Antibiotic Smart Use การใช้ยาปฏิชีวนะอย่าง...

Ward Pharmacist, Siriraj Hospital

Antibiotic Smart Use การใชยาปฏชวนะอยางฉลาด

Pimonrat Chanapiwat

Ward Pharmacist, Inpatient Pharmaceutical Care Unit

Division of Pharmacy, Siriraj Hospital

…..Applied to Clinical Practice…...


Outlines

• Situation of antibiotic resistance in Thailand

• Appropriated antibiotic use strategies

– ASU program

– AMRPC program

– ASP

• Optimized antibiotic based on case studies

– Dosing

– De-escalation

– IV-to-oral

– In vitro susceptibilities

– Duration of treatment


Inappropriate use of antibiotics

• Increasing antimicrobial resistance

• Reduces the effectiveness of antimicrobial

treatment

• Increased morbidity, mortality, and health care

expenditure

A major threat to public health ปญหาหลกทางสาธารณสข


โครงการใชยาปฏชวนะอยางสมเหตผล Antibiotics Smart Use

http://newsser.fda.moph.go.th/rumthai/asu/introduce.php


• วตถประสงค คอ เพอปรบเปลยนพฤตกรรมโดยลดการใชยาปฏชวนะอยาง

พราเพรอใน 3 โรคเปาหมายทพบบอย คอ

– โรคตดเชอทางเดนหายใจสวนบน (เชน หวดเจบคอ) (Respiratory Infection)

– โรคทองรวงเฉยบพลน (Acute Diarrhea)

– แผลเลอดออก (Simple Traumatic Wound)

– การใชยาปฏชวนะเพอปองกนการตดเชอในผคลอดทารกครบกาหนดทางชองคลอดดวยวธปกต

Antibiotic Prophylaxis in Vaginal Delivery of Term Labor (APL)

• หวงใหมการเปลยนพฤตกรรม ดงนนการใหความรอยางเดยวไมเพยงพอในการเปลยน

พฤตกรรม จาเปนตองมการใชมาตรการหลากหลายดานรวมกบการปรบเปลยน

สงแวดลอมใหเอออานวยใหเกดพฤตกรรมนนขน

• การตดตามและประเมนผลการทางาน ไดแก การวดความรทศนคตกอนและหลงการ

อบรม การเปรยบเทยบปรมาณยาปฏชวนะทใชกอนและหลงทาโครงการ และการ

สอบถามอาการและความพงพอใจของผปวย ซงทาใหจงหวดหรอสถานพยาบาลไดขอมล

เพอไปใชประโยชนดานตางๆ ตอไป

โครงการใชยาปฏชวนะอยางสมเหตผล Antibiotics Smart Use

http://newsser.fda.moph.go.th/rumthai/asu/introduce.php


Thailand AMR Containment and Prevention (AMRCP) Program

• AMR in communities in Thailand begins with human and non- human antibiotic use, especially in food animals

– The prevalence of ESBL-producing Enterobacteriaceae in feces of asymptomatic individuals in Thailand is between 29% and 93%

• AMR in Thai hospitals is usually associated with inappropriate use of antibiotics as well as inefficient infection prevention and control practices

– The frequency of inappropriate use of antimicrobials in hospitalized patients in Thailand is between 25% and 92%

– Hospital-acquired infections (HAIs) are common in Thailand, and most of these infections are caused by antimicrobial-resistant bacteria

Thamlikitkul V, et al. Journal of Global Antimicrobial Resistance 3 (2015) 290–294


• Stopping producing AMR

– Requires promoting responsible antibiotic use

• Stopping acquiring and transmitting AMR

– Require promoting good sanitation and hygiene and promoting compliance with infection control and prevention practices

Thamlikitkul V, et al. Journal of Global Antimicrobial Resistance 3 (2015) 290–294


• Antibiotic stewardship Program (ASP)

– Coordinated interventions designed to improve and measure the appropriate use of antibiotics

– Promoting the selection of the optimal antibiotics drug regimen • Dosing

• Duration of therapy

• Route of administration

Barlam TF, et al. CID.2016: e1-27. DOI: 10.1093/cid/ciw118


Recommendation for implementing an antibiotics stewardship program (ASP)

