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colistin,

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(continuous

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(nosocomial

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15

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cefoperazone/sulbactam,
piperacillin/tazobactam,

ciprofloxacin,
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netilmicin

49, 30, 27, 56, 31, 18, 38 57 (7)

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..

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2545-2549

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65

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34

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18

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29

29

36

47

3
254
4
254
5
254
6
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7
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ATM=aztreonem; CZID = ceftazidime; CPZ/SUL=
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cotrimoxazole,
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cefoperazone/sulbactam,

ciprofloxacin

piperacillin,

cefpirome

colistin

..2546 PDR-h MDR-h 46 23
(4)

..

2549-2551

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2 h 



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81

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41

45

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50

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(15)




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nephrotoxicity

30.8)

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chronic

kidney

diseases

hypovolemia (21)

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colistimethate

36

carbapenems,

ampicillin/sulbactam, piperacillin/tazobactam, ceftazidime,

ciprofloxacin cefepime

69

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colistimethate
2.5-5.0 // 3
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(serum

creatinine;
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SCr)

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//

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colistimethate

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70

(22)

colistimethate

h 


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glycylcyclines

tetracyclines

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MDR-h
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2545

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 tigecycline

MDR-h

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2000

54
595

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tigecycline




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carbapenems







imipenem
14

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2-3
8 ( 57) (12)
63

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imipenem-cilastatin 52
( 83) 11 ( 19) (26)

12

MDR-h

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( 75.0) 3 30 (
25.0) (27)

5 

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8-12

(28)

imipenem

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therapy

<
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B2-3? h 



Ampicillin/sulbactam

cefoperazone/sulbactam

h 




sulbactam
h 



MDR-h

XXXX (29)

ampicillin/sulbactam

14

18

64.6)

85.7)

/9

12

ampicillin/sulbactam 24 /8 13

( 62.9) (30)

ampicillin/sulbactam

40

imipenem-resistant h 




6

/3

67.5


ampicillin/sulbactam (29)

cefoperazone/sulbactam
MDR-h

20

cefoperazone/sulbactam 2 /2 8

cefoperazone/sulbactam empirical therapy 14

cefoperazone/sulbactam

13 ( 93) 6 ( 100)

cefoperazone/sulbactam urticaria 1 (
5) (31)

ampicillin/sulbactam

cefoperazone/sulbactam

MDR-h




<
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sulbactam,

doxycycline

polymyxins,
minocycline
MDR-h

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sulbactam

associated

pneumonia;

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VAP)

minocycline

(ventilator

100

12 6 7
( 85.7) (32)

MDR-h

doxycycline

doxycycline

(33)

tetracyclines




tetracyclines







1
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18

33

carbapenem-resistant

h.
15

imipenem 200

sulbactam

120

tobramycin 60 , colistimethate
500000 rifampicin 25

tobramycin,

imipenem,

rifampicin,

sulbactam,

colistinmethatesulphonate,

imipenem tobramycin, imipenem rifampicin,

sulbactam tobramycin, rifampicin tobramycin

11.010.2,

10.73

0.2,

6.61 1.16, 5.620.26, 8.38 1.22, 5.18 0.64, 3.79

0.99,

5.82

1.14,

3.96

0.30

log

cfu/g

imipenem

cfu/g

10.820.33

log

tobramycin,

imipenem rifampicin, sulbactam tobramycin,

rifampicin

tobramycin

(12)

MDR-h

4
22
meropenem 23
sulbactam 23
meropenem sulbactam 23
meropenem 20
8 sulbactam 40 8

meropenem

sulbactam

meropenem sulbactam 9.1,

30.4,

34.8

74.0

(34)


MDR-h

86
20

neutropenia

rifampicin

20 colistin 3
rifampicin colistin
0, 30, 70 70

rifampicin

colistin

colistin

rifampicin
(19)

10

carbapenem-resistant h 



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( 50) 3 ( 30)
(20)









0.

