mdr bacterial infections: our treatment option · mdr bacterial infections: ... ceftriaxone ≥21...

MDR Bacterial Infections:Our Treatment Option

ศ.นพ.อมร ลีลารัศมีภาควิชาอายุรศาสตร

คณะแพทยศาสตรศิริราชพยาบาลมหาวิทยาลัยมหิดล

วันพุธที่ ๑๙ มกราคม พ.ศ. ๒๕๕๔ เวลา ๑๕:๓๐ ถึง ๑๖:๓๐ น.

Definition of MDR, XDR & PDR Bacterial Pathogen

Multiply drug resistant (MDR) bacteria• Resistant to antibiotics of at least three different classes of antimicrobial agents used to treat the infections caused by this bacteria

Extensively drug resistant (XDR) bacteria• Resistant to all antibiotics except only one class of antimicrobial agent used to treat the infections caused by this bacteria (e.g. susceptible to colistin only)

Pan-drug resistant (PDR) bacteria• Resistant to antibiotics of all classes of antimicrobial agents used to treat the infections caused by this bacteria

Optimize Our Antimicrobial Option

Diagnosis of infection (Not just fever/inflammation)• Site of infection• Etiologic bacteria

Empiric antimicrobial selection• Host immunity• Risk factor of acquisition of MDR-bacteria as pathogen • Antimicrobial administration guided by pK/pD criteria

Definite antimicrobial selection• If guided by positive laboratory finding• & Susceptibility testing

10 New Antibiotics by 2020: Why?

March 18, 2010 ( UPDATED March 19, 2010 )

Specially, new antimicrobials needed to treat infections caused by• the so-called "ESKAPE" pathogens• that currently cause the majority of US hospital infections

1. Enterococcus faecium2. Staphylococcus aureus3. Klebsiella pneumoniae4. Acinetobacter baumannii5. Pseudomonas aeruginosa6. Enterobacter species

According to the IDSA, the decreasing investment in antibacterial drug development, coupled with the increase in antimicrobial resistance, represents an "impending disaster.”

IDSA News: 10 New Antibiotics by 2020

1. Enterococcus faecium

2. Staphylococcus aureus

3. Klebsiella pneumoniae

4. Enterobacter species

5. Acinetobacter baumannii

6. Pseudomonas aeruginosa

Vancomycin resistance

ESBL/KPC/NDM-1AmpC production

XDR, PDR bacteria

SME-1, SME-2, SME-3

NARST data

30252422

10

1017

21 2222

21201813151513

107

11

50514849

44

34

262019

42

0

10

2030

40

50

60

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Urine Blood Sputum

ESBL producing E. coli(28 hospitals, 1998-2008)

1316 17 19 21 23

26 2730

05

10152025303540

2000

2001

2002

2003

2004

2005

2006

2007

2008

ESBL by screen testCeftazidimeCeftazidime

2024

29 29 32 3336 38 40

05

101520253035404550

2000

2001

2002

2003

2004

2005

2006

2007

2008

ESBL by screen testCefotaximeCefotaxime

413735

24

9

24211814

9

323430

181514

9768

616359

5248

36

262019

42

010203040506070

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Urine Blood Sputum

sputum sputum

urineurine

bloodblood

%R %R

%R%R

NARST data

40 41 41 41 43 44 45 45 48

01020304050607080

2000

2001

2002

2003

2004

2005

2006

2007

2008

ESBL by screen test

31 33 31 33 36 38 3834

40

01020304050

2000

2001

2002

2003

2004

2005

2006

2007

2008

ESBL by screen test

50.746.1

50.847.6

41.6 44.248.647.4

43.842

32333531

34

3832

32 29 28

43404043

34

4238

3538

30

0

10

20

30

40

50

60

70

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Urine Blood Sputum

4645

60555653

63

48 48 4851 54

42 4446

43394142

62

40

50

4648

4043

47444354

0

10

20

30

40

50

60

70

Urine Blood Sputum

sputum

urine

blood

sputum

urine

blood

ESBL producing K. pneumoniae(28 hospitals, 1998-2008)