• Intervention

• Optimization

• Microbiology and Laboratory Diagnostics

• Measurement

• Special Populations



ASP: Intervention • Recommend preauthorization and/or prospective audit and

feedback

• Against relying solely on didactic educational materials

• Develop facility-specific clinical practice guidelines coupled with a

dissemination and implementation strategy

• Implement interventions to improve antibiotic use and clinical

outcomes that target patients with specific infectious diseases

syndromes

• Design intervention to reduce the use of antibiotics associated

with a high risk of CDI compared with no such intervention

• Encourage prescribers to perform routine review of antibiotic

regimens to improve antibiotic prescribing

• Incorporation of computerized clinical decision support at the time

of prescribing

• Against the use of antibiotic cycling Barlam TF, et al. CID.2016: e1-27. DOI: 10.1093/cid/ciw118


ASP: Optimization

• Recommend implement PK monitoring and adjustment

programs for aminoglycosides

• Suggest implement PK monitoring and adjustment programs for

vancomycin

• Advocate for the use of alternative dosing strategies vs standard

dosing for broad-spectrum β-lactams to decrease

• Increase both appropriate use of oral antibiotics for initial

therapy and the timely transition of patients from IV to oral

antibiotics

• In patients with a history of β-lactam allergy, promote allergy

assessments and penicillin (PCN) skin testing when appropriate

• Reduce antibiotic therapy to the shortest effective duration



ASP: Microbiology and Laboratory Diagnostics

• Development of stratified antibiograms over solely relying on non-stratified

antibiograms to assist ASPs in developing guidelines for empiric therapy

• Selective and cascade reporting of antibiotics over reporting of all tested

antibiotics

• Use of rapid viral testing for respiratory pathogens to reduce the use of

inappropriate antibiotics

• Rapid diagnostic testing in addition to conventional culture and routine

reporting on blood specimens if combined with active ASP support and

interpretation

• In adults in ICUs with suspected infection, suggest the use of serial PCT

measurements as an ASP intervention to decrease antibiotic use

• In patients with hematologic malignancy at risk of contracting invasive fungal

disease (IFD), suggest incorporating non-culture based fungal markers in ASP

interventions to optimize antifungal use



ASP: Measurement

• Suggest monitoring antibiotic use as measured by

days of therapy (DOTs) in preference to defined

daily dose (DDD)

• Recommend measuring antibiotic costs based on

prescriptions or administrations instead of

purchasing data

• Measures that consider the goals and size of the

syndrome- specific intervention should be used



ASP: Special Populations

• Suggest ASPs develop facility-specific guidelines for F&N management

in hematology-oncology patients over no such approach

• Suggest implementation of ASP interventions to improve the

appropriate prescribing of antifungal treatment in immunocompromised

patients

• In nursing homes and skilled nursing facilities, we suggest

implementation of antibiotic stewardship strategies to decrease

unnecessary use of antibiotics

• Suggest implementation of antibiotic stewardship interventions to

reduce inappropriate antibiotic use and/or resistance in the NICU

• In terminally ill patients, we suggest ASPs provide support to clinical

care providers in decisions related to antibiotic treatment



Pharmacist’s Role in Antimicrobial Stewardship and Infection Prevention and Control

• Promoting optimal use of antimicrobial agents

– Appropriate selection

– Optimal dosing

– Rapid initiation

– Proper monitoring

– De-escalation of antimicrobial therapies

• Reducing the transmission of infections

• Educational activities

Am J Health-Syst Pharm. 2010; 67:575-7


ASP: Optimization • Appropriated use antibiotics

– Indication

– In vitro susceptibilities

– Optimized dosing

• Time

• Dose


• Duration

• De-escalation

• IV to oral therapy

– Therapeutic Drug Monitoring (TDM)



Optimized dosing • Time to start antibiotic

• Dose

– Loading dose: Colistin, Vancomycin

• Adjusted from body weight

– Maintenance dose: Beta-lactams

• Adjusted from renal clearance

• Augmented renal clearance (ARC)

– Therapeutic drug monitoring (TDM)


