SEPSIS - MENINGITIS - SEPSIS - MENINGITIS - MALARIAMALARIA

Pr. B. VandercamConsultation Maladies Infectieuses et Tropicales

Cliniques Universitaires St-LucOctobre 2004

Sepsis

• Focus

• Absence of focus– Purpura fulminans

– Community acquired sepsis immunocompentent adult

– Nosocomial sepsis immunocompetent adult

– IV DU

– Asplenic (anatomic or functional)

– Neutropenia

– Toxic shock syndrome

Working definitions associated with sepsis and related disorders

DISORDER DEFINITION/SIGNS

Bacteremia Bacteria present in the blood, as confirmed by the culture.May be transient or associated with sepsis and organ failure

Sepsis (identical toSIRS criteria minusevidence ofinfection)

Confirmed or clinical evidence of infection plus evidence of a systemic responsemanifested by 2 or more of the following :- temperature > 38°C or < 36°C- heart rate > 90 beats/min- respiratory rate > 20 breaths/min or arterial CO2 tension < 32 mm Hg (4.3kPa)- WBC > 12 000 cells/ml, < 4000 cells/ml or > 10% immature forms (bands)

Severe sepsis Sepsis with associated organ dysfunction with one or more of the following :- hypotension, confusion, oliguria- hypowia – not explained by primary respiratory disease- metabolic (lactic) acidosis- disseminated intravascular coagulation (DIC)- hepatic dysfunction – not explained by primary liver disease

Septic shock Severe sepsis plus hypotension despite adequate fluid resuscitation

SIRS : systemic inflammatory response syndromeWBC : white blood count

Source of infection

• Anamnesis (pets, travel, household, …)• Physical examination (purpura, scar …)• Blood culture

Urine culture

RX thorax

Echo (scan abdo) obstacle abscess collection

Echo cardio

• Activated protein C (- 6 %)

• Corticosteroids (low (HC 200-300 mg/day) - long (5-

7d))

• Intensive insuline therapy (- 17%)

• Volume resuscitation (- 15%)

Prior medicare database analyses

• MEEHAN T. Jama 1997; 278:2080 Mortality increased significantly with delay in first Abx dose > 8 hrs (registration to dose)

• GLEASON PP. Arch Intern Med 1999, 159:2562 Mortality based on abx (OR)

Cephalosporin 1.0

Cephalosporin + mac 0.76

Fluoroquinolone 0.64

• Method : review of Medicare database for patients > 65 yrs hospitalized with x-ray confirmed CAP

• Period reviewed : July ’98 - March ’99

• Patients : 13 771

• PSI score : III - 47 % IV - 24 %

Results

Variable < 4 hrs > 4 hrs P

Hosp mortality

30 day mort

LOS

Readmin

6.8%

11.6%

5.1 d

13.1 %

7.4%

12.7%

5.3 d

13.9%

0.005

0.005

0.003

NS11.6

Skin lesions and systemic infections

LESION COMMON PATHOGENS TIME OF APPEARANCEAFTER ONSET OF

ILLNESSToxic erythema Staphylococcus aureus,

Streptococcus pyogenesAt presentation

Rose spots Salmonella spp 5-10 days

Purpuric lesions (in criticallyill patients)

Neisseria meningitidis,Rickettsia spp,Capnocytophaga canimorsus,Gram-negative bacteria

12-36 hours

Macronodular lesions Candida spp,Cryptococcus neoformans,Histoplasma capsulatum,Fusarium spp

Days

Erythema multiforme,bulbous lesions, ecthymagangrenosum

Pseudomonas sppVibrio vulnilicus,Gram negative bacteria

Days

Purpura fulminans : treatment

• Cefotaxime 2 gr q 4 - 6 h

or Ceftriaxone 2 gr q 12 h

• AllergyVanco 1 gr q 12 h

+ Aztreonam 2 gr q 6 h

or Moxifloxacin 0,4 gr q 24 h

or Levofloxacin 0,5 gr q 12 h

Community acquired sepsis - immunocompetent adults

• Infecting organisms – Enterobacteriacae– Staph aureus– Strept pneumoniae & spp– N. meningitidis – Bacteroides spp

