Optimal Antibiotics Administration

Optimal Antibiotics Administration

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Description: Antimicrobial treatment in 2011, Optimal Antibiotics Administration, Patient (Host) factors, Basic principles of Pharmacokinetics & Pharmacodynamics. Types of Antibiotics, Drug selection, Appropriate use; timing and duration, Organism factors: drug-resistant. Time-dependent antibiotics Several clinical studies: Extended infusion vs standard dosing beta-lactams in the acutely ill patient (include meropenem, piperacillin/tazobactam and doripenem), The outcome: varied from no difference in clinic.

 
Author: PornpanKoomanachai, MD (Fellow) | Visits: 1591 | Page Views: 4809
Domain:  Medicine Category: Biotech/Pharma Subcategory: Infectious Diseases 
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Contents:
Antimicrobial treatment in 2011
Pornpan Koomanachai, MD Division of Infectious Diseases and Tropical Medicine Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University

Optimal Antibiotics Administration
Patient (Host) factors Basic principles of Pharmacokinetics & Pharmacodynamics Types of Antibiotics Drug selection Appropriate use; timing and duration Organism factors: drug-resistant

Optimal Antibiotics Administration

Patient (Host) factors

Optimal Antibiotics Administration
Patient (Host) factors
� advanced age
� chronic and/or severe disease � polypharmacy � immunodeficiency � received prior surgical or medical

interventions (i.e., blood products, oncologic, or rheumatologic medications)

Optimal Antibiotics Administration
Patient (Host) factors
� The prior use of antibiotic therapy -> increased risk

of antibiotic-resistant pathogen infection � More severe of the illness
� extended hospital stay � frequently of intubation � parenteral nutrition, or other medical devices (i.e., central venous or urinary catheters)

� Increase the risk of a hospital acquired

infection (HAI) with a drug-resistant pathogen

Optimal Antibiotics Administration
Basic principles of Pharmacokinetics & Pharmacodynamics Types of Antibiotics

Drug selection

Basic principles of Pharmacokinetics & Pharmacodynamics
Common antibiotic pharmacokinetic and minimal inhibitory concentration (MIC) pharmacodynamic relationships

Pharmacodynamic index

Basic principles of Pharmacokinetics & Pharmacodynamics

K. pneumoniae

Ceftazidime vs

S. pneumoniae

Levofloxacin vs

Basic principles of Pharmacokinetics & Pharmacodynamics

Optimal Antibiotics Administration
Time-dependent antibiotics
� Optimal bacterial kill;

maximum amount of time over the MIC

� Extended or continuous infusions of

beta-lactams

Optimal Antibiotics Administration
%T>MIC < 50%

Time-dependent
%T>MIC > 50% 32 MIC90

32

MIC90

More frequent infusion
8 16 24 8 16 24

%T>MIC > 40%

%T>MIC = 100%

32

MIC90

32

MIC90

Prolonged infusion
8 16 24

Continuous infusion
8 16 24

Optimal Antibiotics Administration
Time-dependent antibiotics
Several clinical studies: � Extended infusion vs standard dosing beta-lactams in the acutely ill patient (include meropenem, piperacillin/tazobactam and doripenem)
� The outcome: varied from no difference in clinical

cure in the infusion group to a clinically significant enhanced cure rate

Optimal Antibiotics Administration
Time-dependent antibiotics
Glycopeptides: Vancomycin
� 100 courses of continuous infusion the treatment of

suspected MRSA infections � 78%of patients achieved plateau concentrations (>15mg/L) on Day 1 with minimal risk of toxicity ( MIC for most MRSA)

Guy's and St Thomas' NHS Foundation Trust (GSTT)

Optimal Antibiotics Administration
Concentration-dependent antibiotics
A high initial concentration is required:
� Maximum bacterial kill � Tissue penetration

Aminoglycoside once daily dose

Optimal Antibiotics Administration
Loading dose (LD)
The LD = V�Cp the volume of distribution (V) the required plasma concentration (Cp)
*Hydrophilic agents: which disperse mainly in water *Lipophilic agents: greater affinity for adipose tissue

