The document discusses the role of macrolide antibiotics in treating community-acquired pneumonia (CAP), particularly in the context of increasing antimicrobial resistance. It reviews the effectiveness of combination therapy with beta-lactams and macrolides versus beta-lactam monotherapy and explores the implications of mycoplasma pneumoniae involvement and resistance. Key findings highlight the clinical outcomes associated with different antibiotic therapies and the mechanisms of resistance in Streptococcus pneumoniae.

1. THE ROLE OF MACROLIDE IN THE ERA OF
ANTIMICROBIAL RESISTANCE
Susanna Esposito
Professor of Pediatrics, University of Milan, Director of
the Pediatric Highly Intensive Care Unit, Fondazione IRCCS
Ca’ Granda Ospedale Maggiore Policlinico Milan, Italy
WAidid President (www.waidid.org)

2. AGENDA
• CAP etiology
• Emerging antimicrobial resistance
• Combined beta-lactam/macrolide therapy vs beta-
lactam monotherapy in CAP
• Mycoplasma pneumoniae involvement in upper
respiratory tract infections
• Mycoplasma pneumoniae and macrolide resistance
• Practical implications for real life

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. Clinical characteristics of the study
population at enrollment (Esposito S et al. CID 2002)
Characteristics
Males
Mean age  SD, yrs
Onset
Gradual
Acute
Similar illness
within
the family
Cough
Tachypnea
Fever
Rales
Wheezes
Days of hosp.  SD
S. pneumoniae
infection (%)
(N=48)
25 (52.1)
3.66  0.899
23 (47.9)
25 (52.1)
6 (12.5)
31 (64.5)
12 (25.0)
42 (91.3)
45 (93.7)
6 (12.5)
6.857  3.523
12.325  6.065
Atypical bacteria
infection (%)
(N=46)
22 (47.8)
3.75  1.030
26 (56.5)
20 (43.5)
9 (19.5)
33 (71.7)
11 (23.9)
39 (84.7)
41 (89.1)
7 (15.2)
6.744  2.672
13.3075.089
Mixed S. pneum.-
atypical bacteria
infection (%) (N=16)
8 (50.0)
3.76  1.030
8 (50.0)
8 (50.0)
3 (18.7)
11 (68.7)
4 (25.0)
14 (87.5)
15 (93.7)
2 (12.5)
7.110  2.370
13.7145.517
No significant differences were observed

6. Laboratory data in the various
aetiological groups (Esposito S et al. CID 2002)
Parameter
WBC (cells/L)
Neutrophils, %
Lymphocytes,%
Monocytes, %
Eosinophils, %
Basophils, %
CRP (g/dL)
ESR (mm/1h)
S. pneumoniae
infection (%)
(N=48)
16,669  8,831*°
69  17*°
22  15
7  3
1  2
0.3  0.6
109  110*°
57  28
Atypical bacteria
infection (%)
(N=46)
12,5545,404*
59  18*
28  17
8  3
1  1
0.4  0.7
59  88*
47  27
Mixed S.pneum.-
atypical bacteria
infect. (%) (N=16)
13,141  4,540°
63  16°
25  16
7  3
1  2
0.3  0.4
77  79°
52  44
Mean values  SD. *p < 0.05 vs *atypical bacteria infection and °mixed
S. pneumoniae-atypical bacteria infection; no other significant differences were
observed. WBC, white blood cell count; CRP, C-reactive protein, ESR,
erythrocyte sedimentation rate

7. Comparison of radiographic characteristics of
the study population (Esposito S et al. CID 2002)
Finding
Hyperinflation
Peribronchial wall
thickening
Perihilar linear
opacities
Reticulo-nodular
infiltrate
Segmental or lobar
consolidation
Bilateral
consolidations
Pleural effusion
S. pneumoniae
infection (%)
(N=48)
5 (10.4)
3 (6.2)
15 (31.2)
13 (27.1)
18 (37.5)
7 (14.6)
3 (6.2)
Atypical bacteria
infection (%)
(N=46)
6 (13.0)
4 (8.7)
20 (43.5)
21 (45.6)
12 (26.1)
4 (8.7)
3 (6.5)
Mixed S.pneum.-
atypical bacteria
infect. (%) (N=16)
2 (12.5)
1 (6.2)
9 (56.6)
5 (31.2)
5 (31.2)
2 (12.5)
1 (6.2)
No significant differences were observed

