Antimicrobial Agents and Impact of Antimicrobial Resistance

Antimicrobial Agents and Impact of Antimicrobial Resistance

Wen-Chien KoDivision of Infectious Disease

National Cheng Kung University Hospital

Middle-Age MaleNo specific underlying diseaseOccupation: professional soldierLocal symptom over knee areaClinical Diagnosis: SSTI

Day 0

Pus culture: MRSA

Day 7

Case: Present Illness

• 81 year-old women presented with pneumonia due to multidrug resistance A. baumannii with respiratory s/p tracheostomy, and was referred for salvage antimicrobial therapy

• VRE urinary tract colonization• Past History:

– parkinsonism– vascular dementia– bed ridden with grade II bed sore– diabetes mellitus with anti-hypoglycemic agents

Physical Examination• Consciousness: alert, E4VTM4• Vital sign

– TPR: 37.8/110/23– BP: 112/70 mmHg

• No pale face and conjunctive; no icteric sclera• No jugular vein engorgement• Breathing sound: bilateral coarse crackle• Heart: regular heart beats without heart murmur• Abdomen: soft; liver/spleen: impalpable • Extremities: no pitting edema, free moveable

Laboratory StudyCBC/DC

< 一般血液檢查報告 > 採檢 :96/04/18 全血 8221K94683 -------- ------------- ------------- -------- -------------

-------------WBC 11.6 xK/cmm 3.2-9.2 | RBC 4.23 xM/cmm 3.73-4.93 Hb 10.6 g/dl 11.6-14.8 | Hct 39.7 % 33.8-43.4 MCV 93.8 fl 82.7-95.5 | MCH 32.3 pg 28.2-33 MCHC 34.4 g/dl 33.2-35.2 | RDW H 15.2 % 11.6-13.6 Pl 161 xK/cmm 151-366 | Blast - % Pro - % | Myelo - % Meta - % | Band - % Seg H 77.7 % 43-64 | Eos 2.6 % 0-6 Baso 0.8 % 0-1 | Mono 7.4 % 3-9 Lymph L 21.5 % 27-47 | Aty-lym - % NRBC - /100WBCS | Remarks -

Laboratory StudyBiochemistry Test and Arterial Blood Gas Analysis

< 緊急生化檢驗報告 > 採檢 :96/04/18 血漿 8261A88052 -------- ------------- ------------- -------- ------------- ---------CREA 0.4 mg/dL 0.6-1.2 | AST H 86 U/L 0-39 BUN 13 mg/dL 7-21 | NA L 122 mmol/L 135-148 K 3.6 mmol/L 3.5-5 | ALT 37 U/L 0-54 CRP H 141 mg/L 0-8 | GLU.P.C. 125 mg/dL 80-140OSMO 260 mOsm/kg 280-295 < 緊急生化檢驗報告 > 採檢 :96/04/18 T-Mask (4 l/min) -------- ------------- ------------- -------- -------------

-------------PH 7.41 7.35-7.45 | PCO2 41 mmHg 35-45 PO2 71 mmHg 75-100 | HCO3- 26.6 mmol/L 21-28 TCO2 27.8 mmol/L | BEb 2.4 mmol/L BEecf 1.8 mmol/L | SBC 26.7 mmol/L %sO2c 94.2 % |

X-Ray and Microbiological Report

<細菌檢查報告> 檢查:96/04/18 AEROBIC CULTURE REPORT

菌 名 1.Acinetobacter baumannii

S:Susceptible R:Resistant I:Intermediate M:Moderate

1 Ampi/sulbactam R Piperacillin R Pip/Tazobactam R Gentamicin R Ciprofloxacin R Imipenem R Ceftazidime R Tica/clavulnic R Co-Trimoxazole R Meropenem R Cefepime R Cefpirome R

960418

Microbiological Study

< 細菌檢查報告 > 檢查 :96/04/18 全血 --------------------------------------------------------------- BLOOD CULTURE REPORT No aerobic and No anaerobic pathogens were isolated after 5 days incubation < 細菌檢查報告 > 檢查 :96/04/18 全血 --------------------------------------------------------------- BLOOD CULTURE REPORT No aerobic and No anaerobic pathogens were isolated after 5 days incubation