CeftazidimeCeftazidime CefotaximeCefotaxime%R %R

Definition & Action of KPC, CRKP and CRECRE = carbapenem-resistant or carbapenemase-producing

EnterobacteriaceaeCRKP = carbapenem-resistant Klebsiella pneumoniaeKPC = Klebsiella pneumoniae carbapenemase

The organism can "Pop From one Strain to Another“The organism produces an enzyme that

• degrades a very powerful antibiotic• confers low-level carbapenem resistance• is on a transferable genetic element• can pop from one strain to another and potentially from

one species to another and [be transmitted] from person to person and patient to patient

KPCs display substantial carbapenem hydrolysis & is only weakly inhibited by clavulanic acid & tazobactamKPCs alone reduce susceptibility to carbapenems, they do not confer resistance To achieve full resistance to carbapenems, impaired outer-membrane permeability is often required

Maria Souli, Irene Galani, Anastasia Antoniadou. An Outbreak of Infection due to b-Lactamase Klebsiella pneumoniae Carbapenemase 2–Producing K. pneumoniae in a Greek University Hospital: Molecular Characterization, Epidemiology, and Outcomes. Clinical Infectious Diseases 2010; 50:364–73.

KPC-2–p K. pneumoniae in Greek Hospitals

blaNDM-1 positive Enterobacteria from Chennai 2009

www.thelancet.com/infection Published online August 11, 2010 DOI:10.1016/S1473-3099(10)70143-2

At Chennai, 2009; Enterobacteriaceae analyzed = 3,521• 4% found resistant to carbapenem (n=141)

• E. coli 75• Klebsiella spp. 60• other Enterobacteriaceae 6

• Of these 141 carbapenem-resistant Enterobacteriaceae, • 1.25 % were blaNDM-1 positive 44 (n=3,521)

• E. coli 19• K. pneumoniae 14• Enterobacter cloacae 7• Proteus spp. 2• Citrobacter freundii 1 • Klebsiella oxytoca 1

www.thelancet.com/infection Published online August 11, 2010 DOI:10.1016/S1473-3099(10)70143-2

Antimicrobial Susceptibility for NDM-1–p Enterobacteria


January 2007 - December 2008, 50 patients whom KPC-2–producing K. pneumoniae were isolated

• Admitted in the ICU (n=34)• Colonized (n=32) • Infected ( n=18)

38 patients (76%) were identified after August 2008 • Bacteremia 14• Surgical site infections 2• Lower respiratory tract infections 2 (1 bacteremic)• UTI 1

Most patients received a colistin-containing combination Rx. Crude mortality Attributable mortality

• Among ICU patients 58.8% 22.2%• Among non-ICU patients 37.5% 33.3%

screening test for carbapenemase-

producing bacteria.

KPC screening

A susceptible isolate of E. coli

DH10B is cultured on a

Mueller-Hinton plate to create a

lawn of confluent growth

imipenem disk

Wild-type K. pneumoniaeisolate

KPC-p K. pneumoniaeisolate. (Greece)

KPC-p K. pneumoniaeisolate. (USA)

Carbapenem-resistant K. pneumoniae due to - porin-loss - CTX-M-15 ESBL production- cephalosporinase hyperproduction

Carbapenemase GES-5-p E. cloacae

F = E coli DH10B as lawn bacteria

Modified Hodge Test

Cephalosporin & Aztreonam Breakpoints for Enterobacteriaceae by Year 2009 & 2010

MIC breakpoints (μg/ml):

Agent Old (M100-S19) Revised (M100-S20)Susc Int Res Susc Int Res

Cefazolin ≤8 16 ≥32 ≤1 2 ≥4Cefotaxime ≤8 16-32 ≥64 ≤1 2 ≥4Ceftizoxime ≤8 16-32 ≥64 ≤1 2 ≥4Ceftriaxone ≤8 16-32 ≥64 ≤1 2 ≥4 Ceftazidime ≤8 16 ≥32 ≤4 8 ≥16Aztreonam ≤8 16 ≥32 ≤4 8 ≥16

