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Community Acquired Pneumonia: Risk factors and antibiotic selection

Antonio Anzueto, University of Texas Health Science Center San Antonio, USA


Disclaimer Professional Relationships: Member of the ATS/ERS Task force on COPD and COPD Exacerbations Member of the ATS/IDSA 2001, 2003 and 2007 CAP guidelines Committee Member of the Executive and Scientific Committee of GOLD Advisory board, Consultant, Speaker: Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Merck, Chiesi, Bayer-Healthcare Pharma, Dey Pharma, Forest laboratories. Grants: NHLBI – COPD gene, LOOT GSK – Eclipse, Horizon, Summit Lilly - Severe Sepsis Trial

Stocks: None


Clinical Case – 62 -year-old retired teacher presented to ED brought by daughter complaining 5 days of cough and flu like symptoms. – He has history of prior “heart attack” and maybe diabetes. – Physical Examination: • fever 101.7°F, HR 87/bpm, RR 32/min, BP 70/40 • Left lower lobe crackles


CHEST X RAY


Antibiotic treatment….. •What the likely pathogens ? •How should I treat ?


Antibiotic treatment….. •What the likely pathogens ? •How should I treat ?


Etiology of Community-Acquired Pneumonia Ambulatory patients

Hospitalized (non-ICU)

Severe (ICU)

S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae Viruses

S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella spp. Aspiration

S. pneumoniae H. influenzae Legionella spp. Gram-negative bacilli Staphylococcus aureus Viral: H1N1

ICU = Intensive care unit

ATS/IDSA guidelines 2007.


PCVs have led to a shift in CAP aetiology Children <5 years

Introduction of PCV-7 reduced the incidence of pneumococcal vaccine serotypes in children < 5 years of age

Adults 65 years

Hicks et al. JID, 2007; 196: 1346â&#x20AC;&#x201C;54

At the same time, non-vaccine serotypes increased in patients 65 years of age


S. Pneumo serotypes

Lorking et al IDSA poster -2009


Serotype distribution: PCV-7 VT: serotype included within the 7-valent pneumococcal conjugate vaccine; PCV-13 VT: serotype included within the 13-valent pneumococcal conjugate vaccine; NVT: non vaccine-type.

Bewick et al Thorax 2012


Risk Factors for PRSP & DRSP in CAP • Age < 2 or 65 years • β-lactam therapy, macrolides within 3 months • Alcoholism • Immune suppression (including steroids) • Multiple medical comorbidities • Exposure to child in daycare IDSA/ATS 2007 Guidelines, CID 2007


Score System to Evaluate Risk MDRs

Aliberti et al, CID 2012:54


Antibiotic treatment….. •What the likely pathogens ? •How should I treat ?


Guidelines Concordance and Mortality

Mortensen, Restrepo, Anzueto, AJM 117: 726,2004


ATS/IDSA Algorithm for CAP CAP is present

Outpatient therapy

No cardiopulmonary disease

History of cardiopulmonary disease

Inpatient therapy

Mild to moderate illness

Severe CAP

Risks Pseudomonas No modifiers

+/- modifiers + C/P Disease +/or Modifier

No C/P Disease, No Modifier

Yes

No


Community-acquired Pneumonia: Empiric Therapy – ATS/ IDSA • INPATIENT • General Ward: Resp Fluoroquinolone; • -Lactam* + Macrolide

IDSA/ATS 2007 guidelines, CID 2007


Moxifloxacin vs β-lactam/β-lactamase Inhibitor ± Macrolide Combination Therapy - Outcome Moxifloxacin 100

* 93.4

90

Comparator† 93.7

85.4

**

81.7

80

Percent (%)

70 60 50 40

•Monotherapy with moxifloxacin is superior (p<0.01) to combination comparator at TOC (days 5–7 posttherapy) in the treatment of 538 patients with CAP admitted to a hospital (primary outcome)

30 20 10

n = 258

280

64

71

*p=0.004 **95% CI (1.21%, 22.91%)

0

Clinical success

Bacteriological †Amoxicillin-clavulanate +/- clarithromycin IV/PO. success Finch R et al. Antimicrob Agents Chemother. 2002;46:1746-54.