Optimal Antibiotics Administration Hydrophilic agents
Smaller volume of distribution
Likely to be renally eliminated unchanged

Lipophilic agents
Larger volume of distribution

Likely to be hepatically metabolized
More likely to penetrate deep tissues

Increased clearance in severe sepsis

Beta lactams Aminoglycosides Glycopeptides

Fluoroquinolones
Macrolides Rifampicin Linezolid

Optimal Antibiotics Administration
Appropriate use; Timing and Duration
Timeliness and appropriateness of antibiotic Dosage route duration of administration

Optimal Antibiotics Administration
Get effective antibiotic selection, right first time Base antimicrobial selection, empiric and targeted; local susceptibility patterns Use broad-spectrum "but least" antibiotics early Optimize the dose and route of administration

Administer for the shortest possible duration
Adjust/stop antibiotic to best target the pathogen(s) and remove pressure for resistance development: de-escalation

Optimal Antibiotics Administration
Initiation of antibiotic
� Within the first hour after diagnosis of severe

sepsis and septic shock

Systematic Review and Meta-Analysis The Efficacy of Appropriate Empiric Antibiotic Therapy for Sepsis
� inappropriate empirical antibiotic treatment is

significantly associated with all causes mortality in prospective studies

Optimal Antibiotics Administration
How long should a course of antibiotic therapy last?
The Surviving Sepsis Campaign The duration of therapy should typically be 7�10 days Longer courses may be appropriate if � slow clinical response � an undrainable focus of infection � immunological deficiencies � neutropenia

Optimal Antibiotics Administration
How long should a course of antibiotic therapy last?
Ventilator-associated pneumonia � Clinical effectiveness was achieved with 8 or 15 d treatment � Significant reduction in the emergence of multiresistant pathogens in the shorter course

Optimal Antibiotics Administration
Infection Minimum duration VAP 8 days Pneumococcal meningitis 7 days Pneumococcal pneumonia 5 days Empyema/lung abscess 4 - 6 wks Endocarditis 4 wks Osteomyelitis 4 wks

Optimal Antibiotics Administration

Organism factors: Drug-resistant Gram-Negative Pathogens Drug-resistant Gram-Positive Pathogens

MDR bacterial infection
Risk Factors for MDR Pathogens for Both Nosocomial and Community-Acquired Infections � Antimicrobial therapy in preceding 90 days � Current hospitalization of 5 days or more � High frequency of antibiotic resistance in the community or in the specific hospital unit � Presence of risk factors for health care�associated pneumonia � Hospitalization for 2 days or more in the preceding 90 days
Adapted from Am J Respir Crit Care Med. 2005;171(4):388-416.

MDR bacterial infection
Risk Factors for MDR Pathogens for Both Nosocomial and Community-Acquired Infections � � � � � � Residence in a nursing home or extended care facility Home infusion therapy Chronic dialysis within 30 days Home wound care Family member with multidrug-resistant pathogen Immunosuppressive disease and/or therapy

Adapted from Am J Respir Crit Care Med. 2005;171(4):388-416.

Optimal Antibiotics Administration

Antibiotics For Drug-Resistant GN Infection

Antibiotics For Drug-Resistant GN Infection
Carbapenem
Colistin Tigecycline Combination therapy

Carbapenem
Ertapenem
I/C Community settings intraabdominal or skin and soft tissue infection Out patient ATB Rx

Imipenem

Meropenem

Doripenem

Empirical Rx of serious infections in previously multiple ATBs use Polymicrobial infection Suspected MDR or ESBL producer, Amp C producer GNR MDR P. aeruginosa infection

C/I Dose loading dose maintenance dose prolonged infusion Renal dose adjustment

Relative contraindication to prior hypersensitivity type I to � lactams

1 g IV 1 g IV once daily NA

1 g IV (> 1 g, epileptogenic) 500 mg-1 g IV q 6 h (max 4 g/d) (3 h) Yes

2 g IV 1-2 g IV q 8 h (max 6 g/d) (3 h) Yes

500 mg (1 g ?) IV 500 mg IV q 8 h (1 g IV q 8 h ?) (3-4 h) Yes

Yes

Zhanel GG et al. Drugs 2007;67:1027-52, Chahine EB et al. Am J Health-Syst Pharm 2010;67:2015-24, Mandell's Priniciples and practice of infectious disease 7th 2010