< 細菌檢查報告 > 檢查日： 960424 第 1 次報告------------------------------------------------------- LEGIONELLA ANTIGEN REPORT Legionella antigen (urine): Negative

AEROBIC CULTURE REPORT

< 細菌檢查報告 > 檢查 :96/04/18

菌 名

1. Acinetobacter baumannii

S:Susceptible R:Resistant I:Intermediate

(MIC單位 : μg/ml)

Ampicillin/sulbactum R >32 Impenem R >32 Cefepime R >32 Colistin S <2 Tigecycline S 2

X-ray Serial Following

34.535

35.536

36.537

37.538

38.539

39.5

1 6 11 16 21 26

Tem

p

05

1015

2025

3035

4045

Res

p. rat

e

BT RR

tigecycline

imipenem

colistin inhalation

vancomycin

Candidemia with profound septic shock

Neutropenic feverMRSA, MDRAb pn

eumonia;CoNS bacteremia

B. cepacia bacteremia

Final Diagnosis

• Candidemia• Septic shock, complicated with multiple organs failure• Pneumonia with respiratory failure s/p tracheostomy/ MDR

Ab and MRSA• Parkinsonism• Diabetes mellitus• Related adrenal insufficiency AAD

Alexander FlemingAlexander Fleming

1881-19551881-1955

August 14, 1944 Life

The Ideal Drug1. Selective toxicity: against target pathogen but not against host

– LD50 (high) vs. MIC and/or MBC (low)

2. Bactericidal vs. bacteriostatic3. Favorable pharmacokinetics: reach target site in body with

effective concentration

4. Spectrum of activity: broad vs. narrow

5. Lack of “side effects” – Therapeutic index: effective to toxic dose ratio

6. Little resistance development

Antibiotic Agents Approved, 1993-2004

ERA OF ANTIMICROBIALS 1930s Sulfonamides

1940s Penicillin G; Streptomycin

1950s Erythromycin; Tetracyclines

Early 1960s Methicillin; Ampicillin

Late 1960s Cephalosporins; Aminoglycosides

1970s More penicillins & Cephalosporins

1980s Newer -lactams; Quinolones

1990s-present Newer macrolides, quinolones,

Drugs for resistant organisms:

linezolid, daptomycin, tigecycline

Development of New AntibioticsDevelopment of New Antibiotics

Antibiotic Mechanisms of Action

Transcription

Translation

Translation

Alteration of Cell Membrane Polymyxins Bacitracin Neomycin

Teichoicacid

From: Goodman and Gilman, 9th ed.

Stages of Peptidoglycan Synthesis & Inhibitors

Stage Process Site Inhibitor

1 Precursor formation

Inside cell Cycloserine

2 Transport & Peptidoglycan formation

Cell membrane Bacitracin

3 Crosslinking peptidoglycan chains

Outside cell Penicillins Cephalosporins Vancomycin

Cycloserine: Analog of alanine

CytoplasmCytoplasm

sugarsugar

aminoaminoacidacid

XX

XXXX

XX

Bacitracin

Cell membrane

BatoprenolBatoprenol

PP

PP

Vancomycin

Cell wallCell wall

Teichoicacid

From: Goodman and Gilman, 9th ed.

CrosslinksCrosslinks

Antimicrobials acting on protein synthesis

• Binding to 30s Subunit– aminoglycosides (bacteriocidal)

• streptomycin, gentamicin, amikacin

– tetracyclines

• Binding to the 50s subunit– chloramphenicol – fusidic acid – macrolides (erythromycin, clarithromycin, azithromycin)

Inhibitors of Folic Acid Synthesis

p-aminobenzoic acid + Pteridine

Dihydropteroic acid

Dihydrofolic acid

Tetrahydrofolic acid

Pteridine synthetase

Dihydrofolate synthetase

Dihydrofolate reductase

ThymidinePurines

Methionine

Trimethoprim

Sulfonamides

Antimicrobials acting on nucleic acid synthesis

• Inhibitors of Precursor Synthesis– sulphonamides & trimethoprim are synthetic,

bacteriostatic agents• used in combination in co-trimoxazole

– Sulphonamides inhibit early stages of folate synthesis• dapsone, an anti-leprosy drug, acts this way too

– Trimethoprim inhibits final enzyme in pathway, dihydrofolate synthetase.

