The similarities and differences of the recommendations of azithromycin therapy of CAP - Slideset by Professor Francesco Blasi

As for the characteristics of departments (Pediatrics, Adult, ER), the similarities and

differences of the recommendations of azithromycin therapy of CAP

Prof. Francesco Blasi, MD, FERS

Chairman Department of Pathophysiology and Transplantation,

University of Milan, Italy

Head Cardio-Thoracic Unit and Cystic Fibrosis Adult Center,

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, Italy

Disclosures

I have accepted grants, speaking and conference

invitations from Angelini, AstraZeneca, Almirall, Bayer,

Chiesi, GSK, Guidotti-Malesci, Menarini, Novartis, Pfizer,

Sanofi and Zambon.

I have had recent or ongoing consultancy with Almirall,

Angelini, AstraZeneca, Chiesi, GSK, Menarini,

Mundipharma, Novartis,TEVA, Zambon.

PRINCIPAL BACTERIA CAUSING CHILDHOODCAP BY AGE

(From Principi N & Esposito S, Thorax 2011)

CAP AND ATYPICAL BACTERIA IN 418 CHILDREN

0

10

20

30

40

50

60

70

80

2-4 years 5-7 years > 7 years All

M.p.

C.p.

M.p.+C.p.

All

(From Principi et al., Clin Infect Dis 2001)

%

ANTIBIOTIC TREATMENT OF CAP IN NEONATES AND YOUNGER CHILDREN - I

(From Esposito S et al., Pediatr Infect Dis J 2012)

ANTIBIOTIC TREATMENT IN OLDER INFANTS

AND CHILDREN (II)(From Esposito S et al., Pediatr Infect Dis J 2012)

Risk factors for CAP in adults in Europe: a literature review

Risk factor Evidence Recommendation

Smoking Risk of CAP increased in current and former smokers (9 studies)

Smoking cessation

Alcohol consumption Risk of CAP with high consumption or history of alcohol abuse (4 studies)

Reduce alcohol consumption

Nutritional status Being underweight was generally associated with an increased risk of CAP (4 studies)

Dietary advice to ensure good nutritional status

Contact with children Regular contact with children increased the risk of CAP (3 studies)

Avoid contacts with children with lower respiratory tract infections

Dental hygiene Risk of CAP decreased in individuals with a recent (within past year) dental visit (2 studies)

Ensure regular dental visits

Vaccination against influenza and S pneumoniae

Current guidelines Ensure compliance with guidelines

Torres A et al. Thorax. 2013;68:1057–65CAP community-acquired pneumoniaChart recreated

The risk of health care and polymedication

for the elderly

5,23,6 3

2,2

2,4 4,4

1,6

20,5

2,83,5

2,5

0

2

4

6

8

10

12

14

Nursing Home Home Health Hospice

Urinary tract infection Pneumonia Cellulitis Other

Dwyer LL et al. J Am Ger Soc. 2013;61:341-349

%

11.8% 11.5%10.4%

*

*Estimate does not meet standards of reliability or precision because of small cell size

Infections in long-term care populations in the United States

Graph recreated

The risk of health care and poly-medication

for the elderly

NH Residents Individuals Receiving HHC

Individuals Receiving

Hospice Care

Characteristic Point Prevalence (95% Confidence Interval)

Location before admission or at time of care

Private residence 9.5 (8.4–10.8) N/A 6.5 (5.0–8.4)

Assisted living, board and care, group home, residential care

9.7 (7.6–12.3) N/A ---

NH, hospital skilled nursing facility, rehabilitation facility

11.3 (9.8–12.8) N/A 14.5 (11.0–18.9)

Number of medications received at time of survey interview

<10 (reference) 11.0 (10.0–12.0) 8.9 (6.9–11.3) 11.0 (8.7–13.9)

≥10 13.0 (11.8–14.3) 13.9 (11.3–17.0) 9.8 (7.6–12.5)

Dwyer LL et al. J Am Ger Soc. 2013;61:341-349

Prevalence of infections in nursing home (NH) residents, individuals receiving home healthcare (HHC), and individuals receiving hospice care

Chart recreated

TREATMENT OPTIONS FOR HOSPITALIZED PATIENTS

WITH CAP

(no need for intensive care treatment) (in alphabetical order)

INSIDE HOSPITAL: CAP

• Aminopenicillin macrolide

• Aminopenicillin / ß-lactamaseinhibitor macrolide

• Non-antipseudomonal cephalosporin cefotaxime or ceftriaxone

macrolide

• Levofloxacin

• Moxifloxacin

• Penicillin G macrolide

Woodhead M et al. Clin Microbiol Infect. 2011;17(Suppl 6):E1-E59

TREATMENT OPTIONS FOR PATIENTS WITH SEVERE

CAP (ICU OR INTERMEDIATE CARE)