Carbapenem
Ertapenem
Common ADRs Phlebitis GI upset Rash Pruritus
Less

Imipenem
Phelbitis GI upset Rash Pruritus
0.5-2%

Meropenem
Phlebitis GI upset Rash Pruritus
Less

Doripenem
Headache, insomnia GI upset Elevated liver enz. Phlebitis
Less

Epileptogenicity Special issues

Risk factors: renal ds, pre-exisiting CNS ds or infection, Hx of seizure, high dose ( 4 g/d)

Lowest collateral damage to

P. aeruginosa, A. baumannii

Intraabdominal infection suspected enterococcal coninfection Resist to imipenem Resist to meropenem, or doripenem

US FDA approved for Rx of CNS infection

Similar structure to meropenem In vitro: MIC90 for P. aeruginosa 2-4 times lower than meropenem, but limited clinical data Not substituted to older carbapenems

Zhanel GG et al. Drugs 2007;67:1027-52, Chahine EB et al. Am J Health-Syst Pharm 2010;67:2015-24

Optimal Antibiotics Administration
Carbapenems
For ESBL and AmpC-producing organisms BUT! not for � Carbapenem-resistant P. aeruginosa and Acinetobacter sp. � Intrinsically carbapenem-resistant Stenotrophomonas maltophilia and E. faecium

Polymyxin: Colistin
Spectrums: - Some GN Enterobacteriaceaes, A. baumannii, P. aeruginosa - Poor activity against Serratia spp., Burkholderia spp., Proteus spp., Salmonella spp., Aeromonas spp.
- No activity against GP, most anaerobes

Indication

Preserved for infection from MDR or pan-DR A. baumannii, P. aeruginosa, or enterobacteriaceaes

Contraindication:
polymyxin allergy

Li J et al. Lancet Infect Dis 2006;6:589�601 Mandell's Priniciples and practice of infectious disease 7th 2010

Optimal Antibiotics Administration
Colistin Adverse effect
Nephrotoxicity (10% - 20%) : Acute tubular necrosis Neurotoxicity (7%) : Risk factors of nephrotoxicity Previous renal insufficiency Duration of treatment Concomitant use of other nephrotoxic drugs

Dizziness, weakness, facial paresthesia, vertigo, etc.
Dose dependent & reversible

Optimal Antibiotics Administration
Colistin
Key therapeutic options for carbapenem-resistant organisms ** P. aeruginosa, A. baumannii and carbapenemase producing Enterobacteriacae BUT! not for
� Organisms inherently resistant to polymyxins include

Serratia sp., Proteus sp., Stenotrophomonas maltophilia, Burkholderia cepacia and Flavobacterium sp.

Colistin: dose and administration
Suggested Dosing of Colistin based on PK/PD
� Cr. Clearance > 50 ml/min 300 mg, then 150 mg q 12 h or 100 mg q 8 h


� � �

Cr. Clearance 41 � 50 ml/min
300 mg, then 150 mg q 12 h or 75 - 100 mg q 8 h Cr. Clearance 31 � 40 ml/min 300 mg, then 75 - 100 mg q 12 h Cr. Clearance 21 � 30 ml/min

300 mg, then 75 mg q 12 h or 150 mg q 24 h
Cr. Clearance 11 � 20 ml/min 300 mg, then 100 mg q 24 h
Thamlikitkul V., Koomanachai P., 2011, unpublished data

