impact NHS/society sickness disability 25-30% consult each year with RTIs Very high expectations for antibiotics, most get antibiotics

5 Why:? we need to moderate antibiotic use/..

6 Overview: OM/sinusitis/chest infections: otitis media sore throat Do Abs help symptoms? : not much! Evidence from RCTs, systematic reviews prior duration total Benefit NNT duration after seeing duration from doctor untreated antibiotics 1-2 days 3-5 days 4 days 8-12 hours 18 3 days 5 days 8 days hours sinusitis 5 days 7-10 days days 24 hours 13 bronchitis 10 days days days 24 hours 10-20

7 I ve got tonsillitis again doctor BUT..its Friday pm, you are running late// would you say no antibiotics to these ladies?

8 The potential problem with medicalisation: the iceberg Secondary care: 1:3300 General practice: 1:9 Pharmacy/NHS direct Self care

9 So what is likely to work?

10 Systematic review (CHAMP) Changing behaviour of health care professionals and the general public towards a more prudent use of anti-microbial agents Br J Gen Pract Dec;62(605):e doi: /bjgp12X Sixth Framework Programme: United Kingdom, Belgium, Switzerland, the Netherlands, Poland, Italy, Spain

11 Method: Systematic review of behavioural interventions to improve antibiotic use ofr RTIs targeted at: primary care physicians primary care patients

12 Physician interventions Effective intervention aiming to achieve: significant decrease in total antibiotic prescription, or significant increase in 1 st choice prescription Study designs: RCTs but also CBA, uncontrolled, or controlled but no baseline

13 Interventions aimed at p.c. physicians: characteristics 58 studies designs: mostly CBA, RCT encompassed 101 interventions 77%: multiple, 40%: multifaceted interventions contained an average of 3 intervention elements. Most often used elements: educational material for physician (70%) educational meetings (56%) educational material for patients (40%) audit/feedback (37%) Training in communication (9%) NPT (8%)

14 RTI interventions aimed at p.c. physicians: effectiveness (I) Overall effectiveness 60% of interventions significantly improved antibiotic prescription total prescription (n=59, 43 (73%) effective): mean -11.6% (-72% -19%) 1st choice prescription (n=28, 9 (32%) effective) +9.6% (5% to 41%)

15 Type of study design: less effect in better controlled designs Study type Outcome Total AB (%) n First choice n RCT/CBA -8.7 ( ) ( ) 15 No CBA ( ) (-5 41) 11 CA (-72-1) (2 5.1) 2

16 Determinants of effectiveness: Determinants of effectiveness (multivariate analysis) multiple intervention OR: 6.5 (2-22) physician materials OR: 5.5 (1,7 to 18) patient materials OR 1.4 (0.4 to 5) audit/feedback OR 0.5 (0.2 to 2) NB no Happy Audit! promising: communications skills and near patient testing

17 RTI interventions aimed at patients: Meta-analysis of 33 interventions: key findings modest changes in attitudes, knowledge satisfaction maintained (despite lower antibiotic use) education, information material not effective delayed or refused prescription was effective

18 Delayed prescription

19 An old chestnut!: Sore throat trial 1997 Open trial of prescribing strategies: No offer of antibiotics Immediate antibiotic prescription Delayed prescription

20 Main results sore throat trial (n=715) % p<0.001 p<0.001 % better satis belief Ab future Antibiotic No antib. delayed

21 More studies (LRTI, otitis).. similar results/.

22 If you use delayed prescribing?: how to do it key components for delaying: Emphasise Abs not needed now: modest benefit + Abs have disadvantages (side effects, immunity) Symptom management Advice about natural history 1/2 week(om), 1week(sore throat), 2 weeks(sinus), 3 weeks LRTI) Clarity about when to take much worse or not starting to settle in time frame Safety netting

23 Cochrane review of delayed prescribing:? Is no prescribing better 6 studies Antibiotic use (satisfaction): Immediate 93% (92% satisfied) Delayed 28-30% (87% satisfied) No 4% (83% satisfied) only 3 studies comparing no/delayed! Reconsultation/complications not well addressed/.. DESCARTE cohort/.

