Patient’s Profile

GEW

49

Male

Chinese

150kg (obese)

15/7/09

Name

Age

Gender

Race

BW

DOA

C/O : Transferred from Damansara Specialist

Center Admitted due to fever, sore throat, cough,

headache

HPI : ILI for 3/7

PMH: Hypertension

Throat swab done : H1N1 +ve S/FH :

accountant Single MSM

PMHx : none

Diagnosis : Severe ARDS 2˚ to H1N1 pneumonitis Septic shock 2˚ to severe ARDS 2˚ to H1N1

pneumonitis ARF Juntional bradycardia VAP – MRSA and Acinetobacter Sacral bedsore Pressure sore on both feet

H1N1 introduction

Swine flu – new influenza virus Causing illness in people First detected in US in April 2009

Why called swine flu?

Lab testing showed that many of the genes in this new virus were very similar to influenza viruses that normally occur in pigs (swine) in North America

But further study has shown that this new virus is very different from what normally circulates in North American pigs.

It has two genes from flu viruses that normally circulate in pigs in Europe and Asia and bird (avian) genes and human genes.

Scientists call this a "quadruple reassortant" virus.

CDC, Antiviral Drugs and H1N1 Flu (Swine Flu). http://www.cdc.gov/h1n1flu/antiviral.htm, (accessed May 2009).

H1N1 Flu in Humans

Contagious Spreading from human to human

Through coughing/sneezing Touching something – surface/object with

flu viruses on it and then touching their mouth/nose

Signs and Symptoms

Fever Cough Sore throat Runny / stuffy nose Body aches Headache Chills and fatigue Diarrhea and vomiting

Current Treatments

Oseltamivir (Tamiflu) Zanamir (Relenza) Given 1st to those people who have been

hospitalized or are at high risk of severe illness from flu

Work best if given within 2 days of becoming ill but may be given later if illness is severe or for those at high risk complications

High-risk Groups

Children younger than 5 years old. The risk for severe complications from seasonal influenza is highest among children younger than 2 years old.

Adults 65 years of age and older. Persons with the following conditions:

Chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurologic, neuromuscular, or metabolic disorders (including diabetes mellitus)

Immunosuppression, including that caused by medications or by HIV

Pregnant women Persons younger than 19 years of age who are receiving

long-term aspirin therapy Residents of nursing homes and other chronic-care

facilities.

Centers for Disease Control and Prevention, USA. Interim Guidance on Antiviral Recommendations for Patients with Novel Influenza A (H1N1) Virus

Infection and Their Close Contacts, May 6,2009.

Centers for Disease Control and Prevention, USA. Interim Guidance on Antiviral Recommendations for Patients with Novel Influenza A (H1N1) Virus

Infection and Their Close Contacts, May 6,2009.

ChildrenChildren

AdultAdult

Side Effects

Oseltamivir Nausea (10%) Vomiting (9%) Self-injury and delirium

Less severe if taken with food

Centers for Disease Control and Prevention, USA. Antiviral Agents for Seasonal Influenza: Side Effects and Adverse Reactions

Zanamivir Use in persons w/o underlying respiratory or

cardiac disease

Not recommended for tx for pt with underlying airway disease

Others SE (<5%) : allergic reaction, diarrhea, nausea, sinusitis, bronchitis, cough, headache, dizziness, ear, nose and throat infections

Asthma/COPD + ILI 20% decline in forced expiratory volume 1 second (FEV1)

Mild/moderate asthma w/o ILI BronchospasmRespiratory fx deterioration

Centers for Disease Control and Prevention, USA. Antiviral Agents for Seasonal Influenza: Side Effects and Adverse Reactions

Complications from H1N1

Pulmonary complications are the most common and include : Primary influenza pneumonia 2◦ bacterial pneumonia

Streptococcus pneumonia, Staphylococcus aureus, MRSA, Haemophilus influenza and occasionally other gram-negative bacilli

Micheal B. Rothberg, MD, MPH et al. Complication of viral Influenza,. The American Journal of Medicines, Vol 121, No4, 256-263, April 2008.

Pneumonia due to unusual pathogens/ immunocompromised hosts Aspergillus sp, Chlamydia pneumoniae, B-

hemolytic streptococci, Legionella pneumophila Exacerbation of chronic pulmonary

diseases 25% induce by virus influenza

Micheal B. Rothberg, MD, MPH et al. Complication of viral Influenza,. The American Journal of Medicines, Vol 121, No4, 256-263, April 2008.

