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Pharmacoeconomics for pharmacists: a guide in infectious diseases

Paul Wade

Consultant Pharmacist Infectious Diseases

Directorate of infection, Guy’s & St Thomas’ NHS Foundation Trust

Clinical Senior Lecturer, King’s College, London

Disclosures

Gilead

ICNet

Merck

Novartis

Pfizer

Wyeth

Astellas

AstraZeneca

Baxter

Cardiome

Clinigen

Cubist

Eumedica

Honoraria, consultancy fees & speakers’ bureau fees from:

Global, regional, national importance

http://www.who.int/antimicrobial-resistance/global-action-plan/UpdatedRoadmap-Global-Framework-for-Development-Stewardship-to-

combatAMR_2017_11_03.pdf. Accessed March 2018; https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/EU-guidelines-prudent-

use-antimicrobials.pdf. Accessed March 2018; http://media.dh.gov.uk/network/357/files/2013/03/CMO-Annual-Report-Volume-2-20111.pdf. Accessed March

2018; https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-

%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf. Accessed March 2018.

AMR, antimicrobial resistance.

https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-

%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf.

Accessed March 2018.

WHO priority pathogens

http://www.who.int/medicines/news/2017/world-running-out-antibiotics-WHO-

report/en/. Accessed March 2018.

ECDC data from 2014

https://ecdc.europa.eu/en/publications-data/antimicrobial-resistance-Europe.

Accessed March 2018.

Not just bacteria…

Increase in incidence of invasive candidiasis & candidaemia

Driven by increased usage of immunosuppressive modifying agents, invasive devices & aggressive surgery

Epidemiology of candida infections also changing

Move from albicans to non-albicans strains

Has impact on drug susceptibility & treatment response

Increasing resistance to azoles & echinocandins being seen

Mould infections (with mortality up around 50%) also increasing

Driven by increasing usage of echinocandins & non-mould active azoles

Difficult to diagnose IMI because clinical symptoms, signs, and radiographic manifestations are unspecific

IMI, invasive mould infections.

Enoch DA, et al. Methods Mol Biol. 2017;1508:17–65.

Impact of increasing infection & resistance

*Bacteria and fungus.

https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

Accessed March 2018.

Not just in complex, specialist areas…

https://www.cdc.gov/drugresistance/protecting_yourself_family.html.

Accessed March 2018.

How can we hope to control this?

https://www.cdc.gov/drugresistance/cdc_role.html. Accessed March 2018.

Case identification

Risk factor assessment

Screening

Infection control

Rapid diagnostics

Optimal treatment

Introduction of new drugs

Clatworthy AE, et al. Nature Chem Biol 2007;3:541–548;

Ventola CL. P T 2015;40:277–283.

The number of new antibiotics developed and approved

has decreased steadily over the past three decades

(although four new drugs were approved in 2014), leaving

fewer options to treat resistant bacteria.

Increasing resistance & increasing usage – increased need for new agents

• Significant increase in carbapenem & piperacillin–tazobactam usage over last decade

• Driven by increased prevalence of ESBLs1

• Dosing strategies may be influencing usage volumes – double-dose carbapenems

• There is limited evidence that usage is slowing

• Resistance to carbapenems will increase with increased use of carbapenems

• Ceftazidime–avibactam has demonstrated activity in vitro against two of the pathogen families listed in the critical group:2,3

• Carbapenem-resistant Pseudomonas aeruginosa

• Carbapenem-resistant, ESBL-producing Enterobacteriaceae

ARHAI, Committee on Antimicrobial Resistance and Hospital Acquired Infections; ESBL, extended-spectrum beta-lactamase; MDR, multi-drug resistant;

NHS, National Health Service; PHE, Public Health England; Pip/taz, piperacillin–tazobactam; R&D, research and development.

1. IMS; standard units; J1 infection class 2004 – 2014; 2. WHO publishes list of bacteria for which new antibiotics are urgently needed [press release].

2017; 3. Zavicefta SmPC 2017.

