MANAGEMENT OF TROPICAL INFECTIONS 2012

Piroon Mootsikapun MD.ID UNIT, Department of  Medicine

Faculty of Medicine, KKU

TROPICAL INFECTIONS

BACTERIA Melioidosis, TB

Typhus, Leptospirosis

Salmonella, Shigella, Cholera

PARASITES Protozoa – E .histolytica, Malaria

Helminthes – Strongyloides, Taenia

FUNGI Crytpococcus, Histoplasma, P. marneffei

Dermatophytes, tenia vercicolor

VIRUS worldwide

MELIOIDOSIS

• Caused by gram negative bacilli • Pseudomonas pseudomallei• Most common in Northeast of Thailand, SEA• Risk factors: DM, Thalassemia, chronic liver ds, chronic renal disease + farmer

• Clinical manifestations; acute or chronic onset• ‐ Disseminated dis, severe sepsis, septic shock• ‐ Localized dis: liver/splenic abscess, lung abscess• ‐ any organ infections, mimic TB

Management of melioidosis

• ANTIBIOTIC THERAPY• ‐ Acute phase – to reduce mortality • ‐Maintenance phase – to prevent relapse• SOURCE CONTROL• ‐ incision and drainage• SUPPORTIVE CARE• ‐ fluid, vasopressors

ACUTE THERAPY OF MELIOIDOSIS

Severe melioidosis – c/s + ve, severe sepsis+shockTreatment with iv ATB initially ‐ Ceftazidime 2 gm iv q 8 hr ‐ Imipenem 1 gm iv q 8 hr‐ Meropenem 1 gm iv q 8 hr‐ Cefoperazone/sulbactam 1/0.5 gm iv  8 hr‐ Amoxyclav 2.4  gm loading ‐> 1.2 gm iv q 4 hrDuration – at least 2 weeks or no fever at least 72 hrs and hemo c/s ‐ NG

Ceftazidime Vs Conventional

CEFTAZIDIME 63%

CONVENTIONAL 26%

White NJ. Lancet 1989;ii:697‐700

Ceftazidime + Cotrimoxazole vs Conventional

CEFTAZIDIME + cotrimoxazole

CONVENTIONAL

Sookpranee M. Antimicro Agent Chemother 1992;36:158‐62

Ceftazidime 100 mg/kg/d (2 gm iv q 8 hr)

Ceftazidime 100 mg/kg/d (2 gm iv q 8 hr)

+ Cotrimoxazole 160/800 mg q 8 hr

VS

Ceftazidime

(n= 46)

Ceftazidime

+TMP/SMX

(n= 41)

Ceftazidime

(n= 72)

Ceftazidime

+TMP/SMX

(n= 82)

Death 15.2% 19.5% 26.4% 20.7%

Treatment

failure

23.9% 22.0% 12.5% 5.1%

Khon kaen Ubol

NS

NS

NS

NS

Ceftazidime vs ceftazidime +cotrimoxazole

Imipenem vs Ceftazidime50 mg/kg/d (1 g iv q 8 hr)

CAZN = 106

IMPN = 108

P

Die 40 (38%) 39 (36%) 0.96

Fever clearance 215 (6‐924) 186 (24‐912) 0.87

Overall success rate

44 (42%) 55 (51%) 0.21

Simpson AH. Clin Infect Dis 1999;29:381-7

Outcome of Patients with Melioidosis Treated with Meropenem

Characteristic N (%) P-valueMeropenem

(N=63)Ceftazidime

(N=154)No. of episodes 68 165Pneumonia 40 (59) 74 (44) 0.06

Bacteremia 51 (75) 65 (39) <0.001Severe sepsis 28 (41) 21 (13) <0.001Received G-CSF 21 (31) 0 <0.001Received physiologic dose

of steroid5 (7) 0 0.002

Overall mortality 12 (19) 28 (18) NSMortality from severe sepsis 7 (25) 16 (76) <0.001Mortality from bacteremia 10 (20) 16 (25) NS

Cheng AC, et al. Antimicrob Agents Chemother 2004; 48: 1763-5.

Coamoxyclav Vs. Ceftazidime160mg/kg/d (2.4g loading, 1.2g q 4hr.)