– Non-IV route

– IV route: Extended infusion vs intermittent infusion

• De-escalation

• IV to Oral therapy

• Other: Drug interactions


Antibiotic dosing

• Administration of effective intravenous antimicrobials within the

first hour of recognition of septic shock

• Initial empiric antibiotic of one or more drugs that have activity

against all likely pathogens and that penetrate in adequate

concentrations into tissues presumed to be the source of sepsis

• Empiric combination therapy should not be administered for

more than 3–5 days

• De-escalation to the most appropriate single therapy should be

performed as soon as the susceptibility pro le is known

Dellinger RP, et al. Crit Care Med 2013; 41:580–637



• Dose








– Non-IV route


• De-escalation




Ex: PK and Loading dose Colistin

No loading dose • Cmax 0.6 mg/L (1st dose)

• Cmax (SS) 2.3 mg/L

• Tmax (SS) 2-3 days

Loading dose • Cmax 2.5 mg/L (1st dose)

• Tmax < 12 h

Plachouras D. et, al. AAC. 2009, p. 3430–3436


Ex: TDM Vancomycin

• Recommendation of IDSA/ASHP/SIDP 2009

– For complicated infections (bacteremia, endocarditis,

osteomyelitis, meningitis and hospital-acquired pneumonia

• Target trough serum vancomycin concentrations

– 15–20 mg/L

– Achieve an AUC/MIC of ≥400 (MIC is ≤1 mg/L)

– Trough serum vancomycin concentrations always be maintained

above 10 mg/L to avoid development of resistance

Rybak M, et, al. Am J Health-Syst Pharm. 2009;66(1):82-98.


• In seriously ill patients (sepsis, meningitis,

pneumonia, or infective endocarditis) with

suspected MRSA

• In order to achieve rapid attainment of this target

concentration a loading dose of 25–30 mg/kg

(based on actual body weight) can be considered

Rybak M, et, al. Am J Health-Syst Pharm. 2009;66(1):82-98.

Ex: TDM Vancomycin


Rationale for using loading dose

• Half life vancomycin

– 5-11 hours in adults

– 100-200 hours in end-stage

renal diseases (ESRD)

• Loading dose would allow for

more rapid achievement of

target concentration of 15-

20 mg/L

LD= Desired serum drug concentration x Vd*

LD: Loading dose (mg)

Vd: Volume of distribution (L)

* In critically ill patients often display increase Vd

from sepsis, edema, ascites, and aggressive fluid

resuscitation Leader WG, et, al. Clin. Pharmacokinet. 1995;28(4):327-42.


Rationale for using loading dose

No loading dose Loading dose

Loading dose would allow for more rapid achievement of target concentration


Augmented renal clearance (ARC)

• Creatinine clearance ≥ 130ml/min./1.73 m2

• Full dose 24 – 48 h

– The time course of ARC in the critically ill is still uncertain

– Mean 4.7 days (range 0–11.5 days) of treatment

• NO adjust dose followed by renal function (esp. remained urine residual)

• Loading dose: achive therapeutic level on the first dose

McKenzie C. J Antimicrob Chemother 2011; 66 Suppl 2: ii25–ii31

Udy AA, et al. Clin Pharmacokinet 2010; 49 (1): 1-16



• Dose








– Non-IV route


• De-escalation




Ex: 63 years old, Thai female

• Admitted for Active SLE on Dexamethasone 5 mg

IV q 6 h taper to 5 mg IV q 12 h

• 2 weeks later, produced purulent sputum

– PE: V/S T 39.9 oC, PR 120 bpm, BP 88/54

mmHg, RR 32 /min

– RS: Crepitation both lung Rt > Lt

– H/C: Gram negative rods x II specimens

– Sputum: not acceptable for culture

– CXR: bilateral infiltration at both lung

• 3 days later H/C: Acinetobacter baumannii

(XDR) sense colistin and tigecycline

• Dx: HAP with bacteremia from XDR- A. baumannii


Colistin IV monotherapy

• All Studies

– Clinical response 65 - 80%

– Microbiological response 95%

– 30-days Mortality rate 35 - 50%

– Nephrotoxicity 15 – 35%

Crit Care.2003;7:R78-83.

Intensive Care Med.2005;31:1058-65.

Int J Infect Dis.2007;11:402-6.

Intensive Care Med.2007;33:1162-7.

J Infect.2008;56:432-6.

J Antimicrob Chemother.2010;65:1019-27.