 81,3+0:1B
581,3 :1B
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B0+39 <
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h 



beta-lactams

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MIC 

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4-5

MIC

MIC





meropenem h 


1,748

imipenem

meropenem

T>MIC 40 imipenem 500

6
1

meropenem

500

3 meropenem
1 8
3
h 


73.0, 79.3
86.4
T> MIC 40
meropenem

(35)


 betalactams
24
h 


179
cefepime, ceftazidime
piperacillin/tazobactam
the
steady-state concentration to MIC ratio (Css/MIC)


4 cefepime 3
, cefepime 4 , ceftazidime 2
, ceftazidime 3 ,
piperacillin/tazobactam 6.75
piperacillin/tazobactam 13.5
h 


16, 25, 14, 24, 3 33

h







(36)

beta-lactams




beta-lactams

Css/MIC



1
<










1
2R
R

;R

R

Rungruanghiranya S, Somboonwit C, Kanchanapoom T.

h
  infection in the intensive care unit. J Infect
Dis Antimicrob Agents 2005;22:77-92.
h
  [homepage on the internet]
:
2007. [revise 2007Jun 26; cited 2007 Dec 2]. Available
from: http://th.wikipedia.org/wiki/h
 .R
Smolyakov R, Borer A, Riesenberg K, Schlaeffer F, Alkan
M, Porath A, et al. Nosocomial multidrug-resistant
h
  


bloodstream infection: risk

factors and outcome with ampicillin-sulbactam treatment.

J Hosp Infect 2003;54:32-8.R
R Chaiwarith R, Mahatthanaphak S, Boonchoo M,
Supparatpinyo K, Sirisanthana T. Pandrug-resistant
h
  


at Maharaj Nakorn Chiang Mai
Hospital. J Infect Dis Antimicrob Agents 2005;22:1-8.R
R Keerasuntonpong A, Samakeenich C, Tribuddharat C,
Thamlikitkul V. Epidemiology of h
 



infections in Siriraj Hospital 2002 Siriraj Med
J 2006;58:951-4R
R h
  Pneumonia: A Review. [homepage on the
internet]Hartzell JD, Kim AS, Kortepeter MG, Moran KA.
New York; 2007[cited 2 DEC 07] Available from:
http://www.medscape.com/viewarticle /557767. R
R
. Available at:
http://www.dmsc.moph.go.th. Accessed date: November
28, 2007.R
R Thomson JM , Bonomo RA. The threat of antibiotic
resistance in gram-negative pathogenic bacteria: betalactams in peril. Curr Opin Microbiol 2005;8:518-24R

R wooveren M, Goossens H. Antimicrobial resistance of

h
  spp. in Europe. Clin Microbiol Infect
2004;10:684-704. R
RBaran G, Erbay A, Bodur H, Onguru P, Akinci E, Balaban
N, et al. Risk factors for nosocomial imipenem-resistant
Acinetobacter baumannii infections. Int J Infect Dis
2007[Inpress].
Rh
  baumannii. [homepage on the internet]
Bartlett JG. Baltimore; 2007[cited 2 DEC 07] Available
from: http://www.hopkins-abxguide.orgR
;R Garnacho-Montero J, Ortiz-weyba C, Jime nez FJ,
Almodovar AE, Garca-Garmendia w, Bernabeu-WittelI

M, et al. Treatment of multidrug-resistant h
 




ventilator-associated pneumonia (VAP) with
intravenous
colistin: a comparison with imipenemsusceptible VAP. Clin Infect Dis 2003;36:1111-8.R
R Baraibar J, Correa H , Marisca D, Gallego M, Valle J,
Jordi R. Risk factors for infection by h
 



in intubated patients with nosocomial
pneumonia. Chest 1997;112:1050-4.
RMedina J, Formento C , Pontet J, Curbelo A, Bazet C,
Gerez J, et al. Prospective study of risk factors for
ventilator-associated pneumonia caused by h
 
spp. J Medina 2007 [in press].
RGarmendia J, weyba 1, Montero 1,Jime 1,Paredes
C,Almodo V, et al. Risk Factors for Acinetobacter
baumannii Nosocomial Bacteremia in Critically Ill
Patients: A Cohort Study. Clin Infect Dis 2001;33:939-46.
R Jamulitrat S, Thongpiyapoom S, Suwalak N. An outbreak
of imipenem-resistant Acinetobacter baumannii at
Songklanagarind hospital: the risk factors and patient
prognosis. J Med Assoc Thai 2007; 90:2181-91.
RSurasarang K, Narksawat K, Danchaivijitr S,
Siripanichgon K, Sujirarat D, Rongrungrueng Y, et al.
Risk factors for multidrug-resistant h
 



nosocomial infection. J Med Assoc Thai
2007;90:1633-9.
RMontero A, Ariza J, Corbella X, Domenech A, Cabellos
C, Ayats J, et al. Antibiotic combinations for serious
infections caused by carbapenem-resistant h
 



in a mouse pneumonia model. J Antimicrob
Chemother 2004;54:108591.