CLSI M100-S20 (2010) Cephalosporin and Aztreonam Breakpoint Revisions. Fact Sheet

Year 2010

Disk diffusion breakpoints (mm):

Agent Old (M100-S19) Revised (M100-S20)Susc Int Res Susc Int Res

Cefazolin ≥18 15-17 ≤14 NA NA NACefotaxime ≥23 15-22 ≤14 ≥26 23-25 ≤22Ceftizoxime ≥20 15-19 ≤14 ≥25 22-24 ≤21Ceftriaxone ≥21 14-20 ≤13 ≥23 20-22 ≤19Ceftazidime ≥18 15-17 ≤14 ≥21 18-20 ≤17 Aztreonam ≥22 16-21 ≤15 ≥21 18-20 ≤17

NA = not availableCLSI M100-S20 (2010) Cephalosporin and Aztreonam Breakpoint Revisions. Fact Sheet

Year 2010

Cephalosporin & Aztreonam Breakpoints for Enterobacteriaceae by Year 2009 & 2010

MIC distributions of NDM-1 Enterobacteriaamong Aminoglycoside including ACHN-490

NDM-1 (17) MIC (mg/L)(no. isolates) ≤0.5 1 2 4 8 16 32 64 128 ≥256

ACHN-490 1 1 5 10Amikacin 1 16Gentamicin 1 16Tobramycin 1 16Isepamicin 1 16Arbekacin 1 16Dibekacin 1 16Apramycin 9 8

Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 2011;66:48–53.

= resistant breakpoint by EUCAST

MIC distributions of ACHN-490 among Carbapenem-resistant Enterobacteriaceae

Enzymes produced MIC (mg/L)(no. isolates) ≤0.12 0.25 0.5 1 2 4 ≥64

ACHN-490 (neoglycoside)• KPC (12) 1 5 6• SME-1 1• IMP (13) 1 9 3• NDM-1 (17) 1 16*• VIM (5) 3 1 1• OXA-48 (19) 1 17 1• ESBL+impermeability (10) 1 8 1• AmpC+impermeability (5) 3 2

Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 2011;66:48–53.

Drug of Choice for ESBL-producing Enterobacteria

Carbapenem• Ertapenem• Imipenem• Meropenem• Doripenem• Biapenem

Community-acquired infection• cSSSI• Diabetic infected ulcer• cIAI• Pyelonephritis• CAP due to Klebsiella spp.• Primary bacteremia

Antimicrobial Selection according to Risk of Infection due to ESBL-producing Enterobacteria

Empiric antibiotics by De-escalation Method

Carbapenem:ertapenemimipenemmeropenemdoripenem

CeftriaxoneCeftazidimeCefepime Piperacillin-tazo

Netilmicin/amikacin/levofloxacin/ ciprofloxacin/ Fosfomycin

+

No/Low risk of ESBL Mod./High risk of ESBL

Likelihood of ESBL-p Enterobacteria

Cef: ceftriaxone, cefepime No risk or 0ceftazidime

Cef + fosfomycin + , ++or + amikacin + ciprofloxacin

Ertapenem ± fosfomycin +, ++ ++++

Imipenem, meropenem +++, ++++ & plus Pseudomonas sp., Acinetobacter sp.

Antimicrobial Option by Risk Level of ESBL-p

Multidrug-resistant Gram-negative Infections: What Are the Treatment Options?

Drugs. 2009 Oct 1;69(14):1879-901. Multidrug-resistant Gram-negative infections: what are the treatment options? Giamarellou H, Poulakou G.

AbstractThe emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a challenge in the treatment of nosocomial infections.

While the pharmaceutical pipeline is waning, • Two revived old antibacterials (colistin and fosfomycin)• A newer one (tigecycline)• An 'improved' member of an existing class (doripenem)

are the only therapeutic options left.