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

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

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

14. J Antimicrob Chemother 2016

15. ANTIMICROBIAL SUSCEPTIBILITY OF STREPTOCOCCUS
PNEUMONIAE CAUSING IPD IN THAILAND, 2009-2012
Phongsamart et al., Human Vaccines & Immunother

16. Jeevajothi Nathan et al., Med J Malaysia 2014
SUSCEPTIBILITY RATES OF PNEUMOCOCCAL ISOLATES AND
MIC VALUES FOR 6 ANTIMICROBIALS IN A MULTI-CENTER
STUDY IN MALAYSIA

17. PLOS One, 2016

18. MECHANISMS OF
S. PNEUMONIAE BETA-LACTAM
RESISTANCE
 THE RESISTANCE OF S. PNEUMONIAE TO
BETA-LACTAMS IS RELATED TO TARGET-
MEDIATED CHANGES IN THE SIZE AND
CONFIGURATION OF THE PBPs
 S. PNEUMONIAE HAS 5 PBPs: THE LEVEL OF
RESISTANCE DEPENDS ON HOW MANY OF
PBPs ARE MODIFIED AND TO WHAT EXTENT

19. MECHANISMS OF
S. PNEUMONIAE BETA-LACTAM
RESISTANCE
 RESISTANCE TO PENICILLIN G IS MAINLY
CAUSED BY CHANGES IN PBP2b, WHEREAS
ALTERATIONS IN PBP2x ARE RELATED TO
RESISTANCE TO CEPHALOSPORINS
 THE BETA-LACTAMS WHICH HAVE RETAINED A
GOOD ACTIVITY ARE AMOXICILLIN,
CEFUROXIME AND CEFPODOXIME (ORAL);
CEFTRIAXONE, CEFOTAXIME, CEFPIROME AND
CEFEPIME (PARENTERAL)
 IMIPENEM OR MEROPENEM ARE EVEN MORE
ACTIVE THAN CEPHALOSPORINS

20. CLINICAL RELEVANCE OF
S. PNEUMONIAE BETA-LACTAMS
RESISTANCE
ALL THE BETA-LACTAMS, EVEN THOSE
CONSIDERED IN VITRO NOT ACTIVE,
WITH USUAL DOSES REACH IN BLOOD
AND IN THE EPITHELIAL LINING
FLUID CONCENTRATIONS HIGH
ENOUGH TO ERADICATE ALL THE
INTERMEDIATE AND ALMOST ALL THE
RESISTANT STRAINS OF
S.PNEUMONIAE

21. OUTCOME OF PNEUMONIA IN RELATION TO
PENICILLIN RESISTANCE OF S. PNEUMONIAE
From Friedland JR, PIDJ 1995
0
20
40
60
80
100
PEN-S PEN-R PEN-S PEN-R PEN-S PEN-R
%
resolved improved not improved died
after 2 days after 3 days after 7 days

22. MECHANISMS OF STREPTOCOCCUS
PNEUMONIAE MACROLIDE
RESISTANCE
 ALTERATIONS IN THE RIBOSOMAL
TARGET SITE
 PRODUCTION OF INACTIVATING
ENZYMES
 PRODUCTION AND USE OF ACTIVE
EFFLUX MECHANISMS

23. S. PNEUMONIAE MACROLIDE
RESISTANCE: ALTERATION OF
RIBOSOMAL TARGET SITE
 THIS MECHANISM IS BASED ON THE
PRODUCTION OF RYBOSOMAL METHYLASE,
WHICH ALTERS THE RIBOSOMAL TARGET
SITE OF MACROLIDES
 IT IS CODED FOR BY THE ERMB GENE,
DETERMINES HIGH-LEVEL RESISTANCE AND
CONFERS BROAD CROSS-RESISTANCE TO
MACROLIDES, LINCOSAMIDES AND
STREPTOGRAMINS B

24. S. PNEUMONIAE MACROLIDE
RESISTANCE: EFFLUX MECHANISM
• THIS MECHANISM IS ENCODED BY THE MEFA
OR MEFE GENE
• MEF GENES ENCODE A HYDROPHOBIC
MEMBRANE PROTEIN THAT USES THE ENERGY
OF THE PROTON DRIVING FORCE TO PUMP
MACROLIDES OUTSIDE THE CELL
• THE EFFLUX LEADS TO THE M PHENOTYPE,
DETERMINES LOW-LEVEL RESISTANCE AND IS
SPECIFIC FOR THE 14- AND 15-MEMBERED
MACROLIDES

