Antibiotic Resistance per se Causes Attributable Mortality in VAP Jean-François TIMSIT MD, PhD Medical ICU CHU Grenoble, France 10 th Symposium on Infections in the critically ill patient Porto – January 29th, 2005

No! Fitness of bacterias Positive studies biased Well designed recent studies are negative

What is antibiotic resistant bacterias? Not treated  Risk of death If panresistance Multiple resistant bacterias? –MRSA, P.aeruginosa, A. baumannii, ESBL, ERV Pan resistant bacterias? (tuberculosis) When bacterias are panresistant, infectious diseases always cause some degree of increase in the risk of death

Antibiotic resistant bacteria are less virulent… « when resistance occurs as a consequence of a genetic alteration in a housekeeping gene (ribosome function, cell wall construction, biosynthetic pathway, DNA machinery)…an evolutionary mechanism has deviated from its functional optimum. Resistance should have a direct cost in bacterial fitness. The location of antibiotic resistance in accessory gene elements probably reduces the « direct » costs, but at the expense of the indirect costs of the elements themselves. In both cases, antibiotic resistance should have a fitness cost which might reduce bacterial virulence » Martinez & Baquero – Clinical Microbiology reviews – 2002;

Virulence and resistance MSSA N= MRSA N= p Infecting dose 50 LD 50 Mizobuchi S- Microbiol Immunol 1994;38(8):

The rate of complications associated with VAP is not different between MRSA and MSSA Septic shock Acute renal failure Neurological alteration Hepatic alteration Respiratory distress DIC MRSA N=32 43% 50% 22% 13% 21% 3% MSSA N=54 33% 37% 17% 11% 37% 2% Gonzalez et al – CID 99

Increase in the morbi/mortality? MSSA VAPMRSA VAP Age> 2523/38 (60%)10/11 (91%)<0.05 APACHE II?? MV8.1 d11.9<0.005 Septic shock3/38 (8%)3/11 (27%)NS Mortality11/38 (30%)8/11 (72%)NS Mortality related to VAP 1/38 (3%)6/11 (55%)<0.01 Rello et al – AJRCCM 1994; 150:1545

Risk factors of MRB Risk factors of death Risk factors of NI Confounding factors Severity Procedures Antimicrobials Duration of MV Inappropriate ABx

Duration of stay before VAP LOS (days) MSSAMRSA Gonzalez <.01 Rello 1994 (MV) <.05 Pujol 1998 (MV)618.7<0.001 Pujol 1998 (Hopital) <0.001 Combes 2004 (MV)1019< Zahar 2005 (MV) In all these studies the crude mortality was higher in the MRSA group…

Duration of ICU stay Length of stay before S. aureus bacteremia is a risk factor of MRSA recovery and of death Hurley JC – Clin Infect Dis 2003; 37: Length of stay before bacteremia P<0.005 LOS (days) MSSAMRSA Blot Craven French Harbarth Hershow Lewis Marty Misushima Mylotte Pujol Romero-Vivas Selvey Soriano

Duration of MV before VAP is an independent outcome predictor FactorOR (95% CI)P value Age1.03 ( )0.004 MV duration prior VAP 1.04 ( )0.02 Day 1 ODIN score 1.91 ( ) Methicillin resistance 1.36 ( )0.4 Hospital mortality (Table E7 – electronic supplement) AJRCCM 2004; 170:786

The aim of the matching or adjustment process..Is to obtain exposed and unexposed patients similar in everything except in the resistance profile of the bacteria…. I’m 6 days old… I’m twent y.!!!

Outcomerea study group (65 MSSA, 69 MRSA VAP) Zahar et al; Submitted MRSA-VAPMSSA-VAPp Duration of MV before VAP12 (8-21)6 (4-14) ICU death34 (49.3)19 (29.2) Hospital death41 (59.4)26 (40.0)0.0246

In studies in which previous duration of ICU stay was taken into account MRSA VAP was not associated with an increase in the risk of death ICU death: OR= 1.51 ( ), p=0.42 Hospital death: OR=0.98 ( ), p=0.96 Zahar et al – 2005

Another important confusion factor: Adequacy of antimicrobial therapy Inadequacy of Abx Risk of death MRB ?

MRB is associated with a higher rate of inadequate therapy Ranking of bacterial pathogens associated with inadequate antibiotic treatment (from Luna 1997, Alvarez Lerma 1996, Rello 1997, Kollef 1998) Kollef M – Clin Infect Dis 2003; 31:S131 « Most episodes of inadequate antibiotic treatment were attributed to potentially antibiotic-resistant gram- negative bacteria…S aureus was the second most cause of inadequate treatment, with most strains being methicillin resistant »

Clin Infect Dis 1999; 29: MRSA-P 22 Abx appropriate 10 Abx inapproriate 10 Deaths (100%) 11 deaths (50%) 54 MSSA-P 41 Abx appropriate 13 Abx inapproriate 12 Deaths (93%) 14 deaths (34%) Mortality is associated with Inappropriate therapy but not with methicillin resistance

Clin Infect Dis 1999; 29: MRSA-P 22 Abx appropriate 10 Abx inapproriate 10 Deaths (100%) 54 MSSA-P 41 Abx appropriate 13 Abx inapproriate 12 Deaths (93%) 63 episodes appropriately treated 22 glycopeptides 11 deaths (50%) 17 glycopeptides 8 deaths (47%) 24 other 6 deaths (25%) P=0.17

aOR*CI 95 % Septic shock 61,5 5,7 – 672 Vancomycin treatment 14,5 1,4 – 146 Respiratory distress 8,3 1,5 – patients treated appropriately Vancomycin less effective in S. aureus pneumonia? Gonzalez C et al. Clin Infect Dis 1999; 29: Risk factor of death at the last step of the logistic regression

vanco ELF from Lamer et al AAC 1993 Vancomycin in the BAL fluid

It might be difficult to reach sufficient concentration of vancomycin in MRSA VAP If we want 2 to 4 MIC in the ELF MIC (µg/ml)[C] pulmSerum MIC (µg/ml)[C] pulmSerum 0, , ! ! !!! !!! Use trough level > 15 µg/ml or plateau level > 25 µg/ml +++, and gentamycin in case of susceptible strains

Resistance: no magic bullets anymore… Use of the overall information (gram stain, ecology of the patients, of the unit, previous antimicrobial therapy) Timsit et al – Intensive Care Med 2001; 27:640 –Appropriateness of Abx not significantly reduced: MSSA: 86.1% vs MRSA: 76.8, p=0.2 Zahar et al – 2005 submitted Infectious diseases specialists could be consulted Byl et al – Clin Infect Dis 1999; 29:60 Consider initial bi (tri) antibiotic therapy and subsequent desescalation Trouillet et al – AJRCCM 1998; 157:531 When highly resistant strains are suspected, use PK/PD knowledge Schentag JJ – Crit Care Med 2001; N100

In studies in which treatments followed these guidelines Methicillin resistance was not associated with an increase in the risk of death 28-day mortality: OR=1.72 ( ) p=0.22 (appropriate treatment only) Combes et al 2004 ICU death OR=0.82 [ ] p=0.85 hospital death OR= %CI [ ] p=0.52 (appropriately treated subgroup only) Zahar et al – 2005

Death Severity MRB Nosocomial infections ABx ? Previous LOS Underlying illness Case-mix Procedures Workload

Multiresistance and mortality of VAP Slides are available on Inadequate therapy kill patients In case of pan-resistance Association true Resistant bacteria is less virulent Patients with MRB are different With different medical history Pan-resistance is a very rare issue Optimization of Abx therapy is possible Association false