In vitro activities of fosfomycin and carbapenemcombinations against carbapenem non-susceptible

Escherichia coli and Klebsiella pneumoniae

Netikul T, et al. In vitro activities of fosfomycin and carbapenem combinations against carbapenem nonsusceptibleEscherichia coli and Klebsiella pneumoniae. Int J Antimicrob Agents (2010), doi:10.1016/j.ijantimicag.2010.01.021

Despite no synergy, MICs of these carbapenems were likely decreased when + fosfomycin. (data not shown in the article)

MICs (fold decreased when + fosfomycin)• Ertapenem 2.59 • Imipenem 1.93 • Meropenem 1.79 • Doripenem 1.73

MICs of fosfomycin were decreased ca. 1.89-fold

Only ertapenem MICs were significant decreased by Statistics

Effectiveness & Safety of Fosfomycin Rx in ICU patients for CRKP Infections

Daily dosage of intravenous fosfomycin• Administered via a central venous catheter

1. In patients with normal renal function • daily dose 4 gm q 6 hours

2. In elderly patients (>70 years)3. In patients with renal failure

• daily dose 2 gm q 6 hours• In combination with other antibiotics

Source of fosfomycin = All patients received Infectofos fl 2 g containing 2.64 g fosfomycin-sodium (InfectopharmArzneimittel und Consilium GmgH, Heppenheim, Germany)

Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: A prospective evaluation. Clinical Microbiology and Infection 2010;16:184-6.

0.5, 1.0, 2.0-gm Human Simulated Prolonged Infusion of Doripenem

Previous animal studies have shown efficacy of a 500-mg dose of doripenem given as a 4-h infusion against P. aeruginosa with MICs of <4 g/ml.

The purpose of this study is to evaluate the efficacy of 1- and 2-g-dose prolonged infusions of doripenem against a wide range of P. aeruginosa isolates in the neutropenic murine thigh model.

Eighteen clinical P. aeruginosa isolates (MIC range, 2 to 32 g/ml) were used; 15 of these were multidrug resistant.

Crandon JL et al. AAC 2009;53:4352-6.

Comparative efficacies of 1-g (black bars) and 2-g (white bars) doses of doripenem against a distribution of P. aeruginosa isolates, presented as means ± the standard deviation. Asterisks indicate statistical significance (P 0.05). #, bacterial densities were at the lower limit of detection.

Crandon JL et al. AAC 2009;53:4352-6.

FIC Index & InterpretationInterpretation 3 combo 2 combo

Synergy (S) < 1.0 ≤ 0.5

Partial synergy (PS) - > 0.5 to < 1

Additive (Ad) 1.0 1

Indifference (I) - >1 to < 4

Antagonist (An) > 1 ≥ 4

2 combo = meropenem + colistin3 combo = meropenem + colistin + fosfomycin (87.3 mg/L)

MICs of 5 MDR P. aeruginosa Isolates

Fosfo = fosfomycin; Mero = meropenem;

Strain Fosfomycin Meropenem Colistin

1 > 256 16 2

2 256 16 2

3 > 256 16 2

4 > 256 32 2

5 > 256 32 2

FIC Index of MDR P. aeruginosaStrain no. 3 combo 2 combo

1 0.0456 (S) 1.0 (A)

2 0.0675 (S) 0.503 (PS)

3 0.0756 (S) 1.03 (I)

4 0.0378 (S) 0.75 (PS)

5 0.2578 (S) 0.75 (PS)

2 combo = meropenem + colistin3 combo = meropenem + colistin + fosfomycin (87.3 mg/L)

Pintip Pongpech, Suparak Amornnopparattanakul, Sakulthip Panapakdee, Siriporn Fungwithaya, Penphun Nannha, Chertsak Dhiraputra, Amorn Leelarasamee. Antibacterial activity of carbapenem-based combinations against multidrug-resistant Acinetobacter baumannii. J Med Assoc Thai 2010;93:161-71.