25. MACROLIDE MIC IN ERYTHROMYCIN-
RESISTANT STREPTOCOCCUS PNEUMONIAE
ERYTHRO-
MYCIN
CLARITHRO-
MYCIN
AZITHRO-
MYCIN
ERM B
MIC 90 >32 >128 >32
RANGE 0.25 to>32 0.25 to >128 1 to >32
MEF E
MIC 90 8 4 8
RANGE 0.5 to >32 0.06-8 0.5 to >32

26. Comparison of the clinical outcome of the evaluable children according
to the aetiological diagnosis and antimicrobial therapy
(from Esposito S et al. Clin Infect Dis 2003)
Clinical response
Treated with a -lactam
monotherapy
Cure or improvement
Failures
Treated with a -lactam
plus a macrolide
Cure or improvement
Failures
Treated with a macrolide
monotherapy
Cure or improvement
Failures
S. pneumoniae
infection (%)
(N=44)
28 (63.6)
27 (96.4)*^
1 (3.6)*^
9 (20.5)
9 (100.0)
0
7 (15.9)
6 (85.7)
1 (14.3)
Atypical bacteria
infection (%)
(N=42)
21 (50.0)
11 (52.4)*§#
10 (47.6)*§#
7 (16.7)
7 (100.0)§
0§
14 (33.3)
13 (92.9)#
1 (7.1)#
Mixed S.pneum.-
atypical bacteria
infect. (%) (N=15)
5 (33.3)
2 (50.0)^
2 (50.0)^
6 (40.0)
6 (100.0)
0
5 (33.3)
5 (100.0)
0
*p=0.0003 vs atypical bacteria infection, ^ p=0.034 vs mixed S. pneumoniae-atypical
bacteria infection, §p=0.030 vs atypical bacteria infection treated with a -lactam plus
a macrolide, #p=0.023 vs atypical bacteria infection treated with a macrolide only; no
other significant differences were observed

27. Quantitative Mycoplasma pneumoniae cultures of
bronchoalveolar lavage (BAL) samples from mice
inoculated with M. pneumoniae
Tagliabue C et al. J Infect Dis. 2008;198:1180-1188

28. 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

29. Ambroggio L et al. J Pediatr. 2012;161:1097-1103
LENGHT OF HOSPITAL STAY ACCORDING TO
EMPIRICAL ANTIBIOTIC TREATMENT

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. +
+
+
+
+
+
+
++++++++ ++++ +++
+ + ++
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

38. 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*

39. 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

40. -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

41. 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

42. DEMOGRAPHIC CHARACTERISTICS OF THE
STUDY CHILDREN WITH RECURRENT
RESPIRATORY TRACT INFECTIONS AND
HEALTHY CONTROLS
Esposito S et al., PIDJ 2005; 24: 438-444

43. DISTRIBUTION OF THE STUDY
SUBJECTS ACCORDING TO CLINICAL
DIAGNOSIS
Esposito S et al., PIDJ 2005; 24: 438-444

44. SHORT-TERM OUTCOME ACCORDING
TO THERAPY IN CHILDREN WITH
RRTIs AND ACUTE RTI
Esposito S et al., PIDJ 2005; 24: 438-444

45. LONG-TERM OUTCOME ACCORDING
TO THERAPY IN CHILDREN WITH
RRTIs AND ACUTE RTI
Esposito S et al., PIDJ 2005; 24: 438-444

46. DEEP RED STUDY – RESULTS
MOST FREQUENTLY FOUND MICROBIOLOGICAL
AGENTS IN THE STUDY POPULATION
0
5
10
15
20
25
30
Adenovirus* RSV* M. pneumoniae* S. pyogenes C. pneumoniae*
Patients with pharyngitis Healthy controls
%
*p<0.0001 Esposito S et al., J Med Microbiol 2004

47. VARIABLES SIGNIFICANTLY ASSOCIATED
WITH THE DIFFERENT AETIOLOGICAL AGENTS
IN THE STUDY PATIENTS
0
20
40
60
80
100
Recurrent episodes of
pharyngitis
Having older sibling(s)
Single virus M. pneumoniae* S. pyogenes C. pneumoniae
Esposito S et al., J Med Microbiol 2004
%