• Siriraj Hopital 2007 (N=93)

• Colistin 5 mg/kg/day IV q 12 hour

• MDR A. baumannii (N=83, 89.2%) ,

MDR P. aeruginosa (N=10, 10.8%)

• Presenting infections (Colistin group)

• Pneumonia 76%

• Bacteremia/CRBSI 12.7%

• IAI 7%

• SSSI 7%

• UTI 5.6%


IV ATB+NB colistin

• Rattanaumpawan P, et al 2010 RCT trials in Siriraj Hospital

• VAP (N=100) with MDR A. baumannii, P. aeruginosa, K. pneumoniae

• Antibiotic IV+ colistin NB vs Antibiotic IV

• Dose Colistin NB 75 mg bid

• Clinical response: 51 % vs 53.1% (P=NS)

• Mortality rate: 39.2% vs 36.7% (P=NS)

• Favorable microbiological outcome: 60.9% vs 38.2% (P = 0.03)

JAC. 2010;65:2645-49.

• ADR:

• Nephrotoxicity 25.5% vs 22.4%

• Bronchospasm 7.8% vs 2 %


Nebulized colistin

• Polymyxin E

– Colistimethate ------> Colistin base (active)

– Colistimethate 1 vial = Colistin base 150 mg

• LOW concentration in epithelial lining fluid in lung (site of infection in pneumonia)

• Colistin Nebulized (NB)

– Dilution by NSS (ONLY!!!)

– Final volume 4-5 ml

– Immediately use after dilution

Polymyxin E ----> Polymyxin E1 (bronchospasm) • Use bronchodilator before colistin NB


Ex: 63 years old, Thai female

• Admitted for Active SLE on Dexamethasone 5 mg

IV q 6 h taper to 5 mg IV q 12 h

• 2 weeks later, produced purulent sputum

– PE: V/S T 39.9 oC, PR 120 bpm, BP 88/54

mmHg, RR 32 /min

– RS: Crepitation both lung Rt > Lt

– H/C: Gram negative rods x II specimens

– Sputum: not acceptable for culture

– CXR: bilateral infiltration at both lung

• 3 days later H/C: Acinetobacter baumannii

(XDR) sense colistin and tigecycline

• Dx: HAP with bacteremia from XDR- A. baumannii


High dose tigecycline

• Dose of tigecycline approved for intra-abdominal and skin and soft tissue infections (50 mg every 12 h with a loading dose of 100 mg) does not achieve adequate concentrations for pulmonary infections

• Penetration of tigecycline into ELF is very low, cannot achieve the MIC90

of extracellular pathogens

• Whereas concentration in AC exceed the MIC90 of all atypical bacteria or

intracellular pathogens through the entire dosing interval

MIC 90(mg/L)

S. pneumoniae 0.03

S. aureus 0.25

E. coli 0.25

K. pneumoniae 1.0


Tigecycline: Tissue penetration

Tissue Conc. tissue vs serum AUC0-24 tissue/serum*

Bile - 537

Gallbladder 38 fold 23

Colon 2.3 fold 2.6

Skin blister fluid 0.74 fold 0.73 **

Lung tissue 8.6 fold 2.0

Epithelial lining fluid (ELF) 1.32 fold 1.32 **

Alveolar cells 78 fold 77.46 **

Synovial fluid 0.31-0.58 fold 0.31

Cerebrospinal fluid (CSF) 0.11 fold 0.11

Bone 0.35-0.41 fold 0.41

* Healthy subjects receiving a single dose 100 mg of tigecycline

**Healthy subjects receiving a single 100 mg loading dose of tigecycline followed by six 50 mg doses iv every 12 hours

Peak serum concentration (Cmax): 0.6 mg/L (50 mg IV)

0.79 mg/L

46.8 mg/L

0.44 mg/L

22.8 mg/L

0.06 mg/L

1. MacGowan AP. Tigecycline pharmacokinetic/pharmacodynamic update. J Antimicrob Chemother. 2008;62 Suppl 1:i11-6.

2. Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006;58(6):1221-9.

3. Conte JE, Jr., Golden JA, Kelly MG, Zurlinden E. Steady-state serum and intrapulmonary pharmacokinetics and pharmacodynamics of tigecycline. Int J Antimicrob Agents. 2005;25(6):523-9.