Tigecycline
Derived from minocycline, similar to tetracycline Very broad spectrum wtith bacteriostatic activity - GP include MRSA, E. faecalis, E. faecium, and VRE - GN include ESBL producing E. coli, Klebsiella spp., (A. baumannii, Serratia spp.) S. maltophilia - Anaerobes, atypical pathogens - No activity against P. aeruginosa, Proteus spp.
Contraindication: hypersensitivity to tetracycline, pregnancy, severe hepatic impairment FDA approved: cSSSI, cIAI, CAP
Kasbekar N et al. Am J Health-Syst Pharm 2006;63:1235-43

Tigecycline
Loading dose: 100 mg IV infusion 30-60 min Maintenance dose: 50 mg IV q 12 h Hepatic dose adjustment Severe liver impairment or C-P class C: 100 mg IV loading then maintenance dose 25 mg IV q 12 h Common ADR: GI disturbance Not recommended: UTI and Bacteremia
Kasbekar N et al. Am J Health-Syst Pharm 2006;63:1235-43 Peterson LR. International Journal of Antimicrobial Agents 2008;32:S215-22

MDR bacterial infection

Acinetobacter baumannii

Antibiotics against MDR A. baumannii
Antibiotics Colistin In vitro activities Clinical efficacy Limitation of usage -Nephrotoxicity -Renal dysfunction: dose adjustment -Low serum concentration -Not enough clinical data -Increasing of resistant -Not enough clinical data

Tigecycline



? Case report or Salvage therapy with colistin ?

Sulbactam combination Fosfomycin



Antibiotics against MDR A. baumannii
Combination therapy
Insufficient clinical data

Polymyxins and carbapenems (even in the presence of carbapenem resistance) Polymixin and tigecycline
Polymyxin; in vitro synergism together with or sulbactam/ampicillin, or rifampicin

Antibiotics against MDR A. baumannii Colistin in Combination Therapy
Few comparative studies have analysed.
� No clinical benefits for combination

(colistin plus amikacin or -lactams) therapy in critically ill patients with severe infections by

P. aeruginosa
Clin Infect Dis 2003;37:e154-60

No superiority for the association of meropenem-colistin vs colistin alone
Clin Microbiol Infect 2006;12:1227-30

Antibiotics against MDR A. baumannii
Colistin in Combination Therapy
The clinical response in the patients who received colistin alone was 84.8% and in those who received colistin with other antibiotics (aminoglycosides, or carbapenems) was 77.8%
Int J Infect Dis. 2007 Sep;11(5):402-6

Good response rate (100% of patients, 26/26) from colistin plus rifampicin (10mg/kg q12h) (No control group, limited number of patients)
J Infect 2006;53:274-8

Antibiotics against MDR A. baumannii
Aerosolized Colistin
Adjunct to systemic treatment Current published data; too limited to allow determination Dosing 75-300 mg/d q 12-24h Adverse effect � Induce bronchospasm � Other minor symptoms: cough, sore throat, chest tightness
Crit Care 2005;9:R53-9

Antibiotics against MDR A. baumannii
Direct instillation of
antimicrobial agents into the ventricles
� Occasionally necessary in

Intrathecal Antimicrobial Agents Administered
Antimicrobial Agent Vancomycin Gentamicin Tobramycin Amikacin Polymyxin B Daily Intrathecal Dose 5-20 mg 1-8 mg 5-20 mg 5-50 mg 5 mg

patients � Infections that are difficult to eradicate � The patient is unable to undergo the surgical components of therapy � Must use with intravenous antimicrobial agents

Colistin
Teicoplanin Quinupristin/dalfop ristin Amphotericin B

10 mg
5-40 mg 2-5 mg 0.1-0.5 mg

Mandell, et al. Principles and Practice of Infectious Diseases, 7th Ed(2010)

Antibiotics against MDR A. baumannii
Intrathecal colistin administration
Poorly CSF penetrate � CSF colistin concentration is 25% of serum levels, and remained > to the MIC
Eur J Clin Microbiol Infect Dis2002;21:212

Potentially safe, effective, and treatment option for MDR GNB infection

Largest series, 51 cases of A. baumannii nosocomial meningitis � 100% (8/8) of patients treated with intravenous and IT colistin were survived (p = 0.04)
J Antimicrob Chemother 2008;61:908

