Clinical Case Study 1: How to deal with an MRSA

Benoit GUERY-Infectious Diseases- CHRU Lille-FRANCE

Michel R…, 43 years old Admitted on December 16rd 2003 in the

ER for acute respiratory distress

M. R… / Previous history Non hodgkin Lymphoma (Burkitt), EBV +.

Chemotherapy from November 2000 to November 2001. Complete remission

Zona in 1975 and 1998, Syphilis treated in 1992 B hepatitis infection HIV negative (last serology performed one

month ago) … but otherwise… in very good shape!!

M. R… / Recent history December 11: fever 39°C associated with shivers,

resistant to paracetamol. Did not call his MD. December 14: cough, dyspnea, still a fever (39°C). December 16: calls 911 and admitted in the ER:

Vital parameters Arterial pressure: 120-80 mmHg ; Respiratory frequency : 40/min ; SPO2 : 90 %, Cardiac frequency: 130b/min

Temperature : 40,1 °C Glasgow coma score : 15 Crackles all over the right lung, cyanosis No other clinical abnormalities

M. R… / First biological data Blood gas analysis (O2: 6 l/min) :

pH : 7,49 ; PCO2 : 34 mmHg ; PaO2 : 56 mmHg ; HCO3- : 24

mmol/l Urea : 4 mmol/l (0.24 mg/L) ; creatinin : 75 µmol/l

(8mg/L) Ionogramm (mmol/l) :

Na : 120 ; K : 3,5 ; Cl : 84 ; proteins (g/l) : 61; ASAT-ALATx2/normal

Blood count: Hb : 8 g/dl ; WBC : 3,9 G/l (85 % PMN), platelets : 130 G/l

Lactate : 3,4 mmol/l ; No coagulation abnormalities EKG : tachycardia

7

Question n°1

First line treatment ?

M. R… / First line treatment Failure of the non invasive ventilation

Mechanical ventilation17/12 : PaO2 = 96 mmHg with an FiO2 : 0,6

Initial antibiotics: ceftriaxon (2g IV) + ofloxacin (200 mg IV x 2)

Legionella pneumophila urine antigen : positive

BAL : IF positive (BCYE culture positive on the 4th day)

9

Do you change the antibiotics?

M. R… / Evolution December 18: Change for

levofloxacin (500 mg IV x 2) + rifampin (600 mg IV x 2)

Hemodynamic and respiratory stability until the 21st

December 21st : worsening of the respiratory status: PaO2/FiO2 = 97 with an FiO2 = 1

Associated to septic shock (norepinephrin)

Endotracheal aspiration: direct examination

21 décembre 2002

12

Question n°2

Do you change your prescription ?I guess yes…

M. R… /New molecules prescribed

Vancomycin : bolus 15 mg/kg followed by 30 mg/kg continuous perfusion

Imipenem : 50mg/kg IV Levofloxacine : no change Rifampin : no change

M. R… / Evolution December 22 : 107 CFU S aureus, 1 positive blood

culture with a Gram positive cocci December 23 : Identification of MRSA also resistant

to rifampin, gentamicin and quinolones Treament not changed but imipenem was stopped Within the next few days, the patient remained

critical with an hemodynamical instability, requirement for high oxygen fractions, and persistant fever (40°C).

Positive blood cultures to S. aureus on days 2, 3, 4 after vancomycin initiation

15

Question n°3

And then ?

M. R… / Failure analysis Endovascular explanation

Catheters changed (cultures negative) Transoesophageal echocardiography normal

Pharmacodynamic failure MIC:

vancomycin : 2 mg/l, teicoplanin : 6 mg/l

Blood concentrations (mg/l) D2 : 20 D3 : 20 D4 : 42 D5 : 50

M. R… / End the case… Vancomycine + quinupristin/dalfopristin (7,5

mg/kg x 3) between day 4 and 9 On day 9 : quantitative endotracheal

aspiration: 104 MRSA… Linezolid IV (600 mg x 2) (MIC = 0,5 mg/l)

between day 9 and 11 Day 11 : MRSA positive blood culture Multiple organ failure and death on day 11 Autopsia : bilateral pneumonia with multiple

abcess, no vascular or abdominal localisation.

M. R… / 30 décembre 2002

Map of Brooklyn indicating regionswith low prevalence (white area) and highprevalence (gray area) for S. aureus USA300 strain

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MRSA, the therapeutics options

Linezolide Zyvoxid

Oxazolidinone fonction

Semi-synthetic agent

Nosocomial pneumonia

* mITT : en intention de traiter modifiée.1) Rubinstein E et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32(3): 402-12.

Vancomycine + aztréonam 1-2 g/8 hsi bacille à Gram - prouvé ou suspecté

ZYVOXID® aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté

Clinical response

* mITT : en intention de traiter modifiée.1) Wunderink RG et al. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther 2003; 25(3): 980-92

Vancomycine + aztréonam 1-2 g/8 hsi bacille à Gram - prouvé ou suspecté

ZYVOXID® aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté

Clinical response

* + aztréonam (ou autre) si infection concomitante à gram- documentée ou suspectée.** En intention de traiter.Weigelt J et al. Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005 Jun; 49(6): 2260-6.

International multicentric study Open, randomized Compare the clinical efficacy of

2 protocols for complicated skin and soft tissue infections with suspected or documented Gram positive bacteria

Complicated skin and soft tissue infections

Weigelt J et al. Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005 Jun; 49(6): 2260-6.

Vancomycine***,****ZYVOXID®***

Clinical response

TYGECYCLINE

Tigecycline

Inhibition of protein synthesis Through ribosome 30S fixation Inhibits the link with tRNA

Activity preservationRibosomal protection

Efflux pump protection

Tigecycline: bolus 100 mg and 50mg X 2 /day, 566 patients

Vanco/aztreonam 1g/2g /12h, 550 patient

E.J. Ellis-Grosse et coll. C.I.D. 2005

Clinical response

Bacteriological response

MRSA (n = 37) MIC (mg/l)

MIC90 (range) MBC90 (range)

Ceftobiprole 1 (< 0,125-2) 2 (0,25-2)

Daptomycine 1 (< 0,125-1) 2 (0,25-4)

Linézolide 2 (0,25-4) 128 (4-> 128)

Vancomycine 2 (0,5-2) 4 (1-8)

CNS (n = 51) MIC (mg/l)

MIC90 (range) MBC90 (range)

Ceftobiprole 1 (< 0,125-4*) 1 (< 0,125-8*)

Daptomycine 0,25 (< 0,125-1) 1 (< 0,125-4)

Linézolide 2 (0,25-2) 64 (4-> 128)

Vancomycine 2 (0,25-2) 4 (0,5-8)

Ceftobiprole: endocarditis strain

ICAAC 2006 - M.S. Rouse et al., abstract E-118

MRSA

Vancomycin-teicoplanin: still… Linezolid: the use is increasing Tigecycline: should be restricted? Ceftobiprole, new quinolones, …