• pyramethamine, an anti-toxoplasma and anti-PCP drug acts this way too

ALTERATION OF CELL MEMBRANES Polymyxins and colistin

destroys membranes active against gram-negative bacilli serious side effects used mostly for skin & eye infections

Antimicrobials acting on cell membrane

• polymyxins act like detergents and disrupt Gram-negative outer membrane– Not used parenterally because of toxicity to

mammalian cell membrane

• amphotericin binds to sterol-containing membranes of fungi

• fluconazole and itraconazole interfere with biosynthesis of sterol in fungi

Antimicrobials acting on nucleic acid synthesis

• Inhibitors of DNA replication – Quinolones (e.g ciprofloxacin) inhibit DNA-gyrase– Orally active, broad spectrum

• Damage to DNA– Metronidazole (anti-anaerobes), nitrofurantoin (UTI)

• Inhibitors of Transcription – rifampicin (key anti-TB drug) inhibits bacterial RNA

polymerase– flucytosine is incorporated into yeast mRNA

Agents for Infections Due to Gram-Positive BacteriaS

taph

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idis

MR

SA

Sta

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Str

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p A

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GN

R

RG

NR

Pse

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Penicillin G

Penicillin V

Methicillin, Oxacillin, Nafcillin, Cloxacillin

Dicloxacillin, Cloxacillin

Vancomycin

Dalfopristin/Quinopristin, Linezolid, Daptomycin

Linezolid

I.V.

P.O.

Broad- and Extended-Spectrum PenicillinsS

taph

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idis

MR

SA

Sta

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Str

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)

GN

R

RG

NR

Pse

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Ampicillin

Amoxicillin

Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin

Ticarcillin + Clavulanic Acid = Timentin ®, Piperacillin + Tazobactam = Zosyn®

Ampicillin + Sulbactam = Unasyn®

Amoxicillin + Clavulanic Acid = Augmentin®

Cephalosporins

First Generation        Second Generation     Third Generation       Fourth Generation

                    * Oral Agent

Cefadroxil *   Cefaclor * Cefdinir Cefepime

  Cefazolin    Cefamandole  Cefoperaxone   Cefpirome

  Cefelixin *   Cefonicid  Cefotaxime  

  Cephalothin    Ceforanide Ceftazidime  

  Cephaprin    Cefotetan Ceftibuten  

  Cephradine *   Cefoxitin  Ceftizoxime  

   Cefuroxime

moxalactamCeftriaxone

CephalosporinsS

taph

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idis

MR

SA

Sta

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ure

us

Str

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Pse

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Cefazolin

Cephalexin, Cefadroxil

Cefepime, Cefpirome

Cefuroxime, Cefoxitin

Cefaclor, Loracarbef, CeftibutenCefprozil, Cefuroxime axetil, Cefpodoxime, Cefdinir

Ceftriaxone, Cefotaxime

Cefixime

Ceftazidime

1st Generation

2nd Generation

3rd Generation

4th Generation

Macrolides, Azalides and KetolidesS

taph

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idis

MR

SA

Sta

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us

Str

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NR

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Erythromycin

Azithromycin

Clarithromycin, Azithromycin, Telithromycin

xErythromycin

Broad Spectrum AntibioticsS

taph

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idis

MR

SA

Sta

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Str

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R

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Ciprofloxacin, Levofloxacin, Moxifloxacin, Gatifloxacin

Ciprofloxacin, Levofloxacin, Moxifloxacin, Gatifloxicin

Tetracycline, Doxycycline, Minocycline

Tetracycline, Doxycycline, Minocycline, Tigecycline

Gentamicin, Tobramycin, Netilmicin, Amikacin

Imipenem, Meropenem, Ertapenem

Trimethoprim/Sulfamethoxazole

Trimethoprim/Sulfamethoxazole

Clinical use of antibiotics

Gillespie SH & Bamford KB. 2003. Medical microbiology & infection at a glance.