Miscellaneous complications [3]

Myositis, rhabdomyolisis (rare)

Renal failure (resolve in 4-6 weeks)

Neurologic – encephalophaty, meningitis, focal neurologic disorder [1] (CNS involvement usually occurred in children)

Psychiatric complication – schizophrenia in offspring of women developed influenza during 2nd trimester [2]

CHF, ischemic heart disease, direct cardiac complications (uncommon)

[1] Studahl M. Influenza virus and CNS manifestations. J Clin Virol. 2003;28:225-232.[2] Barr CE, Mednick SA, Munk-Jorgensen P. Exposure to nfluenza epidemics during gestation and adult schizophrenia. A 40-year study.Arch Gen Psychiatry. 1990;47:869-874 .[3] Micheal B. Rothberg, MD, MPH et al. Complication of viral Influenza,. The American Journal of Medicines, Vol 121, No4, 256-263, April 2008.

During 24 days admission

Clinical Progression

H1N1 positive

D1

H1N1 positive

D1

ARDSARDS

Septic shock

D2

Septic shock

D2

VAPD6 C+S : MRSAD15 C+S : Acinetobacter spp

VAPD6 C+S : MRSAD15 C+S : Acinetobacter spp

Throat swab

Cap. Oseltamivir 150mg bd x 5/7

Hypoxeamia : ventilation support

IV Noradrenaline 2ml/h

IV Vancomycin 1.5g tdsIV Vancomycin 2g tds

Neb Polymyxin E 2mu bd

Juntional bradycardiaECG finding

Juntional bradycardiaECG finding

ARFD1-D3 : oliguria

ARFD1-D3 : oliguria

Sacral bedsoreSacral bedsore Pressure sore on both feetPressure sore on both feet

Prolonged hospitalization

Thrombophebilitis

D16

Thrombophebilitis

D16

IV Unasyn 1.5g tds

IV Dobutamine 1.5ml/h

IV Cloxacillin 1g qid

IV Aminolasix

Medications chart

Medications Date started

Date stopped

Durations (days)

Indication

Cap. Tamiflu 150mg bd 15/7 19/7 5 H1N1

IV Azithromycin 500mg od 15/7 20/7 6 Empirical - CAP

IV Augmentin 1.2g tds 15/7 16/7 2 Empirical - CAP

IV Ampicillin 2g qid 16/7 22/7 7 Empiric

IV Meropenem 2g bd 16/7 22/7 7 Empiric

IV Vancomycin 1.5g stat and tds

24/7 28/7 6 MRSA

IV Vancomycin 2g tds 28/7 30/7 3 MRSA

Cap. Rifampicin 600mg od 28/7 30/7 3 MRSA

IV Cloxacillin 1g qid 30/7 3/8 5 Thrombophebilitis

Neb Polymycin 2mu bd 31/7 6/8 7 Acinetobacter MRO

IV Unasyn 1.5g tds 5/8 Sacral bedsore

Days Findings Indications Managements

D1 – D5 H1N1Cyanotic, HypoxaemiaBradycardiaSeptic ShockHypoK

Throat swab : +vePaO2 40mmHg60/minK : 3.3

Start Cap. Oseltamivir 150mg bdVentilatied with high settingsIV Dobutamin 1.5ml/hIV Noradrenaline 2ml/hAdd 1g KCl in IVDAdd mist KCl 1g tds

D6-D10 MRSA infectionHyperbilirubinemia Hypernatremia

WBC : 13->20->18->19T.Bil : 27->25->60Na : 154 -> 156

Start IV Vancomycin 1.5g tdsOn meropenem and ampicillin

D11-D16 MRSA infectionRed man syndrome

WBC : 17->15->15Skin Rashes

IV Vancomycin 2g tds + Rifampicin 600mg odStop IV Vancomycin

D17-D24 Acinetobacter spp infectionBedsore

C+S BAL : acinetobeacter Neb Polymyxin 2mu bdIV Unasyn 1.5g tds

Pharmaceutical Care Issues

Date PCI Recommendations

15/7/09D1

Overdose of Oseltamivir for treating H1N1

Starting dose for Oseltamivir 150mg bd for 5 days

23/7/09D9

Vancomycin dose for MRSA infection

Starting dose for vancomycin15-20mg/kg= 1.5g stat then 1.5g bd then optimized to 2g tds plus rifampicin 600mg od

29/7/09D15

Red man syndrome occurring from vancomycin infusion

Stop IV Vancomycin

Does double dose 150mg bd is appropriate for treating this patient??