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Considerations in managed introduction into practice

• Drug costs

• Administration costs

• Oral v IV; infusion v bolus; intermittent v continuous infusion; administration time; nursing time; dose

& frequency

• Monitoring/safety costs

• Drug levels; ancillary tests/visits; preventative medicines; risk mitigation

• Diagnostics

• Drug susceptibility testing – availability, validation, costs

• Outcomes

• Clinical response (relapse/recurrence); LoS (OPAT?); ICU days; complications (ADRs, resistance,

ongoing care); QALYs

• External drivers/funding models

• Diagnostic tools for invasive fungal infections

ADRs, adverse drug reactions; ICU, intensive care unit; IV, intravenous; LoS, length of stay;

OPAT, outpatient parenteral antimicrobial therapy; QALY, Quality-adjusted life year.

Wade P. Speaker opinion.

Burden of resistance in Gram-negatives

Gram-negative infections:

• Increased severity of illness

• Greater hospital & AB costs

• Longer stay in hospital & ICU

Resistance in GN

• Increased costs ($30k v $80k)

• Increased LoS (13d v 29d)

• Increased ICU stay (1d v 13d)

• Increased mortality (11% v 23%)

AB, antibiotic; GN, Gram negative; ICU, intensive care unit; LoS, length of stay.

Maragakis LL, Crit Care Med 2010;38:S345–51; Evans HL, et al. Crit Care Med 2007;35:89–95; Kaye KS, Pogue JM.

Pharmacotherapy 2015;35:949–62; Sievert DM, et al. Infect Control Hospital Epidemiol 2013;34:1–4.

Burden associated with common bacterial infections

cIAI, complicated intra-abdominal infection; cUTI,

complicated urinary tract infection; ICU, intensive care

unit; NP, nosocomial pneumonia; VAP, ventilator-

acquired pneumonia.

1. Cattan P, et al. European Journal Of Clinical

Microbiology & Infectious Diseases 2002;21:787-793; 2.

Swenson BR, et al. Surg Infect (Larchmt). 2009;10:29–

39.3. Inui T, et al. Surgery. 2009;146(4):654-

661;discussion 661-652. 4. Lau WK, et al. Antimicrobial

Agents and Chemotherapy. 2006;50:3556–3561; 5.

Barie PS, et al. Surg Infect (Larchmt). 2004;5:269–280;

6. Montravers P, et al. Annals of Surgery.

2004;239:409–416; 7. Rocha Lde A, et al. The Brazilian

Journal Of Infectious Diseases 2008;12:80–85; 8.

Martin-Loeches I, et al. Intensive Care Medicine.

2013;39:672–681; 9. Suka M, et al. Infection Control and

Hospital Epidemiology 2007;28:307–313; 10.

Sandiumenge A, et al. Chest. 2011;140:643–651; 11.

Tellado JM, et al. Scand J Infect Dis. 2007;39:947–955;

12. Gastmeier P, et al. Infection Control and Hospital

Epidemiology 2007;28:466–472; 13. Micek ST, et al.

Critical Care (London, England). 2015;19:219; 14.

Dalfino L, et al. WJES. 2014;9:39; 15. Brown P, et al.

PharmacoEconomics. 2005;23:1123–1142; 15.

Zimlichman E, et al. JAMA internal medicine.

2013;173:2039–2046; 16. Kollef MH, et al. Infection

Control and Hospital Epidemiology 2012;33:250–256;

17. Bloom JD, et al. American Thoracic Society;

2011:A4122-A4122; 18. Kanj SS, Kanafani ZA. Mayo

Clinic proceedings. Mayo Clinic. 2011;86:250–259; 19.

Barie PS, et al. Surg Infect (Larchmt). 2004;5(4):

365–373.

Substantial clinical burden

cIAI: reported estimates range from 74 to 18.65 days in

hospital and 35 to 116 days in ICU

cUTI: scarce data available

HAP (inc. VAP): reported estimates range from 9.27 to 53.48

days in hospital and 15.29 to 40.510 days in ICU

Substantial economic burden

cIAI: an Italian study reported that the average cost of care

per patient hospitalised due to cIAI is €4,385 (2009 cost

year)14

cUTI: total costs associated with acute pyelonephritis in the

US in 2000 were estimated to be US$2.14 billion15

HAP (inc. VAP): US studies have reported that hospitalisation

costs are US$30,000 to $40,000 higher for a patient with

VAP than a patient without VAP16-18

• Empiric antibiotic treatment

failure1

• Resistant pathogens2

• Older age3

• Comorbidities19

Substantial mortality

cIAI: reported in-hospital mortality rates range from 4.0%11 to

22.6%20

cUTI: scarce data available

HAP (inc. VAP): reported mortality rates range from 8.9%12 to

35.7%13

Factors contributing to the burden

of cIAI, cUTI and HAP (inc. VAP)

