COVID-19 Mortality from Secondary Acquired Infections

How life has changed: COVID-19 and AMRPresidential Advisory Council on Combating Antibiotic-Resistant Bacteria9 September 2020

Cornelius J. Clancy, M.D.Chief, Infectious Diseases VA Pittsburgh Healthcare SystemAssociate Chief, Infectious DiseasesDirector, XDR Pathogen Lab andMycology Research UnitUniversity of Pittsburgh

Why do COVID-19 patients die?

Postmortem histopathology images from Sekulic et al. Am J Clin Path 2020; Hanley et al. Lancet Microbe 2020.

Diffuse alveolar damage causing acute respiratory distress syndrome (ARDS)

Thromboembolic disease

Multisystem organ failure Immune depletion and dysregulation

Do patients die of secondary infections?

of COVI-19 autopsies have histopathologic findings in lungs that are consistent with superimposed bronchopneumonia or pulmonary infection137%

● Findings due to superimposed infection or COVID-19?● Very limited microbiology and AMR data● More often focal process rather than diffuse disease● Often not recognized or treated with antimicrobials ante-mortem

Images from Sekulic et al. Am J Clin Path 2020; Hanley et al. Lancet Microbe 2020. 1. Histopathologic findings: Intra-alveolar PMN infiltrates or abscess/empyema, in absence of classic viral pneumonia histopathology. N=106/289, from review of data from 51 peer-reviewed publications through 28 August 2020, includes hospital- and community-based deaths

Sizeable minority of COVID-19 decedents die with, but not necessarily from, superimposed bacterial

or (less often) fungal infections

Types of COVID-19 secondary infections

Microbiology and AMR will reflect local epidemiology

and host risk factors

Lung: P. aeruginosa, K. pneumoniae, C. koseri, S. maltophiliaUrine: E. Coli, Proteus, K. pneumoniae

● MDR, ESBL, CRE infections diagnosedBlood: S. aureus, coag negative Staph, Strep spp., Candida

Bloodstream infections● Endocarditis, septic emboli, abscesses

Urinary tract infectionsSkin and soft tissue infectionsClostridiodes difficile infections

Co-infections● Community acquired pneumonia, urinary tract infection, skin/soft tissue

infection, C difficile infection, febrile neutropeniaSecondary infections

● Hospital/ventilator pneumonia, bloodstream infection, urinary tract infection, C. difficile infection

VAPHS experience, through 7/31/20

No co- or secondary infxn, 72%

Present w co-infxn, 9%

Develop secondary infxn, 19%

Buehrle et al. Antimicrob Agents Chemother 2020

COVID-19: Antimicrobial stewardship strategies

Gp 1. No antimicrobials

41%

Gp 2. Empiric treatment, no infxn diagnosed

31%

Gp 3. Treat for co-infxn

9%

Gp 4. Treat for secondary infxn, 19%

Stewardship group Stewardship objectives1. No treatment Limit unnecessary use, include rapid

diagnostics (negative predictive values)2. Empiric treatment

Target most likely pathogens, rapid de-escalation, limit duration, aggressive diagnostic testing (NPVs)

3. Treat co-infection Promote narrow spectrum, short course, oral

4. Treat secondary infection

Target nosocomial pathogens, promote narrow spectrum, short course

Buehrle et al. Antimicrob Agents Chemother 2020

1400

1600

1800

2000

2200

2400

Antib

iotic

Day

s of

The

rapy

(DO

T)