48. CLINICAL OUTCOME OF THE STUDY
SUBJECTS
Esposito S et al., J Med Microbiol 2004

49. DIAGNOSIS OF ATYPICAL BACTERIA
INFECTIONS IN 133 CHILDREN WITH ACUTE
NON-STREPTOCOCCAL PHARYNGITIS
0PCR positive only M. pneumoniae-C. pneumoniae
1 (50.0%)Serology and PCR positive M. pneumoniae-C.
pneumoniae
1 (50.0%)Serology positive only M. pneumoniae-C. pneumoniae
2 (1.5%)M. pneumoniae-C. pneumoniae coinfection
5 (50.0%)Serology and PCR positive
1 (10.0%)PCR positive only
4 (40.0%)Serology positive only
10 (7.5%)C. pneumoniae infection
6 (14.3%)Serology and PCR positive
0PCR positive only
36 (85.7%)Serology positive only
42 (31.6%)M. pneumoniae infection
PATIENTS
(No.=133)
ATYPICAL BACTERIA INFECTION
Esposito S et al., CID 2006

50. SHORT-TERM (AFTER 1-MONTH) OUTCOME IN
CHILDREN WITH ACUTE NON-STREPTOCOCCAL
PHARYNGITIS
Outcome Treated with
azithromycin
Treated with
symptomatics
Infected by atypical bacteria 20 34
Cure 20 (100.0%) 31 (91.2%)
Failure 0 3 (8.8%)
Not infected by atypical bacteria 24 55
Cure 22 (91.7%) 51 (92.7%)
Failure 2 (8.3%) 4 (7.3%)
Total 44 89
Cure 42 (95.5%) 82 (92.1%)
Failure 2 (4.5%) 7 (7.9%)
Esposito S et al., CID 2006

51. LONG-TERM (AFTER 6 MONTHS) OUTCOME IN
CHILDREN WITH ACUTE NON-STREPTOCOCCAL
PHARYNGITIS
Outcome Treated with
azithromycin
Treated with
symptomatics
Infected by atypical bacteria 20 34
No respiratory recurrences 13 (65.0%)* 9 (26.5%)*^
At least 1 LRTI 3 (15.0)* 21 (61.8)*^
Not infected by atypical bacteria 24 55
No respiratory recurrences 14 (58.3%) 27 (49.1%)^
At least 1 LRTI 1 (4.2) 4 (7.3)^
Total 44 89
No respiratory recurrences 27 (61.4%)* 36 (40.4%)*
At least 1 LRTI 3 (6.8)* 25 (28.1)*
*^p<0.05 Esposito S et al., CID 2006

52. MAJOR STUDIES OF THE PREVALENCE OF MACROLIDE-
RESISTANT M. PNEUMONIAE IN DIFFERENT
COUNTRIES AND AT DIFFERENT TIMES
(From Principi N & Esposito S. J Antimicrob Chemother 2013)

53. COMPARISON OF CHILDREN WITH CAP AND
MACROLIDE-RESISTANT AND MACROLIDE-SENSITIVE
M. PNEUMONIAE INFECTION (I)
(From Cardinale F et al., J Clin Microbiol 2013)

54. COMPARISON OF CHILDREN WITH CAP AND
MACROLIDE-RESISTANT AND MACROLIDE-SENSITIVE
M. PNEUMONIAE INFECTION (II)
(From Cardinale F et al., J Clin Microbiol 2013)

55. COMPARISON OF CHILDREN WITH CAP AND
MACROLIDE-RESISTANT AND MACROLIDE-SENSITIVE
M. PNEUMONIAE INFECTION (III)
(From Cardinale F et al., J Clin Microbiol 2013)

57. From Bradley J et al., Pediatr Infect Dis J 2007

59. CASE 1 - EP
• 3-year old male child
• GA 35 weeks, BW 2,700 gr
• Hospitalized for RSV bronchiolitis at 4
months of age
• No other problems in the first year of
life
• Recurrent episodes of wheezing after
the first year of life, always associated
with upper respiratory tract involvement