Current dose for H1N1 treatment is 75mg bd

1. Antiviral therapy

controversial

Centers for Disease Control and Prevention, USA. Interim Guidance on Antiviral Recommendations for Patients with Novel Influenza A (H1N1) Virus Infection and Their Close Contacts, May 6,2009.

Obese??Resistance ??

The conventional oseltamivir dose is 75mg bd (5 days).

Some centres are administering 150mg bd for up to 10 days in the critically ill to attempt to limit the duration of viral

shedding, ensure aggressive antiviral treatment and

therapeutic levels. This is an unlicensed use but there are

no reported safety concerns so far.Pandemic H1N1 2009 Clinical Practice Note – Managing critically ill cases. Royal College of Anaesthetists, Health Proctection Agency, The intensice care Society, 28 July 2009

Obesity vs dose No clinical data yet

Obesity vs severe complications Obese have a higher prevalence of comorbid

conditions Prolonged duration of mechanical ventilation

and longer ICU length of stay, but not mortality, are associated with moderate obesity

Extremely obese ICU patients had higher rates mortality, nursing home admission and ICU complications compared with moderate obese patientIntensive-Care Patients with Severe Novel Influenza A (H1N1) Virus Infection – Michigan, June 2009

It was noted in the CDC study that carrying extra weight can compromise the lungs and therefore may make people more vulnerable to complications from the novel flu virus.

Moreover, impaired breathing due to pressure on the chest and abdomen can restrict a person’s ability to breathe, cough and aerate the lungs.

Obese people possible high risk of complications from Pandemic (H1N1)2009, Manila, July 30, 2009

Drug-resistance vs dose No clinical data yet Few reports of drug resistant

August 09 : 2 reports from MMWR in immunocompromised patients [1]

Washington – both leukemia patients received immunosuppresive chemotherapy

July 09 : 3 reports of oseltamivir-resistant [2]

Hong Kong Japan Denmark

Became ill after receiving oseltamivir for chemoprophylaxis

[1] Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in Two Immunosuppressed Patients --- Seattle, Washington, 2009[2] Three Reports of Oseltamivir Resistant Novel Influenza A (H1N1) Viruses, CDC

The benefits of antiviral treatment with oseltamivir are unknown in patients with influenza presenting later than 2 days after illness onset.

Higher dose (hypothesis) : more rapidly decrease viral replication, reduce the duration and severity of illness, reduce complications, and improve outcomes after infection

with either human or avian influenza. Risk of higher dose :

unlikely worsen the disease caused by the influenza infection related to side effects and toxicities of the drug predictable risk - is primarily an increase in nausea and

vomiting High-Dose versus Standard-Dose Oseltamivir for the Treatment of Severe Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial, Feb 27, 2008

Data to inform clinical guidance are needed on viral shedding pharmacokinetics clinical effectiveness of standard versus higher-dose

oseltamivir treatment on optimal duration of therapy for patients, including obese

persons, with severe or progressive H1N1virus infection. Until additional data are available, higher oseltamivir

dosage (150 mg bd for adults) or extending the duration of treatment can be considered for severely ill hospitalized patients with H1N1 if the patient is well-tolerated.

Intensive-Care Patients With Severe Novel Influenza A (H1N1) Virus Infection --- Michigan, June 2009. www.cdc.gov.mmwr

Patient’s outcomes :

Monitoring Parameters

D1 D2 D3 D4 D5

WBC 7.46 6.85 5.93 9.04 9.98

Temp 36 38 34.8

SpO2 80-85%

95% 96%

Lung Clear CXR - New patch – tracheal secretion creamy and yellowish VAP infection

2. MRSA infection

2º Bacterial infection one of the complications for prolonged hospitalization and with ventilator support.

Started dose with 1.5g tds and then optimized to 2g tds plus rifampicin 600mg od

Date Source Pathogen Sensitivity

S :20/7R: 23/7

BAL MRSACandida Albican

Vancomycin

S: 23/7R: 24/7

Trac Asp MRSA Vancomycin

S: 23/7R: 24/7

NSW MRSA Vancomycin

S: 24/7R: 26/7

Trac Asp MRSA Vancomycin

S: 27/7R: 30/7

Trac Asp MRSA Vancomycin

S: 29/7R: 31/7

BAL Acinetobacter MRO

Polymyxin B

Patient’s outcomes :

BAL C+S : MRSAStart IV Vanco 1.5g tds

IV Vanco 2g tds + Rifampicin 600mg od

Oseltamivir 150mg bd

Addition of rifampicin is often used, perhaps owing to better intraosseous and intracellular penetration, despite a lack of evidence for synergy.