1/18 3/18 5/18 7/18 9/1811/181/19 3/19 5/19 7/19 9/1911/191/20 3/20 5/20

Actual Predicted

2000

2500

3000

3500

4000

Bed

days

of c

are

1/18 3/18 5/18 7/18 9/1811/181/19 3/19 5/19 7/19 9/1911/191/20 3/20 5/20

Actual Predicted

Impact of COVID-19 on hospital antibiotic use

580

600

620

640

660

Day

s of

The

rapy

per

100

0 Be

d D

ays

of C

are

1/18 3/18 5/18 7/18 9/1811/181/19 3/19 5/19 7/19 9/1911/191/20 3/20 5/20

Actual Predicted

7080

9010

011

0D

OT/

1000

BD

OC

3/18

6/18

9/18

12/18 3/1

96/1

99/1

912

/19 3/20

6/20

Actual Predicted

3040

5060

70D

OT/

1000

BD

OC

3/18

6/18

9/18

1218 3/1

96/1

99/1

912

/16 3/20

6/20

Actual Predicted

VAPHS Days of therapy (DOT) VAPHS bed days of care (BDOC) VAPHS DOT/1,000 BDOC

Non-antipseudomonal PNCsDOT/1,000 BDOC

MacrolidesDOT/1,000 BDOC

Significantly increased DOT/1000 BDOC of agents vs. CAP ● Patients with CAP/suspected CAP disproportionately presenting to hospital?● Over-treatment of suspected CAP?

Buehrle et al. Antimicrob Agents Chemother 2020

0

200

400

600

800

1000

1200

1400

1600VAPHS outpatient prescriptions, Nov 2017-July 2020

510

1520

Pres

crip

tions

per

100

0 pe

rson

s

Aug 2014 Aug 2015 Aug 2016 Aug 2017 Aug 2018 Aug 2019

Amoxicillin

510

1520

Pres

crip

tions

per

100

0 pe

rson

s

Aug 2014 Aug 2015 Aug 2016 Aug 2017 Aug 2018 Aug 2019

Azithromycin

02

46

810

Pres

crip

tions

per

100

0 pe

rson

s

Aug 2014 Aug 2015 Aug 2016 Aug 2017 Aug 2018 Aug 2019

Amoxicillin/Clavulanate

Outpatient antibiotic useUS prescription fills, 2014-July 2020 (IQVIA NPA data)

Significant reductions in prescription fills in April 2020 for the ten most commonly prescribed outpatient antibiotics

● No significant rebound, April-July 2020: Azithromycin, amoxicillin-clavulanate, levofloxacin ● Rebound April-July 2020, but still below baseline: Amoxicillin, doxycycline

Prescription fills for outpatient antibiotics recommended against CAP or commonly used against respiratory tract infections remain significantly below baseline

● Patients not seeking care? Clinicians less likely to prescribe (unnecessary) agents?

Will COVID-19 result in increased AMR? Pro• Antibiotic prescribing in excess of secondary

infections, suggesting inappropriate use• Many COVID-19 epicentres also AMR epicentres• Burden of antibiotic use in hospitalized patients

increased, even outside of epicentres• Reports of HAI outbreaks associated with

breakdowns in infection prevention• Effects of COVID-19 on public health infrastructure,

sanitation, healthcare delivery, governance may indirectly impact AMR and transmission

• Secondary infections may increase as COVID-19 treatment evolves (e.g., dexamethasone)

• Co-circulation of SARS-CoV-2 and influenza may fuel inappropriate antibiotic prescribing

• Overall antibiotic use in humans has decreased in many places

• Major determinant of AMR rates is spread, which may be decreased with COVID-19 travel restrictions, enhanced attention to infection prevention, etc.

• Better COVID-19 outcomes may decrease pools of high risk critically ill patients, including those on ventilators, receiving hemodialysis, etc.

• Increased emphasis on diagnosing respiratory viral infections may decrease inappropriate antibiotic treatment

• Data from southern hemisphere suggest that impact of influenza may be lessened by COVID-19 precautions

Clancy, Buehrle and Nguyen. J Antimicrob Chemother-AMR 2020; Collignon and Beggs. J Antimicrob Chemother-AMR 2020

COVID-19 and AMR story will be dynamic, and likely to differ from region to region, hospital to hospital, and unit to unit within hospitals

● AMR was a major problem before COVID-19, and it will remain a problem

Con

COVID-19 and AMR: Needs moving forward

• Report our experiences and data• More rigorous microbiology and

definitions of superimposed infections in clinical and postmortem studies

• Surveillance data on antimicrobial use and AMR

• Education• It’s OK not to get/give an antibiotic• AMR has not gone away