Normal renal function

Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother 2009;53:3430–6

Population Pharmacokinetic Analysis of CMS & Colistin after IV Administration in Critically Ill

Patients

Current dosing regimen of CMS in a typical patient1. 3 MU (240 mg of CMS)2. A 15-min infusion 3. every 8 hours [q8h])

Alternative dosing regimens with 1. Loading doses of

1.1 9 MU CMS (720 mg. of CMS) 1.2 or 12 MU CMS (960 mg of CMS)

2. Duration of infusions 2.1 15 min2.2 or 2 h

3. A maintenance dose of • 4.5 MU (360 mg) CMS • Every 12 h (q12h)

Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother 2009;53:3430–6

Model-predicted CMS & Colistin Concentrations in Critically Ill Patients

Attenuation of Colistin Bactericidal Activity by High Inoculum of Pseudomonas aeruginosa

In vitro time-kill experiments using 8-64 x the MIC of colistinP. aeruginosa PAO1 at initial CFUo of 106, 108, and 109 CFU/ml.

Against PAO Killing rate of the susceptible population- at the 109 CFUo 23-fold slower- at the 108 CFUo 6-fold slower - at the 106 CFUo 1-fold (for comparison)

Bacteria were assumed to release signal molecules stimulating a phenotypic change that inhibits killing.

The extent and rate of killing of P. aeruginosa were markedly decreased at high CFUo compared to those at low CFUo.

Bulitta JB, Yang JC, Yohonn L, Ly NS, Brown SV, D'Hondt RE, et al. Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model. Antimicrob Agents Chemother 2010;54:2051-62.

Pharmacokinetic/Pharmacodynamic Determinant of ColistinActivity against Pseudomonas aeruginosa

Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic/pharmacodynamic(PK/PD) index best correlating with efficacy of colistin remains undefined.

The PK/PD of colistin was studied in neutropenic mouse thigh and lung infection models against three strains of Pseudomonas aeruginosa.

The PK/PD index that correlated best with its efficacy was fAUC/MIC in both thigh (R2 = 87%) and lung (R2 = 89%) infection models.

Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, Nation RL. Elucidation of pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother 2010;54(3):1117-24

Pharmacokinetic/Pharmacodynamic Determinant of ColistinActivity against Pseudomonas aeruginosa

The fAUC/MIC targets Required to achieve kill against the three strains

1-log kill 2-log kill Neutropenic rat model- The thigh infection model 15.6 - 22.8 27.6 - 36.1 - The lung infection model 12.2 - 16.7 36.9 - 45.9

This in vivo study indicated the importance of achieving adequate time-averaged exposure to colistin

The results will facilitate efforts to define more rational design of dosage regimens in humans.

Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, Nation RL. Elucidation of pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother 2010;54(3):1117-24

Extended-spectrum β-lactamase–producing Enterobacteriaceae• Meropenem 1–2 g IV q 8 hr• Imipenem 500 mg IV q 6 h• Doripenem 500 mg IV q 8 hr or as a 1-hr or 4-hr infusion

Carbapenemase-producing Enterobacteriaceae• Colistin 2.5-5.0 mg of colistin base/kg of BW/day q 6-12 h• (equivalent to 6.67–13.3 mg of colistimethate sodium/kg /day); • Tigecycline 100 mg IV as a loading dose, then 50 mg IV q 12 h

Carbapenem-resistant P. aeruginosa• Colistin as for carbapenemase-producing EnterobacteriaceaePossible alternatives • Extended infusion of carbapenem

Recommended Definite Therapy for Serious Infections Caused by Drug-resistant Gram-negative Bacteria

Peleg AY, Hooper DC. Hospital-Acquired Infections Due to Gram-Negative Bacteria . N Engl J Med 2010;362:1804-13.

Carbapenem-resistant A. baumannii• Colistin as for carbapenemase-producing Enterobacteriaceae• Ampicillin-sulbactam, up to 6 g of sulbactam IV per day• Tigecycline 100-mg IV loading dose, then 50 mg IV q 12 h‡

Possible alternatives Extended infusion of carbapenem• Meropenem 1-2 g IV infusion over a 3-hr period every 8 hr• Doripenem, 500 mg- 1 g IV infusion over a 4-hr period q 8 hr• Imipenem 1 g IV infusion over a 3-hr period q 8 hCombination therapy with a nontraditional antibiotic§, including• Rifampin• Minocycline

Recommended Definite Therapy for Serious Infections Caused by Drug-resistant Gram-negative Bacteria

Peleg AY, Hooper DC. Hospital-Acquired Infections Due to Gram-Negative Bacteria . N Engl J Med 2010;362:1804-13.