Suputtamongkol Y. Trans Roy Soc Trop Med Hyg 1991;85:672‐5

CAZN = 106

AMCN = 106

P

Overall mortality 47% 46% 0.40Die in 48 hrs 54% 61% ns

Treatmentfailure

27/75 35/69 0.004

Switch Tx 5% 23%Re‐Tx failure 25% 44%

Cefoperazone/sulbactam vs Ceftazidime (+TMP/SMX)

25mg/kg/d cefoperazone (1g v q 8 hr)

CAZN = 50

CPZ/SULN = 50

P

Die 14% 18% 0.585

Bacterial clearance 48 hr 48 hr 0.791

Fever clearance 11 10 0.857

Septic shock 22% 10% 0.171

Chetchotisakd P. Clin Infect Dis 2001;33:29-34

MAINTENANCE THERAPY OF MELIOIDOSIS

Treatment with iv ATB initially ‐> oral for 20 wks

‐ Cotrimoxazole SS 2‐4 tab x 2 po WEIGHT BASED

‐ Coamoxyclav (625 mg) 2 x3 po

‐ Azithromycin  500 mg/d + ciprofloxacin 500 mg 

BID 

TMP/SMX-Doxy-Chloram

(n= 91)

TMP/SMX-Doxy

(n= 89)

Relapse 19.8% 15.3%

Died 23.9% 22.0%

Switch Rx 52.7% 24.7%

NS

NS

<0.001

TMP/SMX TMP/SMX + DOXY pn = 305 n = 306

C/S proven

Relapse 2.95% 3.59% NS

Overall relapse 5.24% 6.53% NS

Overall mortality 3.9% 3.6% NS

Switch RX 14.4% 21.2% 0.28

GI side effects 11.1% 20.9% 0.001

Rash 11.5% 17.3% 0.04

TMP/SMX alone vs TMP/SMX + DOXY Chetchotisakd P ECCMID 2011

TMP/SMX SS

(80/400 mg)

Weight based

< 40 kg = 2 x 2 po

40-60 kg = 3 x 2 po

> 60 kg = 4 x 2 po

Doxycycline alone Vs. ConventionalDoxy 100mg bid vs Doxy + TMP/SMX + Chloram

Doxycycline Conventional pn=44 n=44

C/S proven

Relapse 26% 2% 0.009

Overall relapse 47% 18% 0.009

Chaowagul W. Clin Infect Dis 1999;29:375-80

Coamoxyclav Vs Conventional30mg/kg/d amoxy (Augmentin 375)

2 tab qid + amoxy500mg qid x 20 wks

Coamoxyclav Conventionaln=49 n=52

C/S proven relapse 16% 4%Fatal relapse 8% 2%Clinical relapse 2% 4%

Rajchanuvong A. Trans Roy Soc Trop Med Hyg 1995;89:546-9

Ciprofloxacin + Azithromycin Vs Conventional2 tab Cipro 250mg bid+2 cap Azithro 250mg od

Cipro Conventional+ Azithro

n=32 n=33 pC/S proven

relapse 22% 3% 0.027Overall relapse 28% 9% 0.048

Chetchotisakd P. Am J Trop Med Hyg 2001;64:24-7.

Comparative in vitro susceptibility of Burkholderia pseudomallei to doripenem, ertapenem, tigecycline and moxifloxacin.

• 100 clinical isolates

• Doripenem MIC90 1.5 μg/mL (range 0.38‐4 μg/mL) 

• Ertapenem, tigecycline and moxifloxacin had limited in 

vitro activity in this study

Int J Antimicrob Agent 2011;37:547-9.

Leptospirosis

• Spirochete

• Leptospira biflexa non-pathogenic

• Leptospira interogans pathogenic

24 serogroups

>200 serovars

Leptospirosis: Transmission

Leptospira in urine of infected animals

water, soil, vegetables

Skin abrasion or wound

mucous membrane

Blood, multi-organ involvement

อาการทางคลินิก• ไม่มีอาการ(symptomatic)

• ไข้เฉียบพลัน(acute uncomplicated febrile illness)

• ไข้ร่วมกับภาวะแทรกซ้อน

• ดซี่าน(jaundice)

• ไตวาย(acute renal failure)

• ดซี่านและไตวาย(Weil’s syndrome)

• เยื่อหุ้มสมองอักเสบ(aseptic meningoencephalitis)

• เลือดออกผิดปรกต(ิhemorrhagic manifestation)

Treatment of leptospirosis

Supportive treatment• IV fluid• Correct complication – dialysis, ventilatorDefinite treatment• Antibiotic• Sensitive – penicillin, amoxycillin,

cefotaxime, ceftriaxone, doxycycline, tetracycline, azithromycin

• Resistant – bactrim, quinolones, ceftazidime

IV Penicillin G

• icteric, late leptospirosis

• 7 days of iv penicillin 6 mu/day

• 75 % Severe : jaundice or serum Cr > 2.0

• Late : > 4 days of symptoms

PGS Placebo

• Fever 4.7 11.5 days

• Cr > 1.5 2.7 8.3 days

Acute febrile illness < 14 days with unidentified sources N = 540

Cefotaxime 1 gm iv q 6 hr PGS 1.5 mu iv q 6 hr

Doxycycline 200 mg iv load,

100 mg iv q 12 hr

Confirmed leptospirosis N = 264 (48.9%)

• Severe leptospirosis:

jaundice or Cr >180

um/L

• Ceftriaxone 1 gm iv OD

vs PGS 1.5 MU iv q 6

hr x 7 days

Panaput T, et al. CID 2003;36:1507-13.