24 Does delayed prescribing prevent complications and reconsultations? DESCARTE sore throat cohort (N>13,000!)

25 Results: Complications are uncommon No antibiotics Antibiotics Delayed Antibiotics Complications (total) 73/4536 (1.6%) 75/5750(1.3%) 16/1664 (1.0%) Quinsy 11/4,536 (0.2%) 30/5750 (0.5%) 4/1,664 (0.2%) Sinusitis 23/4,536(0.5%) 10/5750(0.2%) 2/1,664 (0.1%) Otitis media 30/4,536(0.7%) 26/5750 (0.5%) 10/1,664 (0.6%) Celluliltis/impetigo 10/4,536(0.2%) 9/5750 (0.2%) 0/1,664 (0.00%)

26 Delayed prescribing prevents complications as effectively as immediate antibiotics. Adjusted RRs No antibiotics Antibiotics Delayed Antibiotics Stratified Propensity score (Multiple Imputation) (0.40;0.94) 0.55 (0.31,0.98)

27 ..and lowers reconsultations more effectively than immediate antibiotics Adjustment No antibiotics Antibiotics Delayed Antibiotics Adjusted RRs All control for clustering Stratified Propensity score (Multiple Imputation) (0.68;0.86) 0.58 (0.49,0.67)

28 Targettingin sore throat: Clinical scores and near patient tests (RADTs)

29 PRISM: Can we improve the evidence for better targeting of antibiotics for bacterial throat infections? /..and will it make any difference!

30 Targetting: clinical scores Centor: Group A (pus, nodes, fever, no cough) Are Non Group A important?... Yes, probably! Major virulence factors similar M protein;peptidase;streptokinase etc rates of septicaemia similar to A Norwegian study: C+G 20% and similar presentation to A Confirmed in our UK PRISM cohorts: clinical features of non A very similar to A

31 Predicting A/C/G streptococci? FeverPAIN(AUC 0.70): *Fever last 24h Pus *Attend rapidly (<=3 days) *severely Inflamed tonsils No cough or coryza(i.e. pharyngeal illness) *=univariate and multivariate in both cohorts

32 Does better diagnosis/targetting (using a clinical score or rapid antigen detection test (RADTs)) lead to better outcome?

33 PRISM Trial Empirical delayed prescribing (control) 5 item clinical score (FeverPAIN) 0-1 <20% strep (none), 2-339% strep (delayed), 4+ 63% strep (immediate) RADT Similar but test for higher scores (3+)

34 Results: Delayed (control) FeverPAIN RADT Duration (moderately bad or worse Sx) Median 5 days HR 1.30* (1.03 to 1.63 ) HR 1.11 (0.88 to 1.40) Antibiotic use 75/164 (46%) RR 0.71* (0.05 to 0.95) RR 0.73* (0.52 to 0.98) All models controlled for fever and symptom severity at baseline No difference in returns within one month or following

35 So better diagnosis (targeting using FeverPAIN) improves symptom control and lowers antibiotic use RADTs similar but no clear advantages to a clinical score alone.

36 Targeting in sore throat: Can we predict complications? DESCARTE sore throat cohort (N>13,000!)

37 Results: Complications are uncommon No antibiotics Antibiotics Delayed Antibiotics Complications (total) 73/4536 (1.6%) 75/5750(1.3%) 16/1664 (1.0%) Quinsy 11/4,536 (0.2%) 30/5750 (0.5%) 4/1,664 (0.2%) Sinusitis 23/4,536(0.5%) 10/5750(0.2%) 2/1,664 (0.1%) Otitis media 30/4,536(0.7%) 26/5750 (0.5%) 10/1,664 (0.6%) Celluliltis/impetigo 10/4,536(0.2%) 9/5750 (0.2%) 0/1,664 (0.00%)

38 Can we predict complications in sore throat?: Not very well! Only two variables: severe tonsillar inflammation (OR 1.92) severe earache (OR 3.02) modest utility AUROC 0.61 (chance=0.5!) 70% complications when neither variable present!

39 DESCARTE sore throat cohort So complications /. we cannot very effectively predict them But if considering an antibiotic, consider delayed prescribing? prevents complications, reduces reconsultations at least as effective as immediate antibiotics.

40 GRACE: Targeting in chest infections?: The patient: I ve got green sputum doctor The doctor: how do I know antibiotics won t work for my particular patient? (green sputum, smoker etc)? //.the overall data is modest (few RCTs) and not helpful for subgroups?