Length of hospital stay increased

*Scarce data are available for cUTI. cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; ICU, intensive care unit; LOS, length of stay; NP, nosocomial pneumonia; RCT, randomised controlled trial; VAP, ventilator-acquired pneumonia. 1. Dhupar R, et al. Surg Infect (Larchmt). 2012;13:141–146; 2. Bare M, et al. International Journal of Technology Assessment in Health Care. 2006;22:242–248; 3. Barie PS, Rotstein OD, Dellinger EP, Grasela TH, Walawander CA. The cost-effectiveness of cefepime plus metronidazole versus imipenem/cilastatin in the treatment of complicated intra-abdominal infection. Surg Infect (Larchmt). 2004;5:269–280; 4. Montravers P, et al. Annals of Surgery. 2004;239:409–416; 5. Rocha Lde A, et al. The Brazilian Journal of Infectious Diseases 2008;12:80–85; 6. Martin-Loeches I, et al. Intensive Care Medicine. 2013;39:672–681; 7. Suka M, et al. Infection Control and Hospital Epidemiology 2007;28:307–313; 8. Sandiumenge A, et al. Chest. 2011;140:643–651; 9. Mallick R, et al. Surg Infect (Larchmt). 2007;8:159–172; 10. Hu B, et al. Current Medical Research and Opinion. 2010;26:1443–1449; 11. Cattan P, et al. European Journal of Clinical Microbiology & Infectious Diseases. 2002;21:787–793; 12. Sturkenboom M, et al. British Journal of Clinical Pharmacology. 2005;60:438–443; 13. Swenson BR, et al. Surg Infect (Larchmt). 2009;10:29–39; 14. Carson JG, et al. Surg Infect (Larchmt). 2008;9:15–21; 15. Lau WK, et al. Antimicrobial Agents and Chemotherapy. 2006;50:3556–3561; 16. Barie PS, et al. Surg Infect (Larchmt). 2004;5(4):365–373.

• cIAI: mean LOS estimates range from 2.21 to 18.62 days in hospital (see below) and 33 to 114 days in ICU

• HAP (inc. VAP): reported estimates range from 9.25 to 53.46 days in hospital and 15.27 to 40.58 days in ICU

Hospital LOS of patients with cIAI (mean and/or median days) reported in RCTs and observational studies1-3,9-16

Substantial mortality…

Substantial clinical burden cIAI: reported estimates range from 74 to 18.65 days in hospital and 35 to 116 days in ICU

cUTI: scarce data available

NP: reported estimates range from 9.27 to 53.48 days in hospital and 6.89 to 40.510 days in ICU

Reported in-hospital all-cause mortality rates in patients with cIAI1,2,5-13

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• cIAI: reported in-hospital mortality rates range from 4.0%1 to 22.6%2

• HAP (inc. VAP): reported mortality rates range from 6.2%3 to 35.7%4

*Scarce data are available for cUTI. cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; ICU, intensive care unit; LOS, length of stay; NP, nosocomial pneumonia; RCT, randomised controlled trial; VAP, ventilator-acquired pneumonia. 1. Tellado JM, et al. Scand J Infect Dis. 2007;39:947–955; 2. Barie PS, et al. Surg Infect (Larchmt). 2004;5:365–373; 3. Paladino JA, et al. Journal of the American Geriatrics Society. 2007;55:651–657; 4. Micek ST, et al. Critical Care (London, England). 2015;19:219; 5. Sartelli M, et al. WJES. 2014;9:37; 6. Heizmann WR, et al. The Journal of Antimicrobial Chemotherapy. 2013;68 Suppl 2:ii45–55; 7. Sartelli M, et al. WJES. 2012;7(1):15; 8. Montravers P, et al. Annals of Surgery. 2004;239:409–416; 9. Cattan P, et al. European Journal of Clinical Microbiology & Infectious Diseases 2002;21:787–793; 10. Bodmann KF, et al. Chemotherapy. 2012;58:282–294; 11. Inui T, et al. Surgery. 2009;146(4):654–661; discussion 661–652; 12. Swenson BR, et al. Surg Infect (Larchmt). 2009;10:29–39; 13. Chapman J, et al. Annals of Surgery. 2005;242:576–581; discussion 581–573.