4. Peterson LR. A review of tigecycline — the first glycylcycline. International Journal of Antimicrobial Agents. 2008;32, Supplement 4(0):S215-S22.


High dose Tigecycline: Clinical trial for VAP

• 100 ICU patients who were treated with tigecycline

• High dose (HD) tigecycline 200 mg then 100 mg every 12 hours

• Standard dose (SD) tigecycline 100 mg then 50 mg every 12 hours • 63 VAP patients (HD n=33, SD n=30)

• 53 patients were treated concomitant with other antibiotics

• Colistin 66%

• Aminoglycosides (amikacin, gentamicin) 34%

• Susceptible breakpoints ≤ 2 mg/L, resistance breakpoints ≥ 8 mg/L

Critical Care. 2014;18(3):R90.


• Clinical cure rate: HD 57.5% vs SD 33.3% , P=0.05

• Microbiological eradication: HD 57.1% vs SD 30.4% , P=0.07

• ICU mortality: HD 48.4% vs SD 66.6% , P=0.14

• Overall mortality was 57% without difference between the two groups

Critical Care. 2014;18(3):R90.

High dose Tigecycline: Clinical trial for VAP


HAP/VAP guideline 2016 (IDSA)

• For patients with HAP/VAP suggest that antibiotic

dosing be determined using PK/PD data, rather than

the manufacturer’s prescribing information

• For patients with VAP due to gram-negative bacilli that

are susceptible to only aminoglycosides or polymyxins

(colistin or polymyxin B), we suggest both inhaled and

systemic antibiotics, rather than systemic antibiotics

alone

• In patients with HAP/VAP caused by Acinetobacter

species, we recommend against the use of tigecycline

Kalil AC et, al. CID. 2016 DOI: 10.1093/cid/ciw353



• Dose








– Non-IV route


• De-escalation




Ex: 65 years old, Thai female with fever and fever with chill, decreased diarrhea, decreased urine output and turbid urine

• 2 months PTA

– Bilateral hydronephrosis S/P bilateral DJ stent with foley catheter

• UA: WBC 30-50, RBC 1-2, Bac 3+, Nitrite -, LEU 3+

• UC : E. coli (> 105 cfu/ml)

• H/C: no growth

• Dx: Complicated UTI


• Meta-analysis from 11 studies

• Documented treatment

• Bacteremia with ESBL-producing Enterobacteriaceace

• Carbapenems vs BL/BIs

• RR (95%CI): 0.52(0.23-1.13)

JAC. 2012;67(12):2793-803


• Meta-analysis from 11 studies

• Documented treatment

• Bacteremia with ESBL-producing Enterobacteriaceace

• Carbapenems vs non-BL/BIs

• RR (95%CI): 0.65(0.47-0.91)

JAC. 2012;67(12):2793-803


CLSI breakpoint : Enterobacteriaceae

Agents Susceptible MIC (mg/L) Regimen

Doripenem ≤ 1 500 mg IV q 8 hr

Ertapenem ≤ 0.5 1 g IV q 24 hr

Imipenem ≤ 1 500 mg IV q 6 hr 1 g IV q 8 hr

Meropenem ≤ 1 1 g IV q 8 hr

PK-PD index: 40% T>MIC


Types of infusion

• Intravenous (IV) infusion

– 0.5 – 1 hours

• IV extended / prolong infusion

– 3 hours

– 4 hours

• IV continuous infusion

– 24 hours


Beta-lactams

Extended infusion ---> %T>MIC


Extended infusion of Beta-lactams


Beta-lactams dosing strategies

• Patients treated with carbapenems or PIP/TAZ

– Prolonged (≥3 hours, PI) or continuous (24 h, CI)

– Short-term duration (20-60 min)

• 14 studies (1,229 patients)

• Mortality was lower among patients receiving PI or CI (RR, 0.59;

95% CI, 0.41-0.83)

• Patients with pneumonia who received PI or CI had lower

mortality than those receiving short-term infusion (RR, 0.5; 95%

CI, 0.26-0.96)

• The available evidence from mainly non-randomized studies

– PI or CI of carbapenems or PIP/TAZ associated with lower

mortality

Falagas ME. Et, al. Clin Infect Dis. 2013 Jan;56(2):272-82


Beta-lactams dosing strategies (2)

• Prolonged versus Intermittent Infusion of β-Lactams for the

Treatment of Nosocomial Pneumonia: A Meta- Analysis

Lal A. at, al. Infect Chemother 2016;48(2):81-90


Lal A. at, al. Infect Chemother 2016;48(2):81-90


What do you concerned about extended infusion?

