The role of macrolide in the era of antimicrobial resistance - Professor Susanna Esposito

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)

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

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)

%

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

13.3075.089

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

13.7145.517

No significant differences were observed

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)

12,5545,404*

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

Comparison of radiographic characteristics of the study population (Esposito S et al. CID 2002)

FindingHyperinflation

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

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)

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

Antibiotic combinations…

• The controversy about the necessity to add a macrolide

to a -lactam continues…

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

J Antimicrob Chemother 2016

ANTIMICROBIAL SUSCEPTIBILITY OF STREPTOCOCCUS PNEUMONIAE CAUSING IPD IN THAILAND, 2009-2012

Phongsamart et al., Human Vaccines & Immunother

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

PLOS One, 2016

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

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

CLINICAL RELEVANCE OFS. 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

OUTCOME OF PNEUMONIA IN RELATION TOPENICILLIN RESISTANCE OF S. PNEUMONIAEFrom 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

MECHANISMS OF STREPTOCOCCUS PNEUMONIAE MACROLIDE

RESISTANCE

ALTERATIONS IN THE RIBOSOMAL TARGET SITE

PRODUCTION OF INACTIVATING ENZYMES

PRODUCTION AND USE OF ACTIVE EFFLUX MECHANISMS

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

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

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

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 responseTreated 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

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

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

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

LENGHT OF HOSPITAL STAY ACCORDING TO EMPIRICAL ANTIBIOTIC TREATMENT

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

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

DEMOGRAPHIC CHARACTERISTICS OF THE STUDY CHILDREN WITH RECURRENT

RESPIRATORY TRACT INFECTIONS AND HEALTHY CONTROLS

Esposito S et al., PIDJ 2005; 24: 438-444

DISTRIBUTION OF THE STUDY SUBJECTS ACCORDING TO CLINICAL

DIAGNOSIS


SHORT-TERM OUTCOME ACCORDING TO THERAPY IN CHILDREN WITH

RRTIs AND ACUTE RTI


LONG-TERM OUTCOME ACCORDING TO THERAPY IN CHILDREN WITH

RRTIs AND ACUTE RTI


DEEP RED STUDY – RESULTSMOST 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

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

%

CLINICAL OUTCOME OF THE STUDY SUBJECTS

Esposito S et al., J Med Microbiol 2004

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

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

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

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)

COMPARISON OF CHILDREN WITH CAP AND MACROLIDE-RESISTANT AND MACROLIDE-SENSITIVE

M. PNEUMONIAE INFECTION (I)(From Cardinale F et al., J Clin Microbiol 2013)


M. PNEUMONIAE INFECTION (II)(From Cardinale F et al., J Clin Microbiol 2013)


M. PNEUMONIAE INFECTION (III)(From Cardinale F et al., J Clin Microbiol 2013)

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

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

CASE 1 - EP

• Therapy: inhalatory beta2-agonists

• Outcome: always cure in few days

CASE 1 - EP

The following examinations were performed:

• total IgE (normal) + skin prick test (negative)

• chest radiography (negative)

• immunologic evaluation (normal)

CASE 1 – EP7° episode of wheezing

CASE 1 - EP

After the seventh episode of wheezing:

• Recommended therapy: clarithromycin 15 mg/kg/die in 2 doses for 10 days

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

CASO 1 - EP

What do you think about:

1. diagnostic hypothesis?2. performed examinations?3. prescribed therapies?4. patient’s outcome and prognosis?

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. pneumoniaeDNA in the nasopharynx absent at the end of therapy as well as after 3 and 6 months

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

CASE 2 – SE

CHEST RADIOGRAPHY

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%

CASE 2 – SELABORATORY DATA

ParameterWBC (cells/L)Neutrophils, %Lymphocytes,%Monocytes, %Eosinophils, %Basophils, %

CRP (g/dL)ESR (mm/1h)

Value18,993

732151

0.211070

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

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

CASE 2 – SE

What do you think about:

1. requirement of hospitalization?

2. performed examinations?

3. prescribed therapies?

4. patient’s outcome?

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

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

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

ATYPICAL BACTERIA AS CAUSE OF UPPER RESPIRATORY INFECTIONS IN PEDIATRICS

M. pneumoniae can cause upperrespiratory tract infections in children of all the age groups

These infections often occur in childrenwith history of recurrent respiratorytract 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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Health & Medicine

The role of macrolide in the era of antimicrobial resistance - Professor Susanna Esposito