• Treatment – Cefotaxime or Ceftriaxone– Amoxi clav or cefurox + amino

IVDU

• Infecting organisms– Staph aureus

• Exclude endocarditis

• Previous antibiotherapy

• Treatment

Oxacilline 2 gr q 6 h or Vancomycine 1 gr q 12h

+ Genta 2,5 mg/kg q 12 h

Asplenia

• Overwhelming sepsis

• Stand by therapy– Amoxi clav– Allergy, travel --> Moxifloxacin, Levofloxacin– Vaccination

• Antibioprophylaxis

Asplenia sepsis

• Infecting organisms– S. pneumoniae– H. influenzae– N. meningitidis– Capnocytophaga spp

• Treatment– Ceftriaxone or Cefotaxime

Nosocomial *sepsis - immunocompetent adult

• Infecting organisms– Enterobacteriacae– S. aureus– Strep pneumoniae– Bacteroïdes spp– P. aeruginosa– CNS

* readmission - nursing home

Nosocomial sepsis

• Local epidemiology

• Colonization

• Previous antibiotherapy

• IV line

• Urinary catheter

• Invasive procedure

Treatment

• Vancomycin ?

• Cefotaxime or Ceftriaxone or Pip/tazo

+ amino

• Ceftazidime or Cefepime or Carbapenem

+ amino

Sepsis neutropenia

• Infecting organisms– Strepto spp– CNS– S. aureus– Enterobacteriacae – P. aeruginosa

• Colonization

• Previous antibiotherapy

Neutropenia « Low risk »

Amoxi clav 2 gr q 6-8 h +

Cipro 750 q 12 h OR

Ceftriaxone 2 gr q 12 h +

Amikacin 15-25 mg/kg q 24 h

Neutropenia « High risk »

• Ceftazidime 2 gr q 8 h

• Cefepime 2 gr q 8 h

• Pip/tazo 4 gr q 6 h

• Imipenem 750 mg q 6 h

• Meropenem 2 gr q 8 h

+ amino ???

Toxic shock syndrome

• Infecting organisms– Strepto A, B, C,– Staph aureus

• Treatment– Cefazoline 2 gr q 8 h + Clindamycine 600 mg q

8 h

Clinical diagnosis

• Fever sensitivity 85%

• Menigism 70%

• Altered mental status 60%

• Kernig

Sensitivity 5%

Specificity 95%

Poser la question = y répondre

Case presentation

• 25-year-old man• 2-day history of severe headache, fever, neck

stiffness• 38,3 °C• No rash• Normal mental status and neurologic examination• Pain on neck flexion but able to flex his neck fully• No Kernig and Brudzinski signs

Contraindications of lumbar puncture

• Known or suspected space-occupying lesions with mass effect

LP deferred until CT scan • Severe uncorrected coagulopathy (INR > 1.5)• Trombocytopenia (platelet count < 50 000/mm³)• Infection at the puncture site (decubitus ulcer)

- Glasgow < 13

- Shock

When should a computerized tomography scan precede a lumbar puncture ?

• Age over 60 years

• Immunocompromised state

• History of primary neurologic disease, head trauma, neurosurgery

• History of seizure within the past week

• Altered mental status, cilated or poorly reactive pupils, occular palsy and focal neurologic abnormalities

• Papilledema, bradycardia, irregular respiration

• History of cancer

• Suspicion of brain abscess (endocarditis, bacteremia …)

Empiric anti infective therapy without delay

CSF examination

• Gram stain - Ziehl - Ink

• Culture (bacteria, fungi, brucella, nocardia …)

• Bacterial antigens– if antibiotherapy– Gram or culture negative

• PCR virus + BK

• Blood culture 60 % + in acute bacterial meningitis

CSF characteristics in selected neurologic conditions

Condition Cell count Protein (mg/dl) Glucose

Normal 0-5 lympocytes 15-45 2/3 of serum glucose

Bacterial meningitis 200 – 10 000 cells95 % PMNs

Elevated, usually >100

Low (< 50 mg/dl ; >2,8 mmol/l)