MRSAMRSA

PDRAB

PDRAB

CRABCRAB

PRSPPRSP

VREVREVISA

VISA

VRSAVRSA

ESBLESBL

AmpCAmpC

PDRPA

PDRPA

CRPACRPAPISP

PISP

parCparC

gyrAgyrA

mecAmecA

pbppbp

FungiFungi

?

PDRSM

PDRSMLRSALRSA

Staphylococcus aureus (I)

0

10

20

30

40

50

60

70

80

90

100

Susc

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Oxacillin VancomycinClindamycin ErythromycinGentamicin

台灣院內感染監視資訊系統（ TNIS ）

台灣院內感染監視資訊系統（ TNIS ）

*** *** Emerging Nosocomial PathogensEmerging Nosocomial Pathogens *** *** Species

SAM

P IP

TZP

GN

AN

CIP

IPM

CAZ

TIM

SXT

MEM

FEP

Acinetobacter baumannii R R R R R R R R R R R R

Escherichia coli R R R R R R R R R R

Chryseobacterium spp. R R R R R R R R R R R R

Pseudomonas putida R R R R R R R R R R R R

Pseudomonas spp. R R R R R R R R R R R R

Stenotrophomonas maltophilia R R R R R R R R R R R RSAM= ampicillin-sulbactam; PIP= piperacillin; TZP= piperacillin-tazobactam; GN= gentamicinAN= amikacin; CIP= ciprofloxacin; IPM= imipenem; CAZ= ceftazidime; TIM= ticarcillin-clavuanat

e; SXT= trimethoprim-sulfamethoxazole; MEM= meropenem; FEP= cefepime

Isolate number of pan-resistant Gram-negative bacilli in NCKUH

2001 2002 2003 2004 Total

Acinetobacter baumannii 8 3 13 18 42Pseudomonas putida 1 0 4 3 8Chryseobacterium spp. 2 2 1 1 6Pseudomonas aeruginosa 3 1 1 0 4Stenotrophomonas maltophilia

0 0 3 1 4

Pseudomonas spp. 1 0 0 2 3Escherichia coli 0 0 0 1 1

Impact of Antimicrobial-Resistant Bacteria

Increased risk of death

Prolonged hospitalization

Treatment with more toxic/expensive antibiotics

Limited antimicrobial therapy for certain resistant pathogens

Excess costs: $100 million-30 billion dollars annually

Clinical outcome in relation to whether empiricaltherapy was judged appropriate or not

Int J Antimicrob Agents 29 Suppl. 3 (2007) 1–7

Outcome of infections with antibiotic-resistant bacteria

MRSA: 2X mortality c/t MSSA

VRE: 2X mortality c/t VSE

Multidrug-resistant gram-negative bacteria: up to 5X mortality compared to susceptible strains

Outcomes and Adjusted Analysis for Patients With Bacteremia Caused by Multidrug-Resistant (MDR) Acinetobacter baumannii (Case Group) or Non-MDR A. baumannii (Control Group)

Infect Control Hosp Epidemiol 2007; 28:713-719

Mechanisms of Antibiotic Resistance

• Enzymatic inhibition• Altered target site/enzyme• Over-production of target enzyme• Bypass inhibited steps• Membrane impermeability• Active pumping out of drug in use

12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

1. Vaccinate

2. Get the catheters out

3. Target the pathogen

4. Access the experts

5. Practice antimicrobial control6. Use local data7. Treat infection, not contamination8. Treat infection, not colonization 9. Know when to say “no” to vanco10.Stop treatment when infection is

cured or unlikely

11. Isolate the pathogen12. Break the chain of

contagion

Diagnose and Treat Infection Effectively

Prevent InfectionUse Antimicrobials Wisely

Prevent Transmission

12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

Thanks for Your Attention !Thanks for Your Attention !