‡ This regimen would not be recommended for bloodstream infection, owing to low serum drug levels.

§ Use of these antibiotics is based on in vitro data and animal models and on clinical case reports and studies of small series of patients.

• Azithromycin• Doxycycline

Therapeutic Efficacy of Vancomycin in Relation to MIC or Bactericidal Activity

Vancomycin Therapy in MRSA Bacteremia

100

0

60

80

40

20

56%

10%

≤ 0.5 1.0-2.0Vancomycin (MIC, ug/ml)

n = 9

n =21

Success rate % Success rate %

Log10 of Killing (CFU/ml)<4.71 4.71-6.26 >6.26

0%

100

0

60

80

40

2023%

50%

n = 8n = 13

n = 9

Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia J Clin Microbiol 2004;42:2398-402.

P value < 0.05 P value < 0.05

Exposure of MRSA 107 to 108 CFU/ml to vancomycin (16 µg/ml) for 72 hr.

Breakpoint Criteria of Vancomycin for S. aureus

MIC Result

CLSI prior to CLSI after EUCAST 2006 (g/ml) 2006 (g/ml) (g/ml)

Susceptible (VSSA) ≤4 ≤2 ≤2

Intermediate (VISA) 8-16 4-8 -

Resistant (VRSA) ≥32 ≥16 ≤4

The breakpoints for other infectious agent remain unchanged.

For vancomycin susceptibility testing: needs MIC

Comparison of simulated target attainment profiles for dalbavancin (AUC14 days/MIC > 1000) and vancomycin (AUC/ MIC > 300) for Staphylococcus aureus

James A. Dowell, et al. Pharmacokinetic-Pharmacodynamic Modeling of Dalbavancin, a Novel Glycopeptide Antibiotic. J Clin Pharmacol 2008;48:1063-8.

These simulations assumed a vancomycin clearance of 4.7 L/h, with a coefficient of variation of 43% and a dosage regimen of 1 g every 12 hours. The pharmacodynamic target was a 24-hour AUC/MIC ratio of 300 because target AUC/MIC ratios of 200 to 400 have been reported in studies with vancomycin.

Staphylococcus aureus

One Gram bid: Enough for Vancomycin? Conclusions: 1. Parameter best predicts vancomycin efficacy is AUC/MIC

(= 400 mg.h/L is adequate for MRSA MIC ≤ 0.5 mg/L)2. No relationship between Time>MIC and response3. Trough serum conc. can be used as surrogate measure of AUC

(optimal trough level 15-20 mg/L)4. 1 gm q 12 h is suboptimal for 80 kg patient with normal renal

function (AUC/MIC = 250 mg.h/L) for MRSA MIC > 1 mg/L5. A daily dose of 3-4 gm. required for 100 & 90% target attainment

(AUC/MIC = 400) for a MICS. aureus = 0.5 & 1 mg/L respectively6. Mean trough level = 20 mg/L AUC/MIC = 418 mg.h/L7. If MICS. aureus = 2 mg/L, probability of target attainment = 0

Rybak M, Lomaestro B, Rotschafer JC, Moellering R, Craig W, Billeter M, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66(1):82-98.