INSIDE HOSPITAL: CAP

NO RISK FACTORS FOR P. aeruginosa

• Non-antipseudomonal cephalosporin III + macrolide

or

• moxifloxacin or levofloxacin ± non-antipseudomonal cephalosporin III

RISK FACTORS FOR P. aeruginosa

• Antipseudomonal cephalosporin or

• acylureidopenicillin / ß-lactamase inhibitor or

• Carbapenem

(meropenem preferred, up to 6 g possible, 3x2 in 3hours infusion)

plus

Ciprofloxacin

or plus

Macrolide + aminoglycoside (gentamicin, tobramycin or amikacin)

Woodhead M et al. Clin Microbiol Infect. 2011;17(Suppl 6):E1-E59

Kollef MH, et al. Clin Inf Dis 2008;46:S296-334

HCAP health care associated pneumoniaCAP community acquired pneumoniaVAP ventilator associated pneumonia

CAP HAP

Woodhead M, et al.Clin Microbiol Infect 2011; 17(Suppl. 6): E1–E59.CAP community acquired pneumoniaHAP hospital acquired pneumonia

Antibiotic combinations…

• The controversy about the necessity to add a macrolide

to a -lactam continues…

Rodrigo C et al. Thorax. 2013; 68:493-5

Adding a macrolide in adults?

• 5240 adults hospitalised with CAP from 72

secondary care trusts across England and

Wales.

• The overall 30-day inpatient death rate

was 24.4%.

• Combination therapy was prescribed in

3239 (61.8%) patients.

CAP community acquired pneumonia Rodrigo C et al. Thorax. 2013; 68:493-5

AUDIT, RESEARCH AND GUIDELINE UPDATE

Single versus combination antibiotic therapy in adults

hospitalised with community acquired pneumonia

Chamira Rodrigo, Tricia M Mckeever,

Mark Woodhead, Wei Shen Lim on behalf

of the British Thoracic Society

Adding a macrolide in adults?

Outcome measures Total (n=5240)β-lactam therapy

(n=2001)β- lactam/

macrolide therapy (n=3239)

Adjusted OR(95% CI)

p Value

30 day IP death rate 1281 (24.4) 536 (26.8) 745 (23.0)0.72 (0.60 to

0.85)*<0.001

ICU admission 419 (8) 136 (6.8) 282 (8.7) 0.94 (0.72 to 1.22) 0.635

Need for MV 151 (2.9) 58 (2.9) 93 (2.9) 0.99 (0.71 to 1.38) 0.508

Need for INS 130 (2.5) 42 (2.1) 88 (2.7) 0.87 (0.55 to 1.38) 0.544

30 day IP death rate stratified by pneumonia severity

Low severity(CURB65=0–1)

201/2247 (8.9) 95/908 (10.5) 106/1339 (7.9) 0.80 (0.56 to 1.16) 0.238

Moderate severity(CURB65=2)

370/1480 (25) 171/561 (30.5) 199/919 (21.7) 0.54 (0.41 to 0.72) <0.001

High severity(CURB65 ≥3)

710/1513 (46.9) 270/532 (50.8) 440/981 (44.9) 0.76 (0.60 to 0.96) 0.025

Rodrigo C et al. Thorax. 2013; 68:493-5

Multivariate analyses of the association between antibiotic therapy and clinical outcomes

IP inpatientMV mechanical ventilationINS intropic supportCURB65 confusion, urea, respiratory rate, blood pressure, age of 65 years or older

Chart recreated

Adding a macrolide in children?

Ambroggio L et al. J Pediatr. 2012;161:1097-1103

• 20743 patients hospitalized with CAP.

• 24% received beta-lactam and macrolide

combination therapy on admission.

CAP community acquired pneumonia

THE JOURNAL OF PEDIATRICS

Comparative Effectiveness of Empiric Beta Lactam

Monotherapy and beta–Lactam-Macrolide Combination

Therapy in Children Hospitalized with Community-Acquired

PneumoniaLilliam Ambroggio, Jennifer A Taylor, Loni Philip Tabb, Craig J Newschaffer,

Alison A Evans and Samir R Shah

Effect of macrolide resistance on the presentation and outcome of patients hospitalized for S. pneumoniae

pneumonia

Dual therapy, not including a macrolide (n=33)

Dual therapy including a macrolide (n=71)

P value

Bacteremia, n (%) 17 (52) 36 (51) 0.99

Days of hospital stay, median (IQR)

11 (6–18) 8 (4–13) 0.12

30 days in hospital mortality, n (%)