Antibiotics against MDR A. baumannii
Intrathecal colistin administration
Dosing Variable doses ranging from 1.6 to 20 mg/day (q12-48h)
J Infect. 2005;50: 348, J Clin Microbiol. 2005;43:4916, J Antimicrob Chemother. 2004;54:290 J Clin Microbiol. 2000;38:3523 , Clin Infect Dis. 1999;28:916

Neurotoxicity - Meningeal irritation; most frequent (20%) 33% of patients had to be stop treatment 33% of patients, doses had to be reduced - Neurological signs of meningismus with increased cell count in CSF
Int J Antimicrob Agents 2007;29:9-25

MDR bacterial infection
Extended-Spectrum -Lactamases (ESBL)-producing bacteria

Extended-Spectrum -Lactamases; ESBL-producing bacteria
Hydrolyze
� extended-spectrum cephalosporins
Cefotaxime Ceftriaxone Ceftazidime

with an oxyimino side chain � oxyimino-monobactam: aztreonam

Resistance to these antibiotics and related oxyimino-beta lactams

ESBL-producing bacteria
Enterbacteriaceae spp.: ESBL testing?
Epidemiology
Latin America Asia/Pacific Rim 44.0% 22.4%

Risk factors
Increasing length of hospital or intensive care unit (ICU) stay More severity of clinical status Insertion of various types of catheter or devices Invasive procedures or surgical interventions Renal replacement or oxyimino-b-lactams therapy fluoroquinolones, The use of antibiotics
J of Hosp Infec 2009: 73;345

Europe
North America

13.3%
7.5%

J Antimicrob Chemother 2007;60:1018

ESBL-producing bacteria
Treatment of ESBL producing gram-negative bacterial infection
Antibiotics In vitro activities Cefepime was less effective than imipenem in the Carbapenem small Pip/Tazo: One clinical studies retrospective study Fluoroquinolone X
-Low serum concentration Cephalosporin -Depend BL/BI* on level of resistant -Not enough clinical data



Clinical efficacy X ? ? ? ? ?

+/

Tigecycline Colistin

Aminoglycoside

-No clinical data to support -No clinical data to support

Optimal Antibiotics Administration

Antibiotics For Drug-Resistant GP Infection

Antibiotics For Drug-Resistant GP Infection
Vancomycin
Fosfomycin Linezolid Daptomycin

Tigecycline

Anti-gram positive agents
Vancomycin
Activity Spectrum Bactericidal Gram+ve plus MRSA, PRSP Enterococcus spp. Bactericidal Gram+ve plus MRSA, Enterococcus spp. (! Increased MIC)

Fosfomycin

Indication

Community or nosocomial infection caused by GP esp. MRSA, MRCNS, PRSP Antibiotic-associated colitis (oral)

Community or nosocomial infection caused by GP esp. MRSA, MRCNS, PRSP Alternative to vancomycin � Fosfomycin 1g has sodium salt 14.5 mEq � IV only

Precaution

Need drug monitoring -Patients with unstable renal function (either deteriorating or significantly improving) -Prolonged courses of therapy -Total trough serum vancomycin concentrations of 15�20 mg/L for bacteremia endocarditis, osteomyelitis, meningitis, HAP

Anti-gram positive agents
Vancomycin
Dose and Administration loading dose of 25�30 mg/kg/day (based on ABW) then 1 g iv drip over 1-2h q8-12h
Renal dose adjustment Common ADRs -Nephrotoxicity -Auditory toxicity -Interstitial nephritis -Infusion-related reactions

Fosfomycin
2-4 g/day divided into every 12 h 4 g every 12 h for treatment of meningitis or osteomyelitis
Renal dose adjustment Mild increased of transaminase and reversible

Anti-gram positive agents
Linezolid
Activity Spectrum Bacteriostatic GP plus MRSA, vancomycin-R enterococci Bactericidal GP plus MRSA, vancomycin-R enterococci