การใชยา vancomycin ในการรักษาโรคติดเช้ือ MRSAการใชยาบางขนานมีความจําเพาะกับเช้ือกอโรค ขนาดยาที่ใชตองเหมาะสมกับสภาพของโรคติดเช้ือและมีการตรวจหาคา MIC และระดับยาดวย เชน การใชยา vancomycin ในการรักษาโรคติดเช้ือ MRSA

• ขนาดของยา vancomycin ในผูใหญคือ 15–20 มก./กก. /ครั้ง • ใหใชน้ําหนักตัวที่ช่ังได (actual body weight) • ใหยาทุก 8–12 ช่ัวโมง • ใหไมเกินครั้งละ 2 กรัมในผูปวยที่มีหนาที่ไตปกติ • ในรายที่ปวยรุนแรง เชน sepsis, meningitis, pneumonia, infective endocarditis แนะนํา ให loading dose ขนาด 25–30 มก./กก. (actual body weight) ในการใหยาครั้งแรก• ถาขนาดยามากกวา 1 กรัมตอครั้ง อาจจะหยดยานาน 1-2 ช่ัวโมง และฉีดยา antihistamine กอนจะให loading dose ได

Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the Treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:1–38

การใชยา vancomycin ในการรักษาโรคติดเช้ือ MRSAการใชยาบางขนานมีความจําเพาะกับเช้ือกอโรค ขนาดยาที่ใชตองเหมาะสมกับสภาพของโรคติดเช้ือและมีการตรวจหาคา MIC และระดับยาดวย เชน การใชยา vancomycin ในการรักษาโรคติดเช้ือ MRSA

• ควรวัดระดับยาในระยะ trough concentration ในระยะ steady state เชน วัดระดับยากอน จะใหยาครั้งที่ 4 หรือ 5 เปนตน • ระดับยาในระยะ trough concentration ควรอยูที่ 15-20 ไมโครกรัมตอ มล. ในการรักษา โรคติดเช้ือ MRSA ที่รุนแรง เชน sepsis, infective endocarditis, osteomyelitis, meningitis,

pneumonia, necrotizing fasciitis • สวนในรายที่ไมอวน และหนาที่ไตปกติ และติดเช้ือไมรุนแรงหรือไมถึงกับ sepsis ใชยา

vancomycin ขนาด 1 กรัม ทุก 12 ช่ัวโมงไดและไมตองวัดหา trough concentration• ไมแนะนําใหหยดยาขนานนี้แบบตอเนื่องนาน 24 ช่ัวโมง


ความไวของเช้ือ MRSA กับยา vancomycinการเลือกใชยา vancomycin ตามความไวของเช้ือ MRSA ตอยา vancomycin

• ถาเช้ือ MRSA มีคา MIC ตอยา vancomycin เทากับ 2 ไมโครกรัมตอ มล. หรือ นอยกวา หากผูปวยตอบสนองตอการรักษาดวย empiric vancomycin ก็ใหยา vancomycin ในขนาด เดิมตอไปและติดตามผลการรักษาตอไปอยางใกลชิด • ถาลักษณะคลินิกไมตอบสนองตอยาแมวา ทําการระบายหนองหรือตัดเนื้อตายทิ้งแลว ควรใชยาขนานอื่นแทน vancomycin เลยแมวาเช้ือจะมีคา MIC ตอ vancomycin ในระดับ ที่ต่ํากวา 2 ไมโครกรัมตอ มล. ก็ตาม • ถาเช้ือ MRSA มีคา MIC ตอยา vancomycin มากกวา 2 ไมโครกรัมตอ มล. (เชน เช้ือ VISA หรือ VRSA) ใหเลือกใชยาขนานอื่นแทน vancomycin


ยาขนานอื่น ถาเช้ือ MRSA ไมไวตอยา vancomycinถาโรคติดเช้ือ MRSA ไมตอบสนองตอยา vancomycin และยังคงมี MRSA bacteremiaแนะนําใหกําจัดแหลงติดเช้ือหรือระบายหนองออก ถอดเอาส่ิงแปลกปลอมหรือสายสวนที่ติดเช้ือออก แลวพิจารณาใหยาดังตอไปนี้

• ยา daptomycin ขนาด 10 มก./กก./วัน + ยาขนานใดขนานหนึ่ง ดังตอไปนี้• ยา gentamicin ขนาด 1 มก./กก. หยดเขาทางหลอดเลือดดําทุก 8 ช่ัวโมง• ยา rifampin ขนาด 600 มก. กินหรือฉีด วันละครั้ง หรือขนาด 300-450 มก. กินหรือฉีด วันละ 2 ครั้ง• ยา linezolid ขนาด 600 มก. กินหรือหยดเขาหลอดเลือดดํา 30-60 นาที วันละ 2 ครั้ง• ยา TMP-SMX ขนาด 5 มก./กก. หยดเขาหลอดเลือดดําวันละ 2 ครั้ง• อาจจะพิจารณาใชยากลุม beta-lactam รวมดวย