RPantopoulou A, Giamarellos EJ, Raftogannis M, Tsaganos

T, Dontas I, Koutoukas P, et al. Colistin offers prolonged
survival in experimental infection by multidrug-resistant

h
  


: the significance of coadministration of rifampicin. Int J Antimicrob Agents
2007;29:51-5.
;RSaballs M, Pujol M, Tubau F, Pea C, Montero A,
Domnguez MA, et al. Rifampicin/imipenem combination
in the treatment of carbapenem-resistant h
 



infections. J Antimicrob Chemother
2006;58(3):697-700.
;RKoomanachai P, Tiengrim S, Kiratisin P, Thamlikitku V.
Efficacy and safety of colistin (colistimethate sodium) for
therapy of infections caused by multidrug-resistant
5 
 

  and h
  


in
Siriraj Hospital, Bangkok, Thailand. Int J Infect Dis
2007;11:402-6.
;;RRosa R, Estens SE, Senz G, Canales HS, Gonzalvo R,
Vidal G, et al. Safety and efficacy of colistin in
h
  spp. and 5 
 spp. infections: a
prospective cohort study. Intensive Care Med [serial
online] 2005 June [cited 2007 Dec 2];1(1):[10 screens].
Available from: URw: http://www.springerlink.com.
;R Tiengrim S, Tribuddharat C, Thamlikitkul V. I 

activity of tigecycline against clinical isolates of
multidrug-resistant h
  


in Siriraj
Hospital, Thailand. J Med Assoc Thai 2006;89:102-5.
;R Jones RN, Ferraro MJ, Reller wB, Schreckenberger PC,
Swenson JM, Sader HS. Multicenter studies of tigecycline
disk diffusion susceptibility results for h
  spp.
J Clin Microbiol 2007;45(1):227-30.
;R Henwood CJ, Gatword T, Warner M, James D, Stockdale
MW, Spence RH, et al. Antibiotic resistance among
clinical isolates of h
  in the UK and
 

evaluation of tigecycline (GAR-936). J Antimicrob
Chemother 2002;49:479-87.

;R Wood

GC, Hanes SD, Croce MA, Fabian TC, Boucher

BA. Comparison of ampicillin-sulbactam and imipenemcilastatin
for the treatment of h
  ventilatorassociated pneumonia. Clin Infect Dis 2002;34:1425-30.
;RChoi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK,
et al. Comparison of efficacy of cefoperazone/sulbactam
and imipenem/cilastatin for treatment of h
 



. Yonsei Med J 2006;47:63-9.
; RAntonio-Velmonte M, Santana RT, Manalastas R, Ang
CF. Open trial of imipenem/cilastatin in the treatment of
nosocomial infections caused by susceptible pathogens.
Phil J Microbiol Infect Dis 1991;20(2):59-63.
;
Rwevin AS, wevy CE, Manrique A, Medeiros E, Costa SF.
Severe nosocomial infections with imipenem-resistant
h
  


treated with
ampicillin/sulbactam. Int J Antimicrob Agents
2003;21:58-62.
RBetrosian AP, Frantzeskaki F, Xanthaki A, Georgiadis G.
High-dose ampicillin/sulbactam as an alternative treatment
of late-onset VAP from multidrug-resistant h
 



. Scand J Infect Dis 2007;39:38-43[abtract].
RBeloborodova NV, Kuznetsova ST, Popov DA,
Bachinskaia EN, Vostrikov TIu. Clinical experience with
the treatment of severe nosocomial infections by inhibitorprotected 3rd generation cephalosporin
cefoperazone/sulbactam. Antibiot Khimioter 2005;50(4):
33-40[abstract].
;RWood GC, Hanes SD, Boucher BA, Croce MA, Fabian
TC. Tetracyclines for treating multidrug-resistant
h
  


ventilator-associated pneumonia.
Intensive Care Med 2003;29(11):2072-6.
RHolloway KP.RPolymyxin B and doxycycline use in
patients with multidrug-resistant h
  


infections in the intensive care unit. Ann Pharmacother

2006;40:193945.
RKo WC, wee HC, Chiang SR, Yan JJ, Wu JJ, wu Cw, et al.
I 
 and
 
 activity of meropenem and sulbactam
against multidrug-resistant h
  



strain. J Antimicrob Chemother 2004;53:393-5.
RFrei CR, Burgess DS. Continuous infustion -lactams for
intensive care unit pulmonary infections. Clin Microbiol
Infect 2005;11:418-21.
Rwomaestro BM, Drusano Gw. Pharmacodynamic evalution
of administration time of meropenem using a monte carlo
simulation. J Antimicrob Chemother 2005;49:461-3.