Daptomycin

Atypical organisms: Nocardia spp., NTM
Indication Community or nosocomial infection caused by GP esp. MRSA, MRCNS, VRE MDR gram positive CNS infection Alternative to vancomycin Precaution Pre-existing thrombocytopenia Concomitant use with serotonergic agents, pseudoephedrine Complicated skin and soft tissue infection Caused by GP esp. MRSA

S. aureus bacteremia with right-sided IE
Alternative to vancomycin Pulmonary infection Concomitant use with statins

Perry CM et al. Drugs 2001;61:525-51 Sauermann R et al. Pharmacology 2008;81:79�91 Mandell's Priniciples and practice of infectious disease 7th 2010

Anti-gram positive agents
Linezolid
Dose and Administration Oral and IV formulations Oral bioavailability 100%
Serious infection 600 mg IV or oral q 12 h

Daptomycin
IV formulation, diluted in 0.9% NaCl only

S. aureus infection
- bactermia w/ or w/o IE 6 mg/kg IV q 24 h - Skin/soft tissue infection 4 mg/kg IV q 24 h Renal dose adjustment GI disturbance, phlebitis, headache Important ADR: - muscle toxicity, elevated CPK (interval F/U CPK recommended))
Perry CM et al. Drugs 2001;61:525-51 Sauermann R et al. Pharmacology 2008;81:79�91 Mandell's Priniciples and practice of infectious disease 7th 2010

No renal and hepatic dose adjustment Common ADRs Diarrhea, headache Important ADR: - reversible thrombocytopenia (esp. Rx duration 2 weeks)

MDR bacterial infection

Enterococcus spp.

CASE 3 (cont.) infection Enterococcal
Risk factors � Debilitated patients - cystoscopy - cesarean section who have received - prostatectomy antibiotics - transrectal prostatic biopsy - transjugular intrahepatic � Have serious portosystemic shunt (TIPS) underlying conditions - extracorporeal shock wave
lithotripsy - colonoscopy - fiberoptic sigmoidoscopy liver biopsy

The infection usually originates from
� The genitourinary or

gastrointestinal tract � Procedures associated with the development of enterococcal endocarditis � Malignant and inflammatory lesions of the gut and biliary tract may also be the source of endocarditis

Clin Microbiol Rev 1990; 3:46-65 Medicine (Baltimore) 2007; 86:363-377 Mandell, et al. Principles and Practice of Infectious Diseases, 7th Ed(2010)

Vancomycin-Resistant Enterococcus (VRE)
Risk factors for VRE colonization and infection Prolonged hospital stays
Exposure to intensive care units Post-transplantation Hematologic malignancies Exposure to antibiotics
� Vancomycin
� The extended-spectrum cephalosporins** � Antibiotics with potent activity against anaerobic bacteria

Antibiotics against Enterococcus spp.
Antibiotics
Penicillin
Ampicillin

E. faecalis
+
+

E. faecium
+ /+

VRE
+/(if suscept.)

Pip/Tazo
Imipenem

+
+

+/+/-

-

Meropenem

+/-

-

-

Microbiology (2009), 155, 1749-1757 Emerg Med Clin N Am 2008; 26:813-834 Mandell, et al. Principles and Practice of Infectious Diseases, 7th Ed(2010)

Antibiotics against Enterococcus spp.
Antibiotics
Aminoglycoside Vancomycin Linezolid Daptomycin

E. faecalis
+ + + +

E. faecium
+ (gentamicin) + + +

VRE
+ (if suscept.) + (bacteriostatic) (not approved by FDA) +/(limited clinical data)

Tigecycline

+

+

Microbiology (2009), 155, 1749-1757 Emerg Med Clin N Am 2008; 26:813-834 Mandell, et al. Principles and Practice of Infectious Diseases, 7th Ed(2010)

Important messages
Factors influencing antimicrobial use......
Consideration of drugs � Dose and route of administration result in adequate drug level at the site in sufficient period � Have bactericidal activity against the pathogenic organism Consideration of organisms � MDR � Clinical data evidence Consideration of host and site of infecton � Local factors at the site � Host defenses/host factors � Adjunctive therapies : remove foreign body, drainage, immunomodulation, etc

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