ยาขนานอื่น ถาเช้ือ MRSA ไมไวตอยา vancomycinถาโรคติดเช้ือ MRSA ไมตอบสนองตอยา vancomycin และยังคงมี MRSA bacteremiaแนะนําใหกําจัดแหลงติดเช้ือหรือระบายหนองออก ถอดเอาส่ิงแปลกปลอมหรือสายสวนที่ติดเช้ือออก แลวพิจารณาใหยาดังตอไปนี้หากเช้ือไมไวตอ vancomycin และ daptomycin ใหเลือกใชยาขนานใดขนานหนึ่ง หรือใชยารวมกันดังนี้• ยา quinupristin/dalfopristin ขนาด 7.5 มก./กก/ครั้ง หยดเขาหลอดเลือดดําทุก 8 ช่ัวโมง• ยา TMP-SMX ขนาด 5 มก./กก./ครั้ง หยดเขาหลอดเลือดดําวันละ 2 ครั้ง• ยา linezolid ขนาด 600 มก. กินหรือหยดเขาหลอดเลือดดํานาน 30-60 นาที วันละ 2 ครั้ง• ยา telavancin ขนาด 10 มก./กก./ครั้งหยดเขาหลอดเลือดดํา วันละ 1 ครั้ง

ในประสบการณของผูเขียนเอง ในผูใหญอาจจะเลือกใชยา fosfomycin ขนาด 2-4 กรัมหยดเขาหลอดเลือดดํานาน 60 นาที ทุก 8 ชั่วโมง นาจะไดผลดี อาจจะใหรวมกับยาขนานอ่ืนๆ ก็ได


Early Combination Rx vs. Monotherapyin Septic Shock

Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D, Laporta D, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 2010;38:1773-85.

Septic shock in the ICU represents • The major cause of infection-associated mortality

The possibility that combination antibiotic therapy of bacterial septic shock improves outcome

• Is controversial

Current guidelines do NOT recommend combination therapy • Except for the express purpose of broadening coverage

when resistant pathogens are a concern.

In patients with bacterial septic shock, to evaluate the benefit of • Early combination therapy• Comprising at least two antibiotics • of different mechanisms • with in vitro activity for the isolated pathogen

DESIGNRetrospective, propensity matched, multicenter, cohort study.

ICUs of 28 academic and community hospitals in three countries between 1996 and 2007.



A total of 4,662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated.

The primary outcome of study was 28-day mortality.

Using a Cox proportional hazards model, Combination Rx MonoRx

• 28-day mortality 355/1223 (29%) 444/1223 (36.3%) • Hazard ratio 0.77 • 95% CI 0.67-0.88 (p = 0.0002)



The beneficial impact of combination therapy applied to • Gram-positive infection• Gram-negative infection • BUT was restricted to patients treated with

• Beta-lactams in combination with (either one) 1. Aminoglycosides2. Fluoroquinolones3. Macrolides/clindamycin



Combination Rx MonoRx• ICU admission 352/1,223 (28.8%) 437/1,223 (35.7%) • Odds ratio 0.75• 95% CI 0.63-0.92 (p = .0006)

• Hospital mortality 457/1,223 (37.4%) 584/1,223 (47.8%) • Odds ratio 0.69• 95% CI 0.59-0.81 (p < .0001)



Combination Rx MonoRxVentilator-free day

• Median 17 10• Interquartile range 0-26 0-25 (p = .008)

Pressor/inotrope-free day • Median 25 23• Interquartile range 0-28 0-28 (p = .007)

up to 30 days

Early combination antibiotic therapy is associated with decreased mortality in septic shock

Prospective randomized trials are needed



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