60. CASE 1 - EP
• Therapy: inhalatory beta2-agonists
• Outcome: always cure in few days

61. CASE 1 - EP
The following examinations were
performed:
• total IgE (normal) + skin prick test
(negative)
• chest radiography (negative)
• immunologic evaluation (normal)

62. CASE 1 – EP
7° episode of wheezing

63. CASE 1 - EP
After the seventh episode of wheezing:
• Recommended therapy: clarithromycin 15
mg/kg/die in 2 doses for 10 days

64. CASE 1 - EP
• Outcome: after 40 days new episode of
wheezing, more severe than the previous
ones; hospitalization was required and
i.v. steroid was used
• Further examinations: allergy was
excluded; IgM and IgG to M. pneumoniae
>1:100 and >1:400, respectively; IgM
and IgG to C. pneumoniae neg. and
>1:64, respectively; nasopharyngeal
aspirate positive for M. pneumoniae DNA

65. CASO 1 - EP
What do you think about:
1. diagnostic hypothesis?
2. performed examinations?
3. prescribed therapies?
4. patient’s outcome and prognosis?

66. CASE 1 - EP
• Prescribed therapy: azithromycin 10
mg/kg/die in one dose for 3 days for 3
consecutive weeks
• Outcome: clinical cure in few days and no
respiratory recurrences in the following
6 months
• Further examinations: M. pneumoniae
DNA in the nasopharynx absent at the
end of therapy as well as after 3 and 6
months

67. CASE 2 – SE
• 14-year old female
• No relevant diseases in the previous
history
• Ten days ago, a history of pharyngitis
treated with symptomatics only
• Since 5 days appearance of cough,
dyspnoea, fever (T 40°C) and pain in the
chest
• During the visit, dyspnoea/tachypnoea and
abnormal chest signs in the medium/low
part of both the emithorax (breath
reduction with coarse crackles) were
observed

68. CASE 2 – SE
CHEST RADIOGRAPHY

69. CASE 2 – SE
Additional data of our patient:
• Respiratory rate of 36/min
• Blood pressure 85/55 mmHg
• Temperature 40°C
• Heart rate 125/min
• Sodium 128 mmol/L
• SaO2 88%

70. CASE 2 – SE
LABORATORY DATA
Parameter
WBC (cells/L)
Neutrophils, %
Lymphocytes,%
Monocytes, %
Eosinophils, %
Basophils, %
CRP (g/dL)
ESR (mm/1h)
Value
18,993
73
21
5
1
0.2
110
70

71. CASE 2 – SE
Performed microbiological investigations:
• blood culture
• sputum culture
• pleural fluid analysis by PCR
• urinary antigen test for Legionella
pneumophila and Streptococcus
pneumoniae
• search of influenza and RSV by rapid
tests on respiratory secretions
• specific serologic response to Mycoplasma
pneumoniae and Chlamydophila pneumoniae

72. CASE 2 – SE
• Clinical hypothesis: CAP due to S.
pneumoniae
• Empiric recommended therapy: i.v.
third generation cephalosporin
• Outcome: persistence of fever (T
38°C) as well as CAP signs and
symptoms (although less severe) after
72 hours of therapy

73. CASE 2 – SE
What do you think about:
1. requirement of hospitalization?
2. performed examinations?
3. prescribed therapies?
4. patient’s outcome?

74. CASE 2 – SE
After 72 hours, these were results of
microbiological investigations:
• blood culture and sputum positive for
Streptococcus pneumoniae
• pleural fluid positive for Mycoplasma
pneumoniae DNA
• IgM to M. pneumoniae 1:300, IgG
1:1000

75. CASE 2 – SE
• Oral azithromycin 10 mg/kg/day for 3
days was added in the antibiotic
regimen
• Fever disappeared in 36 hours and
clinical conditions appeared rapidly
better
• The patient was discharged after 3
days of the new therapy and had no
more respiratory problems

76. 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 children and adults with CAP
Combination therapy reduces mortality and
complications both in children and adults,
particularly in moderate-severe pneumonia

77. ATYPICAL BACTERIA AS CAUSE OF UPPER
RESPIRATORY INFECTIONS IN PEDIATRICS
 M. pneumoniae can cause upper
respiratory tract infections in children of
all the age groups
 These infections often occur in children
with history of recurrent respiratory
tract infections
 Treatment with macrolides can solve the
acute illness and reduce the risk of new
recurrences that can involve also the
lower respiratory tract

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