Stability of Antibiotics in Solution (hours)



• Dose








– Non-IV route


• De-escalation




Ex: 65 years old, Thai female with fever and fever with chill, decreased diarrhea, decreased urine output and turbid urine

• 2 months PTA

– Bilateral hydronephrosis S/P bilateral DJ stent with foley catheter

• UA: WBC 30-50, RBC 1-2, Bac 3+, Nitrite -, LEU 3+

• UC : E. coli (> 105 cfu/ml)

• H/C: no growth

• Dx: Complicated UTI


De-escalation

• A strategy to replace empirical broad-spectrum

antimicrobial treatment by using a narrower antimicrobial

therapy or discontinuation of an antimicrobial agent once

culture results were available

• A protective factor for 90-day mortality in patients with

septic shock and severe sepsis

Garnacho-Montero J. el, al. Intensive Care Med (2014) 40:32–40


International Journal of Infectious Diseases 16 (2012) e47–e52

• Protective predictors of 30-day mortality

• Definitive antimicrobial therapy using

• ertapenem (p < 0.0001)

• imipenem/meropenem (p = 0.002)


International Journal of Infectious Diseases 16 (2012) e47–e52



• Dose








– Non-IV route


• De-escalation




• Dyspnea 2 weeks PTA, no underlying diseases, no history of admission

• PE (at ER):

– BT 38.4 oC, PR130, RR24, BP110/73, SpO2 93%

– Lung: Decreased breath sound, right lung

– CXR: multi-loculated pleural effusion at right lung

– Right thoracocentesis: Pus 50 ml

– Pleural fluid G/S: • Numerous gram negative rod

• Numerous gram positive cocci un pair and chains

• Numerous gram positive rod, non-spore forming

• Probably mixed aerobic and anaerobic bacteria

– C/S: Pending

• Dx: Empyema thoracis

• Empirical ATB: Ceftraixone 2 g IV OD + Clindamycin 600 mg IV q 8 h

• After 2 day of ATB: no fever, BP drop 92/68, SpO2 89% RA on ETT

• At ward: Changed ATB to Piperacillin/tazobactam 4.5 g IV q 6 h

Ex: 56 years old Thai male Patient


Management: Empyema thoracis

• Antibiotics

– All patients should receive antibiotics.

– Antibiotics to cover anaerobic infection should be used

in all patients except those with culture proven

pneumococcal infection

– Duration: 4 - 6 weeks

• Thoracocentesis

• ICD

• Surgery

Thorax 2010;65(Suppl 2):ii41eii53


Inoculum effect

• Laboratory phenomenon – Significant 8-fold or greater increase in MIC of antibiotic when

the number of organisms inoculated is increased

– Penicillins against Enterobacteriaceae and Pseudomonas spp.

– Cephalosporins (cefepime, cefotaxime, and ceftriaxone)

• Predictive value in identifying increased risk of therapeutic failure in serious infections

• High inoculum occur in endocarditis, meningitis, septic arthritis, osteomyelitis, abscesses, and other deep-seated infections

• High inoculum: > 107 cfu/mL

Thomson KS and Molan ES.AAC.2001;45(12):3548-54. Lo´pez-Cerero L, et al.Clin Microbiol Infect 2010; 16: 132–136


Ex: 56 years old Thai male Patient

– Pleural fluid C/S: Streptococci, alpha-hemolytic

– AST: Sense to Penicillin, Cefotaxime, Clindamycin, Vancomycin

– Anaerobe C/S:

• Numerous Prevotella intermedia

• Numerous Peptostreptococcus spp.