41 GRACE trial : 3012 adult patients with LRTI in 12 countries acute cough (<28 d) main symptom or GP suspects acute bronchitis or pneumonia 2061 randomised: amoxycillin 1 gr TID or placebo

42 Resolution of bad symptoms: overall data Whole data set (n=1799) Day 7-8 survivor vs Log rank P= (0.96 to 1.18) Hazard ratio P/NNT 1.06 NNT 15 P=0.229

43 Resolution of moderately bad symptoms ( whole data set) Kaplan-Meier survival estimates analysis time groupnumber = 0 groupnumber = 1 time to resolution of moderately bad symptoms

44 What about my particular patient? Hazard ratio P Interaction term? (p) Smokers n= (p=0.121) 1.23 (1.01 to 1.50) NNT 9 Age 60+ n= (p=0.166) 0.95 (0.79 to 1.14) NNT 143 Green Sputum n= (p=0.059) 1.31 (1.05 to 1.65) NNT 8 Comorbid n= (p=0.914) 1.06 (0.86 to 1.31) NNT 14

45 Green sputum subgroup Kaplan-Meier survival estimates analysis time groupnumber = 0 groupnumber = 1 time to symptom resolution - green phlegm subgroup

46 Smokers Kaplan-Meier survival estimates analysis time groupnumber = 0 groupnumber = 1 time to symptom resolution - current smoker subgroup

47 Benefits vs harms: side effects! Nausea, rash, or diarrhoea NNH 21 Antibiotic 29% Placebo 24%

48 Targetting?: 6 symptoms and signs predict consolidation History (day 1) Severe cough present 931 (33) 56 (40) 1.4 ( ). 1.1 ( ) Phlegm present 2239 (79) 120 (86) 1.6 ( ) N.A. Breathlessness present Severe breathlessness present 1594 (57) 197 (7) 96 (69) 17 (12) 1.7 ( ) 1.9 ( ) 1.4 ( ) 1.3 ( ) Runny nose absent 807 (29) 61 (44) 2.0 ( ) 1.9 ( ) <0.001 Fever present 989 (35) 82 (59) 2.8 ( ) N.A. Chest pain present 1304 (46) 80 (57) 1.6 ( ) 1.2 ( ) Severe chest pain present 141 (5) 13 (9) 2.1 ( ) 1.5 ( ) Diarrhoea present 199 (7) 15 (11) 1.6 ( ) 1.5 ( ) Physical examination (day 1) General toxicity 739 (26) 43 (31) 1.3 ( ) 1.1 ( ) Diminished vesicular breathing 362 (13) 31 (22) 2.0 ( ) 1.7 ( ) Crackles 264 (9) 44 (31) 5.3 ( ) 3.5 ( ) <0.001 Tachycardia (pulse >100 beats/min) 111 (4) 17 (12) 3.7 ( ) 2.3 ( ) Tachypnoea (>24 breaths/min) 55 (2) 6 (4) 2.4 ( ) 1.4 ( ) Blood pressure <90/60 mmhg 71 (3) 9 (6) 2.9 ( ) N.A. Temperature >37.8 C 156 (6) 22 (16) 3.5 ( ) 2.5 ( ) <0.001

49 Simple risk stratification 2 history: Breathless, no coryza 2 chest signs: bronchial, crackles 2 vital signs: pulse >100, temp. > = 1% have consolidation 1-2= 5% (most here/) 3 = 20%

50 Will antibiotics work for my particular patient with a chest infection?: Modest benefits even in key clinical subgroups, modest disbenefits/ Don t prescribe for the vast majority! Consider antibiotics/delayed antibiotics for 3+ key symptoms/signs? So we need to be able to communicate effectively And what about CRP?...

51 CRP?: ROC area analysis (0 36 months initial cohort; months continued cohort with nested trial).

52 Can we improve communication, and/or use CRP..and will it help reduce antibiotic use?

53 GRACE INTRO (INternet TRaining for antibiotic use) Trial Paul Little, Beth Stuart, Elaine Douglas, Sarah Tonkin-Crine, Sibyl Anthierens, Nick Francis, Kerry Hood, Mark Kelly, Hasse Melbye, Jochen Cals, Mike Moore, Samuel Coenen, Maciek Godycki-Cwirko, Artur Mierzecki, Toni Torres, Carl Llor, Peter Edwards, Miriam Santer, Mark Mullee, Gilly O Reilly, Curt Brugman, Samuel Coenen Herman Goossens Theo Verheij, Chris Butler, Lucy Yardley, on behalf of the GRACE consortium. Thanks to ORION diagnostica

54 How to change prescribing behaviour?

55 NPTs/communication skills for LRTI Calset al Four groups Antibiotic use Usual care 67% CRP 39% Communication skills 33% Both 23% Communication skills training: Seminar 11 key tasks, mainly: Explore fears and expectations, opinion on antibiotics Information provision: natural duration of cough Peer review of transcripts with simulated patients

56 Communication: internet training using a booklet Francis et al: children with RTIs Antibiotic use: 19.5% booklet 40.8% usual care encouraged booklet use within the consultation to facilitate the use of communication skills: exploring the parent s main concerns/expectations discussing prognosis, treatment options any reasons that should prompt reconsultation