Moxifloxacin vs β-lactam/β-lactamase Inhibitor ± Macrolide Combination: Time to Afebrile and IV-PO Conversion Moxifloxacin 58.6

60

Comparator †

* 50.2

50

46.7

% Patients

40

Fast IV to oral conversion

Faster fever resolution

30

17.8

20 10 0

n=

239

255

Patients Afebrile Day 2 *P=0.025

301

320

IV to PO Conversion Day 3 P=Not Reported

†Amoxicillin-clavulanate

+/- clarithromycin IV/PO. IV formulation of comparators is not approved in the US. Finch R et al. Antimicrob Agents Chemother. 2002;46:1746-54.


Rates of treatment failure according to CAP severity and antibiotic treatment.

Ott et al Eur Respir J 2012; 39: 611â&#x20AC;&#x201C;618 *** p<0.001 # p=0,002


CAPRIE: clinical outcomes Moxifloxacin Clinical recovery rate (95% CI: 1.7, 14.1); P=0.01

Success rate (% of patients)

100

97.9 90.0

Levofloxacin Clinical cure rate (95% CI: –1.9, 11.9); P=0.2

92.9

87.9

80 60 40 20 138/141

126/140

131/141

123/140

0 Days 3-5

Anzueto et al. Clin Infect Dis 2006; 42: 73–81

Test of cure


MOXIRAPID Clinical Trial: Faster Fever Resolution in CAP Fever Resolution Moxifloxacin

(n=161)

Day 3.8

Ceftriaxone Âą macrolide(n=156) Day 4.8 P =0.0027

0

1 2 3 4 5 Mean time to defervescence (Days)

Welte T, et al. Clin Infect Dis 2005; 41: 1697-1705

6


MOXIRAPID Clinical Trial: Faster IV/PO Switch and Hospital Discharges IV/PO Switch Moxifloxacin

Hospital Discharges Moxifloxacin

(n=161)

(n=161)

Day 5.4

Day 9.8

Ceftriaxone ± macrolide (n=156)

Ceftriaxone ± macrolide (n=156)

Day 9.5

Day 11.1 p = 0.0005

0

2

4

6

8

Number of days on IV therapy

Welte T, et al. Clin Infect Dis 2005; 41: 1697-1705

10

0

2

4

6

8

10

12

Mean number hospitalization days


CAP: Overall Treatment Cost

# p=0.018 (p-value compared to CURB-65 score 0) Âś p<0.001 (p-value for comparison with treatment success) *** p<0.001 (p-value for comparison with CURB-65 score 0)

Ott et al. Eur Respir J 2012; 39: 611â&#x20AC;&#x201C;618


Pharmacodynamic Profile Efficient Penetration of Moxifloxacin* Bronchial Mucosa n=8

5.5

Alveolar Macrophages n=5

61.8

0

1

2

3

4

5

6

7

8

60 65

Mean Concentration ( g/g or mg/L)

Achieves tissue levels at 3 hours well above MIC90sâ&#x20AC;  for key RTI pathogens

Capitano B et al. Chest. 2004 Mar;125(3):965-73.


Pharmacodynamic Profile Moxifloxacin versus Levofloxacin Lung Tissue Penetration after 24 Hours* Levofloxacin n=15

Alveolar Macrophages

Moxifloxacin n=16 32.8 **

8.2

**p=0.04

5.7 †

Epithelial Lining Fluid

2.9

†p=NS

0

10

20

30

40

Tissue Concentrations (mg/L) Capitano B et al. Chest. 2004 Mar;125(3):965-73.


Moxifloxacin serum concentrations in critically ill patients

Pletz et al ICM 2010; 36:979


Moxifloxacin plasma and bronchial concentrations in MV patients

Leone et al Antimicrobial Agent and Chemo 2004; 48; 638


Ongoing challenges in the Management of CAP • CAP continue to be an important cause of morbidity and mortality • S. pneumoniae is the most frequent pathogen isolated in CAP, with increased bacterial resistance. • Fluoroquinolones, especially moxifloxacin, is a viable therapy option in CAP patients. • Outcomes may be improved and antimicrobial resistance slowed if guidelines are applied


-Klebs in 1875 was the first person described presence of bacteria in the airway of a patient who died of pneumonia.



3_CAPALAT2012