Combination antibiotic therapy bacteremic

pneumococcal pneumonia: PRO

Antoni Torres.

Universitat de Barcelona. Spain

IDSA/ATS Clin Infect Dis

2007;44:S27-72

OutlineWhy combination therapy?

What agents?

For how long?

Is combination therapy enough?

Pneumococcal pneumonia

Two retrospective studies (1,2) and a prospective study (3) have observed a lower mortality in patients with community-acquired bacteraemic pneumococcal pneumonia treated with combination therapy compared with subjects treated with only one antimicrobial

One retrospective study (4) concluded that combination antibiotic therapy does not decrease mortality in patients with severe pneumococcal infection

(1) Arch Inter Med 2001; 161: 1837-1842 (3) Am J Resp Crit Care Med 2004; 170: 440-444. (2) Clin Infect Dis 2003; 36: 389-395. (4) Eur J Clin Microbiol Infect Dis. 2005; 24: 688-690.

14-d mortality Combination therapy: 23.4%

Monotherapy: 55.3%p = 0.0015

Combination therapies prescribed in critically ill patients

ß-lactam/macrolide 14Vancomycin/ß-lactam 12ß-lactam/aminoglycoside 7vancomycin/other antibiotic 4 ß-lactam/quinolone 4 double ß-lactam therapy 2 ß-lactam/chloramphenicol 2ß-lactam/TMP-SMX 1Clindamycin/quinolone 1

• Retrospective study of a cohort of

1,840 adult patients with severe sepsis or septic shock enrolled in two multicenter clinical trials

107 patients with monobacterial pneumococcal sepsis

75 patients with bacteremic pneumococcal pneumonia

Community-acquired pneumonia with shockProspective observational study. 33 Spanish ICUs

529 patients were enrolled, of whom 270 (51%) developed septic shock.

Monotherapy (n = 52) Β-lactam (n=25; 48.2%) Fluoroquinolone (N=22; 42.2%) Macrolides were not administered in monotherapy.

Combination therapies β-lactam/macrolides (n = 131; 48.5%) β -lactam/fluoroquinolones (n = 54; 20.0%).

Rodriguez A. Crit Care Med 2007; 35: 1493-1498

Community-acquired pneumonia with shock

Rodriguez A. Crit Care Med 2007; 35: 1493-1498

Survival was higher for both antibiotic combinations•β-lactam plus macrolide (HR, 1.73; 95% CI, 1.08–2.76; p = .02)•β-lactam plus fluoroquinolones (HR, 1.77; 95% CI, 1.01–3.15; p = .05).

Levofloxacin as monotherapy in severe CAP

Prospective, randomized 1:1, comparative, open trial

398 randomized patients who had been admitted to the ICU with severe CAP without shock.

Monotherapy: Levofloxacin Combination therapy: Cefotaxime plus ofloxacin

Clinical efficacy, bacteriologic response and mortality was similar in both group

Chest. 2005; 128:172-183.

Patients on MV

Although in patients on MV, the cure rate and overall mortality rates were not statistically different in both treatment groups,

the noninferiority of L to C + O could not be demostrated.

Chest. 2005; 128:172-183.

Β-lactam and Macrolide Combination

Therapy vs. Fluoroquinolone Monotherapy

BL+M F BL+M F

Antimicrob Agents Chemother 2007; 51: 3977-3982.

0

30

50

10

20

40

Mo

rtal

ity

(%)

PSI 4 PSI 5

p=0.6 p=0.05

What agents?Macrolides or fluoroquinolones? That’s the question.

172 episodes of severe CAP

Multivariate analysis. 30-day MortalityB-lact+fluoroq OR 2.71 (95%IC 1.2-6.1)

• Retrospective analysis of 2,209 Medicare patients with bacteremic pneumonia

Initial use of any antibiotic active against atypical organisms was independently associated with a decreased risk of 30-day mortality

the benefits of atypical treatment were associated with the use of macrolides, but not the use of fluoroquinolones or tetracyclines

•Critical care patients: 20%

Outcome of intubated patients with CAP: Impact on outcome of combination antibiotic with macrolides

Eu-VAP/CAP study: 218 patients on invasive mechanical ventilation for CAP

Monotherapy was given in 43 (19.7 %) and combination therapy in 175 (80.3%) patients

Empirical antibiotic therapy was in accordance with 2007 IDSA/ATS guidelines in 100(45.9%) patients

Macrolides 46 patients Fluoroquinolones: 54 patients

I. Martin-Loeches et al, Intensive Care Med 2010

Cox regression analysis

Macrolide use was associated with lower ICU mortality (HR 0.48 95%CI 0.23-0.97, p = 0.04) when compared to the use of fluoroquinolones. Patients with severe sepsis or septic shock (n=92): Similar results (HR 0.44 95%CI 0.20-0.95, p = 0.03)

Días UCI

6040200

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Días UCI

6040200

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I. Martin-Loeches et al, Intensive Care Med 2010

macrolides

macrolides

quinolones

quinolones

S pneumoniae resistance (Barcelona)