Antoine Hamel et al Efficacy of quinupristin/dalfopristin versus vancomycin, alone or in combination with rifampicin, against methicillin-resistant Staphylococcus aureus in a rabbit arthritis model, sept 2007

Vancomycin + Rifampicin

Working??? Or not working??

Is not recommended combination treatment for MRSA if Vancomycin alone is not working

Consider to change to Linezolid

Therapy Subjects Microbiological response within 72 hours

Success rate

Mortality rate

Linezolid +/- carbapenem

n=35 75% 88% 13%

Vancomycin + rifampicin / aminoglycosides

n=35 17% 0% 53%

Jang HC et al, Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Aug 2009.

Conclusion : Linezolid-based salvage therapy effectively eradicated S. aureus from the blood for patients with persistent MRSA bacteremia.

On D15 patient developed red man syndrome due to concentrated dilution

Vancomycin was diluted 2g in150cc which makes the final concentration 13.33 mg/ml

Run for 4 hoursMax conc < 5mg/ml

Fluid restriction, max conc

10mg/ml

Infusion rate 10mg / minDose Infusion time Dilution

500-1000mg 1 hour 100-200ml

1250-2000mg 1.5-2 hour 250-500ml

Complication Managements

Recommended empirical antibiotics for CAP

1. Respiratory Management

Populations Recommended

Healthy A microlide ORDoxycycline

+ comorbidities Fluoroquinolone ORB-lactam + a microlide

Regions with high rate infection (>25%) (without comorbidities)

Fluoroquinolone ORB-lactam + a microlide

Non-ICU Fluoroquinolone ORB-lactam + a microlide

ICU B-lactam + azithromycin / fluoroquinolone

Special concernsPseudomonas

CA-MRSA

B-lactam (Pip-tazo, cefepime, imipenem, meropenem) + ciprofloxacin/ levofloxacin ORAbove B-lactam + aminoglycoside + azithromycin ORAbove B-lactam + aminoglycoside + fluoroquinolone

Vancomycin or linezolid

The Canadian Pandemic Influenza Plan for the Health Sector 2006

1. Respiratory Management (cont) Rapidly progressive respiratory failure is

relatively common preceding ICU admission Monitoring must include respiratory rate and SpO2

Hypoxaemia is also common Standard management by starting ventilation

High PEEP / high frequency oscillation may cause alveolar over-distension or worsen

oxygenation/haemodynamics. refractory hypoxaemia may persist for 48–72 hours

on antivirals before improving. prone positioning and nitric oxide have also been

used the outcomes are unclear

Pandemic H1N1 2009 Clinical Practice Note – Managing critically ill cases. Royal College of Anaesthetists, Health Proctection Agency, The intensice care Society, 28 July 2009

2. Cardiovascular Management Moderate hypotension is relatively common with

predictable increases in cardiac output and decreases in systemic vascular resistance. [1]

Most patients respond to fluid therapy +/- vasopressor therapy

volume expansion should be undertaken with caution as over-hydration seems to worsen outcome and as a result a conservative fluid strategy is recommended.

Patient receiving clopidogrel [2]

Inhibit hydrolysis of oseltamivir by 90% making this drug therapeutically in active.

[1] Pandemic H1N1 2009 Clinical Practice Note – Managing critically ill cases. Royal College of Anaesthetists, Health Proctection Agency, The intensice care Society, 28 July 2009[2] Deshi Shi et al. Anti-Influenza Prodrug Oseltamivir is activcated bye Carboxylesterase Human Carboxylesterase1, and the Activation is Inhibited by Antiplatelet Agent Clopidogrel, Sept 1, 2006

3. Renal Management

Impairment of renal function is common Continuous renal replacement therapy

(CRRT) maybe required in 10-50% Negative fluid balance by either diuretics

or continuous ultraflitration improves oxygenation

Pandemic H1N1 2009 Clinical Practice Note – Managing critically ill cases. Royal College of Anaesthetists, Health Proctection Agency, The intensice care Society, 28 July 2009

The dose for oseltamivir also need to be adjusted according to CrCl. >30ml/min : no dose adjustment – 75mg bd <30ml/min : 75mg once daily

Oseltamivir is not recommended for patients undergoing routine HD and PD with end stage renal disease

Tamiflu® PI, June 4 2009

Thank you~~