Azithromycin vs doxycycline in LEPTOSPIROSIS

Azithromycin 1 g D1, 500 mg/d D2,3 vs Doxycycline 100 mg BID X 7 d

No difference in

fever clearance

More side effect in

doxy group

Scrub and murine typhus

Scrub typhus

• Zoonosis• Pathogen - Orientia tsutsugamushi• Gram negative coccobacilli• Common in rural Southeast Asia• No cross immunity• Multiple infections can occur

Scrub typhus

• Transmission - mite larva (chigger) bite

• Leptotrombidium mite - transovarian Tx

• Rattus rat- mite reservoir

Reservoir Host :Rattus rattus

Murine typhus

• Common zoonosis in Thailand• Pathogen - Rickettsia typhiTransmission • Rattus rattus, R. norvegicus rat- flea reservoir• rat flea (Xenopsylla cheopis) -transovarian Tx• flea bite -> defecation in wound -> Human• No person to person transmission

Scrub typhus and murine typhus

Clinical symptoms• Fever

• Headache

• Myalgia

• Conjunctival suffusion

• Regional lymphadenopathy

• Rash - maculopapular

• Eschar only in scrub typhus

Scrub typhus and murine typhus

Treatment• Prompt ATB is important!• Short S&S, speed convalescence, reduce

mortality• Doxycycline 100 mg po BID x 7 days• Tetracycline 500 mg po QID x 7 days• Choramphrenicol 50-75 mg/kg/d x 7days• Shorter course associated with recrudesences

3-day Doxycycline vs 7-day Tetracycline

Song JH. CID 1995

Doxycycline100 mg BID X 3 d

n = 66

Tetracycline500 mg QID X 7 d

n = 50

Cure rate 93.9% 100%

Azithromycin500 mg once

(n = 47)

Doxycycline100 mg BID X 7 d

(n = 46)

Outcome 47 (100) 43 (93.5)

Cure 47 (100) 43 (93.5)

Failure 0 3 (6.5)

Relapse 0 0

Time to defervescence (h) 21 (1-120) 29 (4-176)

Kim YS. CID 2003

Rifampicin in scrub typhus

Watt G. Lancet 2000

Doxycycline100 mg BID X 7

d n = 40

Rifampicin600 mg once x 7

d n = 38

Rifampicin900 mg once x 7 d

n = 37

Time to defervescen

ce

52 h 27.5 h 22.5 h

within 48 hr 46 % 77% 79%

Relapse 2 0 0

P =0.02

Azithromycin vs doxycycline in LEPTOSPIROSIS

Azithromycin 1 g D1, 500 mg/d D2,3 vs Doxycycline 100 mg BID X 7 d

No difference in

fever clearance

More side effect in

doxy group

Treatment of murine typhus

No.of Pt.Total = 87

Days of fever(mean + SD)

Doxycycline 29 2.89 + 1.23

Ciprofloxacin 14 4.23 + 2.07

Chloramphrenicol 12 4.00 + 1.07

Doxy + chloram 23 3.44 + 1.37

Doxy + cipro 9 4.00 + 1.93

MALARIA

• Plasmodium falciparum• Plasmodium vivax• Plasmodium malariae• Plasmodium ovale

Treatment of complicated P. falciparum

• WHO 2006• Artesunate 2.4 mg/kg iv

loading dose D1 X 3 dose

(Hr 0, 12, 24)

-> 2.4 mg/kg iv once a day

-> 2.4 mg/kg oral once a day

Total 7 days

Lancet 2005;366:717-25.

การรักษามาลาเรียทีไ่ม่มภีาวะแทรกซ้อน

การรักษามาลาเรียทีไ่ม่มภีาวะแทรกซ้อน

การให้ยาป้องกนัมาลาเรีย (chemprophylaxis)

• ไมแ่นะนํา

• แนะนําให้ใช้เป็นการป้องกนัทางกายภาพ มุ้ง ยากนัยงุ

• ยกเว้นในกรณีที่มีความเสี่ยงสงู อาจเป็นปัยหาในการวินิจฉยั เช่น

ชาวตา่งชาติ

–Doxycycline 100 mg/day ตัง้แตว่นัแรกที่เข้าไปในพืน้ที่และกินทกุกวนัและกินตอ่ไปอีก 4 สปัดาห์หลงัออกจากพืน้ที่

– ตรวจหามาเลเรียเมื่อมีไข้