4 (12) 4 (6) 0.25

ICU admission, n (%) 14 (42) 15 (21) 0.024

Mechanical ventilation, n (%) 0.28

None 22 (81) 57 (86) 0.55

Noninvasive 1 (4) 0 (0) 0.29

Invasive 4 (15) 9 (14) 0.88

Pulmonary complications, n (%) 14 (42) 18 (25) 0.079

Multilobar infiltration 11 (33) 11 (15) 0.038

Pleural effusion 7 (21) 9 (13) 0.26

ARDS 2 (7) 3 (4) 0.61

Acute renal failure, n (%) 11 (33) 25 (36) 0.81

Shock, n (%) 2 (6) 6 (8) 0.67

Outcomes of patients with macrolide-resistant S. pneumoniae pneumonia treated withdual antibiotic regimens that did or did not contain a macrolide

Cilloniz C et al. Am J Respir Crit Care Med. 2015;191(11):1265-72Chart recreated

Garin N et al. JAMA. 2014;174(12):1894-1901

Original investigation

β – lactam monotherapy vs β – lactam–macrolide combination treatment in moderately severe community-acquired pneumoniaA randomized non-inferiority trialNicolas Garin, Daniel Genné, Sebastian Carballo, Christian Chuard,Gerhardt Eich, Olivier Hugli, Olivier Lamy, Mathieu Nendaz,Pierre-Auguste Petignat, Thomas Perneger, Olivier Rutschmann, Laurent Seravalli, Stephan Harbarth, Arnaud Perrier

Randomization of patients in the study

300 allocated to monotherapy arm291 treated with initial monotherapy

9 excluded after randomization6 had another diagnosis or no pulmonary infiltrate2 had exclusion criteria1 withdrew his consent

302 allocated to combination therapy arm289 treated with initial combination therapy

13 excluded after randomization7 had another diagnosis or no pulmonary infiltrate5 had exclusion criteria1 withdrew his consent

291 completed 30-day follow-up 289 completed 30-day follow-up

291 included in analysis for the primary end point 289 included in analysis for the primary end point

602 patients randomized

Garin N et al. JAMA Intern Med. 2014;174(12):1894-1901Chart recreated

Primary and secondary end points

End pointMonotherapy

(n=291)Combination therapy

(n=289)P

value

Primary end point

Patients not reaching clinical stability at day 7 120 (41.2) 97 (33.6) .07

Secondary end points

Intensive care unit admission 12 (4.1) 14 (4.8) .68

Complicated pleural effusion 8 (2.7) 14 (4.8) .19

Length of stay, median (IQR), d 8 (6-13) 8 (6-12) .65

Any change in the initial antibiotic treatment 39 (13.4) 46 (15.8) .39

In-hospital death 8 (2.7) 7 (2.4) .80

30-day death 14 (4.8) 10 (3.4) .42

90-day death 24 (8.2) 20 (6.9) .54

30-day readmission 23 (7.9) 9 (3.1) .01

90-day readmission 47 (16.2) 37 (12.7) .25

New pneumonia within 30 days 10 (3.4) 6 (2.1) .31

Garin N et al. JAMA Intern Med. 2014;174(12):1894-1901Chart recreated

Hazard ratios for clinical stability in the monotherapy arm vs combination arm

VariableNo. of patients

Hazard ratio(95% CI)

Pvalue

Unadjusted 0.93 (0.76-1.13) .46

Adjusted for age and PSI category 0.92 (0.76-1.12) .41

Stratified

Atypical 31 0.33 (0.13-0.85) .02

Nonatypical 549 0.99 (0.80-1.22) .93

P value for interaction .03

PSI category IV 240 0.81 (0.59-1.10) .18

PSI category I-III 340 1.06 (0.82-1.36) .66


CURB-65 category 2-5 311 0.80 (0.61-1.06) .12

CURB-65 category 0-1 269 1.13 (0.85-1.50) .40


Age, y

<65 150 1.09 (0.75-1.59) .65

≥65 430 0.87 (0.70-1.10) .25


Garin N et al. JAMA Intern Med. 2014;174(12):1894-1901PSI pneumonia severity indexCURB-65 confusion, urea, respiratory rate, blood pressure, age of 65 years or older

+++

++

++

+++++++ + ++++ ++++ + ++

Proportions of patients not reaching clinical stability

100

90

80

70

60

50

40

30

20

10

0

0 5 10 15 20 25 30

Time, days

Pat

ien

tsn

ot

reac

hin

g cl

inic

al s

tab

ility

, %

MonotherapyCombinationP=.44 (log-rank test)

+

++++

+++++++++++++ ++++++++ ++++ + + ++

Conclusions and relevance: We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.