Let’s not forget the fungi: Length of stay…

+62 days (p<0.001)

Haematology

patients without

invasive fungal

infection(n=NR)

Haematology patients

with invasive

fungal infection

(n=NR)

Length of hospital stay (days)*

*Data from a UK prospective study of 203 haematology patients likely to be rendered neutropenic (<0.5x109/L) during treatment from 2008–2010.

Species responsible for infection not listed and may have included non-Aspergillus and Mucorales species.

All high-risk patients (allogeneic haematopoietic stem cell transplant, acute myeloid leukaemia/myelodysplastic syndrome and salvage lymphoma chemotherapies) received

mould-active primary prophylaxis. IA, invasive aspergillosis; NR, not reported.

Ceesay MM et al. J Antimicrob Chemother 2015;70:1175–81.

In untreated mucormycosis, mortality rates can approach 100%1–3

Let’s not forget the fungi: Mortality…

Significant increase in mortality for IA and mucormycosis if prompt & appropriate antifungal cover not given

+34%(p<0.05)

12-week

mortality in

mucormycosis

patients*

(%)1

Timely**

treatment

(n=35)

Delayed†

treatment

(n=35)

*Retrospective chart review study of 70 haematological malignancy patients with mucormycosis from 1989; IA, invasive aspergillosis.

1. Chamilos G et al. Clin Infect Dis 2008;47:503–9;

2. Skiada A et al. Haematologica. 2013;98:492-504;

3. Roden MM et al. Clin Infect Dis. 2005;41:634–53.

<6 days of diagnosis ≥6 days of diagnosis

Let’s not forget the fungi: Costs…

High costs of IA & mucormycosis

Driven by prolonged treatment, increased LOS & ADRs

Mean cost

of care

(£)*1

Haematology patients

without invasive fungal

infection

Haematology patients

with invasive fungal infection

£54,836(p<0.001)

Inpatient stays account for around three quarters of the cost of treating invasive fungal infections

£88,911

£34,075

*Prospective, single-centre cohort analysis of 203 adult haematology patients likely to be rendered neutropenic. Patients followed for median of 18.5 months. Costs are 2010 UK £ and included antifungal

prophylaxis, antifungal treatment, diagnosis and monitoring, and inpatient stays and outpatient visits. The species responsible for invasive fungal infection was not listed. IA, invasive aspergillosis.

Ceesay MM et al. J Antimicrob Chemother 2015;2015:1175–81.

External drivers

https://www.england.nhs.uk/wp-content/uploads/2016/11/cquin-2017-19-guidance.pdf.

Accessed March 2018.

External drivers

https://www.england.nhs.uk/wp-content/uploads/2016/11/cquin-2017-19-guidance.pdf.

Accessed March 2018; CQUIN Indicator Specification Information on CQUIN 2017/18–2018/19.

External drivers

https://www.theguardian.com/society/2016/may/26/uk-doctors-told-to-halve-inappropriate antibiotic-prescriptions-by-

2020. Accessed March 2018; https://www.england.nhs.uk/wp-content/uploads/2016/11/cquin-2017-19-guidance.pdf.

Accessed March 2018; CQUIN Indicator Specification Information on CQUIN 2017/18–2018/19.

2021

How to balance these variables?

Conclusions

Antimicrobial resistance is a global, national, regional & local problem

Increasing resistance brings increasing costs for healthcare

Many components within an AMR control plan

Introduction of new antimicrobials is one element

Current financial climate requires careful evaluation of new agents

Multiple factors involved in pharmacoeconomic evaluation

Some simple, some much more complex

Some universal, some more country/area-specific

Importance of each factor will be user-/organization-dependent

AMR, antimicrobial resistance.

CORMIM02

Typewritten Text

PP-GEP-IRL-0767 Date of Preparation: June 2018

Any questions?

Email: paul.wade@gstt.nhs.uk