57 GRACE INTRO trial: Aim To develop and evaluate the effectiveness of internet training (enhanced communication skills +/-CRP) in modifying antibiotic prescribing for RTIs

58 Web based training for easy implementation: four groups No training Communication enhanced communication training + booklet CRP training cut points; kit demonstration Both: Communication and CRP n=6771 baseline Post-intervention n=4264

59 Enhanced Communication /Information sharing Addressing the patients world Concerns, Expectations, Attitudes Information exchange: booklet Natural history; Risks/benefits of antibiotics Self-help Safety netting Wrap up Summarise Check understanding, other concerns

60 We can communicate effectively and it makes an important difference: RR Control 1.0 (adjusted for patient variables) p CRP 0.47 (0.35 to 0.64) <0.001 Communic n 0.66 (0.50 to 0.85) <0.001 Both 0.39 (0.28 to 0.54) <0.001

61 Can we help symptoms with simple advice (PIPS study)?

62 PIPS study Randomised strategies analgesic strategies Paracetamol vs ibuprofen vs combination; steam inhalation

63 Patients complied / BUT trivial differences in symptom severity overall 10 symptoms: 0=no problem//6 as bad as it could be Whole cohort (743/889;84%) Pmol (control) Ibuprofen (-0.11 to 0.19) Both (-0.04 to 0.26) Ibuprofen better in chest infections and for children

64 Ibuprofen interfering with the immune response?: More reconsultations:same/new/worse symptoms Reconsultation (same Sx, new Sx, or worse Sx) Adjusted RR Pmol (control) Ibuprofen Both 35/300 58/295 48/295 (12%) (20%)** (17%) (1.12 to 2.38) 1.49 (0.98 to 2.18) ** p=<= p=0.06

65 Complications higher Pmol (control) Complication 2/300 (0.6%) 1 cellulitis 1OM Ibuprofen 11/295 (3.7%): 1 Quinsy 3 sinusitis 1 meningitis 1pneumonia 5 OM (2 not new) Both 4/295 (1.4%): 1 Quinsy 2 sinusitis (1 not new) 1 cerv. adenitis

66 Steam? No benefit Mild thermal injury in 4 patients (2%) who returned full diaries No reconsultations with scalding

67 We are probably doing more harm than good with widely given self help advice! ibuprofen little help overall? for chest infections and children. BUT progression of symptoms/complications Advice to use steam does not help and occasional harm

68 Can we prevent infections? The PRIMIT trial of a web based behavioural intervention to reduce infection transmission

69 Handwashing? Hand-washing widely advocated e.g. H1N1 pandemic but role of handwashing debated! No good randomised evidence among adults in our (resource rich) setting. So/initial intervention development/piloting brief 4 sessions increase handwashing Main trial: 20,066 randomised; 16,908 (84%) followed-up

70 PRIMIT main trial results: infections prevented Intervention Control p Any RTI at 4 months 51% 59% <0.001 Any RTI (in household) 44% 49% <0.001

71 Transmission reduced to and from household members Intervention Control p Transmission to household Transmission from household 7.8% 9% < % 8.8% <0.001

72 Infections slightly less severe Intervention Control p Days more severe symptoms if RTI 4.1 days 4.3 days 0.008

73 Reduced consultations, reduced GI infections Intervention Control p Consultations for RTIs 16.0% 17.3% <0.001 (notes) GI infections 21.5% 25% <0.001

74 We can prevent infections! A free standing web intervention increases hand-washing reduces infections, their severity, and transmission,?pandemic: will access internet for advice.

75 Have we learned anything useful? For symptoms: antibiotics overall/subgroups mostly not helpful Delayed prescription is effective in reducing antibiotic use A bacterial score in sore throat helps symptoms, reduces antibiotics Commonly given advice (steam/ibuprofen) is probably harmful! For complications: Sore throat: Uncommon/difficult to predict: Good safety netting skills if antibiotics are considered, consider delayed prescribing? Chest infections: basic clinical history/exam. help identify consolidation For prevention: a behavioural web handwashingintervention helps prevents infections, reduces severity, and reduces transmission

76 Multifaceted interventions (outreach,audit, interactive booklets) are effective Training in enhanced communication skills is effective Training in use of CRP also effective (short term) Acute infections are relatively quick/easy consultations in a world of increasing demands/but: a central public health role a central role for better communication a little more time, BUT saves time in future! brief training for experienced GPs helps

77 Had enough?