Garin N et al. JAMA Intern Med. 2014;174(12):1894-1901

PSI pneumonia severity indexIV four

Graph recreated

Postma DF et al. NEJM, 2015;372:1312-23

The NEW ENGLAND JOURNAL of MEDICINE

ORIGINAL ARTICLE

Antibiotic Treatment Strategies for

Community-Acquired Pneumonia in Adults

Douwe F. Postma, M.D., Cornelis H. van Werkhoven, M.D.,

Leontine J.R. van Elden, M.D., Ph.D., Steven F.T. Thijsen, M.D., Ph.D.,

Andy I.M. Hoepelman, M.D., Ph.D., Jan A.J.W. Kluytmans, M.D., Ph.D.,

Wim G. Boersma, M.D., Ph.D., Clara J. Compaijen, M.D., Eva van der Wall, M.D.,

Jan M. Prins, M.D., Ph.D., Jan J. Oosterheert, M.D., Ph.D., and

Marc J.M. Bonten, M.D., Ph.D., for the CAP-START Study Group*

90-day mortality2 (0.3%) missing data59 (9.0%) ITT52(8.5%) SA 42(9.0%) AA

90-day mortality1 (0.1%) missing data

78 (8.8%) ITT70(8.5%) SA53(7.4%) AA

90-day mortality1 (0.1%) missing data82 (11.1%) ITT68 (10.5%) SA55 (10.2%) AA

610 (93.0%) SA468 (71.3%) AA142 (21.6%) MD46 (7.0%) NA

823 (92.7%) SA712 (80.2%) AA111 (12.5%) MD65 (7.3%) NA

650 (88.0%) SA538 (72.8%) AA112 (15.2%) MD89 (12.0%) NA

656 - included in study 888 - included in study739 - included in study

993 -assigned to receive beta-lactam

1277 - assigned to receive fluoroquinolone

1055 - assigned to receive beta-lactam-macrolide

3325 patients were eligible

Inclusion of patients, rates of adherence and mortality

Postma DF et al. NEJM. 2015;372:1312-23

ITT intention-to-treat population; SA strategy-adherent populationAA antibiotic-adherent population; MD motivated deviation

NA non-adherent

Chart recreated

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL

AdjustedRisk difference

Other strategy better Beta-lactam better

A Intention-to-treat analysis

90% CI95% CI

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL



B Intention-to-treat analysis (radiologically confirmed CAP)

90% CI95% CI

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL



C Strategy-adherent analysis

90% CI95% CI

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL



D Strategy-adherent analysis (radiologically confirmed CAP)

90% CI95% CI

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL



E Antibiotic-adherent analysis

90% CI95% CI

-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ

BLM

FQL

Crude

BLM

FQL



F Antibiotic-adherent analysis (radiologically confirmed CAP)

90% CI95% CI

Post

ma

DF

et a

l. N

EJM

.20

15

;37

2:1

31

2-2

3

Ch

art

recr

eate

d

Limitations

• The population included does not clearly capture unequivocally

patients usually addressed as CAP. Around one quarter did not

have radiological confirmation of CAP

• CAP severity was very low, with a mean CURB-65 of 1, and no

patient exceeding a CURB-65 of 2. Since a CURB-65 of 1 might

result of just an age above 65 years, any severity criteria were

rare in this population, and it is unclear why all of these

patients were hospitalized at all.

• So far, an advantage for combination treatment in retrospective

studies has primarily been shown in hospitalized patients with

severe CAP

CAP community-acquired pneumonia Author’s opinion

Improving the probability of

positive outcomes

Early recognition of infection

Selection of appropriate antibiotic

(eg through in vitro susceptibility

determination)

Optimisation of therapy using

pharmacodynamic principles

Ball P et al. J Antimicrob Chemother. 2002; 49:31-40

Fine class IV or V CAP patients included in a multicentre,

interventional, before-and-after study:

1. retrospective phase (1443 patients)

2. guideline implementation phase

3. prospective phase (1404 patients)

OR 0.73(95% CI 0.69–1.00)

p=0.049

After protocol implementation, 44% compliance

with guideline recommendations (was 33%)

16.2%

9.1%

15.9%

5.7%

12.2%

Azithromycin in pneumonia: When and Why

• From 1 to 3 months of age

• From 5 ys to 18 ys of age

• In combination with beta-lactams in hospitalised adults with CAP

• Combination therapy reduces mortality and complications both in children and adults, particularly in moderate-severe pneumonia

THANK YOU FOR YOUR ATTENTION

Health & Medicine

The similarities and differences of the recommendations of azithromycin therapy of CAP - Slideset by Professor Francesco Blasi