Am J Resp Crit Care Med 1999; 159: 1835-1842 Chest 2006; 130: 800-806

Penicillin Cefotaxime Eritrhomycin

*Significant difference

0

20

60

100

80

40

Resistance (%)

1999-2002 (N= 123)1996-1998 (N=101)

*

*

Potential Mechanisms for Mortality Reduction in severe CAP

Uncovered pathogen with monotherapy

Altered antibiotic pharmacokinetics during critical illness

Immunomodulatory effects of macrolides

Immunomodulatory effects of macrolides

Pro-inflammatory effects of macrolides Enhance phagocytosis

Anti-inflammatory effects of macrolides Inhibit iNOS gene expression and NO release Inhibit the expression of ICAM, thereby

modulating the recruitment of neutrophils to inflamed sites

Inhibit NF- B activation leading to decreased production of cytokines (TNF-, IL-1, IL-6 and IL-8)

Inhibit reactive oxygen species production

Virulence factors of S pneumoniae

Macrolides and pneumolysin production

Pneumolysin is one of the most important virulence factors of S. pneumoniae.

It augments intrapulmonary growth and dissemination during the early pathogenesis of S. pneumoniae.

It disrupts epithelial tissues that form a mechanical barrier, and allow S. pneumoniae to penetrate into the blood stream.

Macrolides attenuate the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae

Eur Respir J. 2006;27:1020-5 J Antimicrob Chemother. 2007; 59:224-9

Is azithromycin the first choice macrolide for CAP?

Patients with CAP who received ceftriaxone combined with a 3-day course of azithromycin or a 10-day course of clarithromycin were compared in an open-label, prospective study

Of 896 assessable patients, 220 received clarithromycin and 383 received azithromycin.

There were no significant differences between groups with regard to the severity of illness or the incidence of bacteremia

Clin Infect Dis 2003; 36:1239-1245.

Patients with CAP who do not require ICU admission

Len

gth

of

stay

(d

ays)

0

6

10

2

4

8

AZT CLT 0

6

10

2

4

8

Mo

rtal

ity

(%)

AZT CLT

Clin Infect Dis 2003; 36:1239-1245.

For how long?

No previous study has been designed to determine the optimal duration of combination therapyCurrent guidelines do not establish duration of combination therapyOnce the etiology of CAP has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation; level III evidence.IDSA)

Combination therapy: 3-5 days

“If our conclusions are confirmed by other prospective studies, we recommend that clinicians target combination antibiotic treatment only for those patients who are critically ill, and limit the duration of the combination to 3–5 days”.

Delay of antimicrobial therapy and mortality

Arch Intern Med 2004; 164: 637-644

Adjusted odds ratio of death1.0 1.1 1.2 1.3

All

Documented

Suspected

Culture +

Culture -

Bacteraemia +

Bacteraemia -

Community

Nosocomial

Gram +

Gram -

Fungal

Respiratory

Urinary tract

Intra-abdominal

Skin/soft tissue

1385

769

608

1546

459

1695

2154N

912

1242

768

584

838

131

230

156

641

Kumar, et al. Crit Care Med 2006;34:1589–1596

Risk of death with increasing antimicrobial delay: subgroupsRisk of death with increasing antimicrobial delay: subgroups

X, delay (hours)X, delay (hours)

Bacteremic pneumococcal CAP 125 episodes

Independent risk factors associated with in-hospital mortality.aHR CI 95% p

Charlson comorbidity index 1.13 (0.98 - 1.32) 0.131Sepsis severe/ septic shock 5.06 (1.631 – 15.71) 0.0051st adequate atb ≥ 4 hours 2.62 (1.06 - 6.45) 0.037

Independent risk factors associated with mortality at 90 days HRa CI 95% p

Charlson comorbidity index 1.17 (1.02 - 1.34) 0.023Sepsis severe / septic shock 3.03 (1.22 – 7.51) 0.0161st adequate atb ≥ 4 hours 2.21 (1.01 - 4.86) 0.048

Scand J Infect Dis 20010(accepted)

Bacteremic pneumococcal CAP 125 episodes

The use combination therapy was not included in these models but was a protective factor for delayed adequate therapy [aHR 0.53 (95% CI 0.29-0.95); p=0.033].

days6050403020100

Su

rviv

al

1,0

0,9

0,8

0,7

0,6

0,5

0,4

0,3

After 4 hours Before 4 hours

Adecuate antibitic dose

Scand J Infect Dis 2010 (accepted)

ConclusionsCombination therapy is mandatory in all patients with severe CAP and particularly in case of bacteremic pneumococcal pneumonia

As in other patients with severe sepsis, early administration of adequate therapy is also crucial in these patients

ConclusionsA macrolide might be a superior option than a fluoroquinolone to be added to a -lactam agent

Macrolides might lessen the inflammatory response generated by microbial proliferation and increased by treatment with a -lactam agent