Viralmeningoencephalitis

6-1000 cells,lymphocytespredominance butmay show PMNsearly

Elevated, usually >100

Normal

Tuberculous orfungal meningitis

10-500, lymphocytepredominance

Greatly elevated,100 to > 3000

Low (< 50 mg/dl ; >2,8 mmol/l)

Brain abcess Elevated, usually <500 lymhocytepredominance, PMNsif rupture intoventricle

Elevated, usually >100

Normal

Subarachnoidhemorrhage

Mildly elevated,lymphocytepredominance,xanthochromia

Elevated Normal or low

Guillain-Barrésyndrome

Normal Elevated Normal

PMN, polymorphonuclear cell

• Purpura, petechia N. meningitidis

• Cellulitis face S. aureus

H. influ

• VRS, VRI S. pneumoniae

H. influ

• Parotitis Mumps

• Endocarditis S. aureus

• Septic arthritis S. pneumoniae S. aureus

• Pregnancy Listeria

Acute meningitis treatment

• IV line - blood cultures

• AB + dexa 10 mg within 30 min(*)

• LP if no contraindication

• Chest x-ray

• Delta scan if needed

(*) S. pneumoniae : 4 h

N. meningitidis : 2 h LCR

Antibiotherapy

• Listeria : ampi or CTX

• S. pneumoniae : peni i 10% cef 3 i 1%

• H. influ : vaccination

Antibiotherapy dosage

Penetration - bactericide - CMI

• Cefotax 2 gr -(4 gr) q 4h (ratio 25%) • Ceftriaxone 2 gr q 12h (ratio 15 - 30%)• Ampi 2 gr q 4h (ratio 10 - 15%)• Cefepime (ratio 10%)• Ceftazidime (ratio 20 - 40%)• Cotrimoxazole (ratio 30 - 35%)

Antibiotic therapy in meningitis

• IV from the beginning to the end …

• Standard therapy– 7 days for N. meningitidis– 10 - 14 days for S. pneumoniae– (14) - 21 days for L. monocytogenes

Meningitis : child > 3 months - adults < 50 yrs

• Infecting organisms– S. pneumoniae– N. meningitidis– H. influ– L. monocytogenes

• Treatment– Cefotaxime + ampicilline– Ceftriaxone + ampicilline

Meningitis : alcoohol - adults < 50 yrs Cellular immune deficiency - Debilitating illness

• Infecting organisms– S. pneumoniae– L. monocytogenes – N. meningitidis– Gram negative bacilli

• Treatment– Cefotaxime + ampicilline– Ceftriaxone + ampicilline

Meningitis : HIV /AIDS

• Infecting organisms– C. neoformans– S. pneumoniae– M. tuberculosis– L. monocytogenes – T. pallidum– N. meningitidis– HIV

Meningitis : cerebrospinal fluid shunt

• Infecting organisms– Coag neg staph– S. aureus– Diphteroids– Enterobacteriaceae

• Treatment– Vancomycin + cefta

Meningitis : after cranial or spinal trauma

• Infecting organisms– S. pneumoniae– H. influ

• Treatment– Cefotaxime or Ceftriaxone

Meningitis after cranial or spinal trauma (> 4 days)

• Infecting organisms– Enterobacteriaceae– S. aureus– P. aeruginosa– S. pneumoniae

• Treatment– Vancomycin + ceftazidime

People on the move: demographics year 2003

• 175 million persons live outside of their country of origin (2,9%) of the world's population

• Population of concern to UNHCR: 21,6 million

• Refugees 11,7 million

• Internally displaced persons: 20-30 million

• Rural to urban migration: 20-30 million/year

• 1-2 million migrate permanently every year

• 700 million tourist arrivals/year

01643

Malaria risk pyramid for 1 month of travel without chemoprophylaxis

• Oceania 1:5

• Africa 1:50

• South Asia 1:250

• Southeast Asia 1:2500

• South America 1:5000

• Mexico and Central America 1:10 000

Délai d’apparition de malaria selon espèce

Schwartz NEJM 2003; 349, 1510

Malaria en Belgique

Institut de Santé Publique-Louis Pasteur

Who dies from travelers’ malaria ?