• Dx: Empyema thoracis S/P ICD

• De-escalation ATB:

– Amoxicillin/clavulanic acid 1.2 g IV q 8 h

• After inserted ICD + amoxicillin/clavulanic acid

– Clinical stable, no fever

• IV to oral:

– Amoxicillin/clavulanate 1 g PO bid pc + amoxicillin 1000 mg

PO tid pc


Types of IV to PO Therapy Conversions

• Sequential therapy

– Ciprofloxacin 400 mg IV q 12 h Ciprofloxacin 500

mg PO q 12 h

• Switch therapy

– Ciprofloxacin 400 mg IV q 8 h Levofloxacin 750 mg

PO OD

• Step-down therapy

– Ceftazidime 2 g IV q 8 h Cefdinir 300 mg PO q 12 h

Kuper KM.ASHP. 2008:349-51


Selection of Patients for IV to PO Therapy Conversion

• At least 48–72 h of previous IV treatment

• The patient should be hemodynamically stable, his condition should be

improving with a trend towards normalization of the body temperature

and the peripheral leukocyte count

• Availability of an oral antibiotic which could provide adequate levels in

the site of infection

• Patient able to take oral medication with functioning gastrointestinal

tract and no signs of malabsorption

• Patients whose disease state or infection does not permit conversion

(e.g. high-risk neutropenia, meningitis, endocarditis, intracranial

abscesses, endocarditis, mediastinitis and other equally severe

infections)

Lelekis M and Gould IM, Journal of Hospital Infection (2001) 48: 249–257


Examples of gastrointestinal absorption for antibacterial agents

Lelekis M and Gould IM, Journal of Hospital Infection (2001) 48: 249–257



• Dose








– Non-IV route


• De-escalation




Drug interaction: Antibacterial agents

• Drug-Drug interaction

– Enzyme inhibitors

• Macrolides: erythromycin, clarithromycin

– Enzyme inducers

• Rifampicin

– Chelating with multivalent ions

• Tetracyclines: doxycycline

• Fluoroquinolones

• Cefdinir

– Linezolid – SSRIs : serotonin syndrome

• Food-Drug interaction

– Penicillins: cloxacillin, dicloxacillin

– Cephalosporins: cefdinir, cefditoren pivoxil

Drugs 2011; 71 (14): 1839-1864

Clin Pharmacokinet 1993; 25 (6): 450-482

Clin Pharmacokinet 2003; 42 (9): 819-850



http://www.ema.europa.eu/



• US FDA Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) at 2008

– Carbapenems

• Meropenem

• Ertapenem

• Imipenem

• Doripenem

– Sodium valproate

http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm116263.htm


Carbapenems – Sodium valproate

• Mechanism

– Alterations in the intestinal absorption of valproate

– A shift in the distribution of valproate

– Interference with valproate metabolism

Erin E Mancl and Barry E Gidal. Ann Pharmacother. 2009;43:2082-7.

Mori H, et al.Drug Metabolism Reviews, 39: 647–657, 2007



• Effect

– Decreased serum valproate concentration 50-95%

within 24 hours

– Clinical outcomes

• VPA concentrations

• Decreased within about 1-7 days of initiation of

carbapenems therapy

• Recovered completely within 3 days - 2 weeks after

discontinuation of carbapenems



Tzu Chi Medical Journal 24 (2012) 80e84


• Management

– Clinicians should be aware of this potential

interaction and closely monitor serum valproate

levels and possible failure to control seizures

with the concomitant use of carbapenems

– Increasing valproate dose may not be adequate

to achieve levels

– Change valproate to another anticonvulsants



Tzu Chi Medical Journal 24 (2012) 80e84




Meropenem – Sodium valproate

• Results of a retrospective study (N=36)

• Mean serum valproate concentration decreased from

50.8 ± 4.5 mg/mL to 9.9 ± 2.1 mg/mL following

meropenem administration and remained low for 7

days

• Then gradually increased 8 to 14 days after

discontinuation of meropenem

• Reaching values comparable to those before

initiation of meropenem

Erin E Mancl and Barry E Gidal. Ann Pharmacother. 2009;43:2082-7. Mori H, et al.Drug Metabolism Reviews, 39: 647–657, 2007


Promote Optimal Use of Antimicrobial Agents

Reduce the Transmission of Infections

Educational Activities

Appropriate individual care •Effective antimicrobial (Overcome MDR organism)

•Less adverse event

Protecting public health • Avoid overuse ATB (induce resistant organism)

Conclusion

Thank You…

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