The document discusses recommendations for antibiotic therapy for community-acquired pneumonia (CAP) in different patient populations. It finds that for children hospitalized with CAP, combination therapy with a beta-lactam and macrolide was not significantly more effective than beta-lactam monotherapy. For adults hospitalized with CAP, combination therapy was associated with a lower 30-day mortality compared to beta-lactam monotherapy alone, especially for patients with moderate severity based on CURB-65 scores. A randomized controlled trial found no significant difference in clinical stability at day 7 between beta-lactam monotherapy and beta-lactam-macrolide combination therapy for moderately severe CAP in adults.

1. 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

2. 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.

3. PRINCIPAL BACTERIA CAUSING CHILDHOOD
CAP BY AGE
(From Principi N & Esposito S, Thorax 2011)

4. 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)
%

5. ANTIBIOTIC TREATMENT OF CAP IN
NEONATES AND YOUNGER CHILDREN - I
(From Esposito S et al., Pediatr Infect Dis J 2012)

6. ANTIBIOTIC TREATMENT IN OLDER INFANTS
AND CHILDREN (II)
(From Esposito S et al., Pediatr Infect Dis J 2012)

7. 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;68:1057–65
CAP community-acquired pneumonia
Chart recreated

8. The risk of health care and polymedication
for the elderly
5,2
3,6 3
2,2
2,4 4,4
1,6
2
0,5
2,8
3,5
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

9. 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 health
care (HHC), and individuals receiving hospice care
Chart recreated

11. 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

12. 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

13. Kollef MH, et al. Clin Inf Dis 2008;46:S296-334
HCAP health care associated pneumonia
CAP community acquired pneumonia
VAP ventilator associated pneumonia

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

15. Antibiotic combinations…
• The controversy about the necessity to add a macrolide
to a -lactam continues…
Rodrigo C et al. Thorax. 2013; 68:493-5

16. 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

17. 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 inpatient
MV mechanical ventilation
INS intropic support
CURB65 confusion, urea, respiratory rate, blood pressure, age of 65 years or older
Chart recreated

18. 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
Pneumonia
Lilliam Ambroggio, Jennifer A Taylor, Loni Philip Tabb, Craig J Newschaffer,
Alison A Evans and Samir R Shah

19. 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 with
dual 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

20. 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 pneumonia
A randomized non-inferiority trial
Nicolas 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

21. Randomization of patients in the study
300 allocated to monotherapy arm
291 treated with initial monotherapy
9 excluded after randomization
6 had another diagnosis or no pulmonary infiltrate
2 had exclusion criteria
1 withdrew his consent
302 allocated to combination therapy arm
289 treated with initial combination therapy
13 excluded after randomization
7 had another diagnosis or no pulmonary infiltrate
5 had exclusion criteria
1 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

22. Primary and secondary end points
End point
Monotherapy
(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

23. Hazard ratios for clinical stability in the
monotherapy arm vs combination arm
Variable
No. of patients
Hazard ratio
(95% CI)
P
value
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
P value for interaction .18
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
P value for interaction .09
Age, y
<65 150 1.09 (0.75-1.59) .65
≥65 430 0.87 (0.70-1.10) .25
P value for interaction .32
Garin N et al. JAMA Intern Med. 2014;174(12):1894-1901
PSI pneumonia severity index
CURB-65 confusion, urea, respiratory rate, blood pressure, age of 65 years or older

24. +
+
+
+
+
+
+
++++++++ ++++ +++
+ + ++
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
Patientsnotreachingclinicalstability,%
Monotherapy
Combination
P=.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 index
IV four
Graph recreated

25. 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*

26. 90-day mortality
2 (0.3%) missing data
59 (9.0%) ITT
52(8.5%) SA
42(9.0%) AA
90-day mortality
1 (0.1%) missing data
78 (8.8%) ITT
70(8.5%) SA
53(7.4%) AA
90-day mortality
1 (0.1%) missing data
82 (11.1%) ITT
68 (10.5%) SA
55 (10.2%) AA
610 (93.0%) SA
468 (71.3%) AA
142 (21.6%) MD
46 (7.0%) NA
823 (92.7%) SA
712 (80.2%) AA
111 (12.5%) MD
65 (7.3%) NA
650 (88.0%) SA
538 (72.8%) AA
112 (15.2%) MD
89 (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 population
AA antibiotic-adherent population; MD motivated deviation
NA non-adherent
Chart recreated

27. -0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
A Intention-to-treat analysis
90% CI
95% CI
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
B Intention-to-treat analysis (radiologically confirmed CAP)
90% CI
95% CI
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
C Strategy-adherent analysis
90% CI
95% CI
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
D Strategy-adherent analysis (radiologically confirmed CAP)
90% CI
95% CI
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
E Antibiotic-adherent analysis
90% CI
95% CI
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06Δ
BLM
FQL
Crude
BLM
FQL
Adjusted
Risk difference
Other strategy better Beta-lactam better
F Antibiotic-adherent analysis (radiologically confirmed CAP)
90% CI
95% CI
PostmaDFetal.NEJM.2015;372:1312-23
Chartrecreated

28. 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

29. 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

30. 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%)

31. 16.2%
9.1%
15.9%
5.7%
12.2%

32. 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

33. THANK YOU FOR YOUR ATTENTION