USA & Canada (n = 21) Total (%)

No chemo 21 100

Dealy seeking care 1 5

Missed by MD 13 62

Lab misdiagnosis 9 43

Mistreatment 11 52

MMWR July 20, 2001 & 1999; 48:SS-1 Kain K et al. CMAJ 2001, 164:654-659

Toute fièvre au retour des tropiques est une malaria

jusqu’à preuve du contraire !!

Contribution de certaines anomalies biologiques au diagnostic de la malaria

• Thrombopénie : 60-85%Si de plus GB N : VPP : 77% VPN : 92%

• Leucopénie ou GB N : quasi-constante• CRP: 100% (mais très peu spécifique)

PrécoceTrès élevé // à parasitémie et à évolution VPN très bonne (probable) si CRP N

LDH : (très) sensible : 83-100%peu spécifique : 60%

haptoglobine : 90% des casVPN élevée de taux NIntérêt potentiel couplé à CRP

Malaria à P. falciparum

Règles: Vu la provenance essentiellement africaine des souches isolées en Belgique

Hospitaliser si:- patient non immun- patient immun avec > 2% GR+

et/ou critères de gravité

Préférer un traitement à base de quinine (5j ± 2j)si malaria sévère (+ doxycycline)

La parasitémie peut augmenter durant les premières 24h de traitement(action sur points limités du cycle qui continue à évoluer "malgré" le traitement)

Résistance R3 est déterminée à 48h (où diminution de 75% doit être obtenue)

La température peut persister pendant 72-96h sans signification péjorative

Si haute suspicion de malaria, et GE (-) :répéter 3 - 4 x sur 48h

Traitement de la malaria à P. falciparum sévère

• Bihydrochlorate de quinine– 500 mg IV (dans 250ml glucosé ED) en 4h/ 3x/j pdt 3-7j– 10 mg/kg (soit 8mg/kg de quinine base) 3x/j chez enfant

N.B.: si origine S. Est Asiatique (ou si malaria sévère ?)dose charge : 20 mg/kg (donc 1 seule fois)

ou (dès que possible/début si pas V /peu critères gravité)

• Sulfate de quinine: 500 mg per os 3x/j pdt 3-7 jours

+ Doxycycline 200 mg/j puis 100 mg/j pdt

6 jou

Clindamycine 600 mg 3-4x/jour pdt 3-7 j

(par exemple, si grossesse)

Malaria treatment

P. falciparum (zone A) - P. vivax, P. ovale (*)

• Day 1 : nivaquine 600 mg + 300 mg

• Day 2 : 300 mg

• Day 3 : 300 mg

(*) Primaquine 15 mg q 24 h x 14 days

Malaria treatment

P. falciparum

• Malarone P.O 4 x 3 days (food, milky drink)• Quinine sulfate 500 mg q 8 h x 3-7 days

+ Doxy 100 mg q 12h x 7 days• Quinine I.V. 10-20 mg/kg over 4 h in 5% dextrose

Quinine I.V. 10 mg/kg over 4 h q 8 h

+ Doxy 100 mg q 12h or Clinda 10 mg/kg q 8h• Qt ! Halofantrine ! Mefloquine 2 weeks

Co Artemether (Riamet® Novartis)

• Fixed combination of lumefantrine (halofantrineanalogue) PLUS artemether (artemisinin derivative)

• Fast acting (artemisinin), but low recrudescence rate(lumefantrine)

• Highly effective in its 6-dose regimen to treat malaria

• Low propensity for resistance to be developed

• Registered in > 75 countries ; more in the pipeline,including the USA

• Short half life of artemether mitigates against use inprophylaxis ; presumptive treatment under consideration

• Special price for product in DECs is facilitating access