Patcharasarn Linasmita MDInfectious Diseases Unit

Department of Medicine Faculty of Medicine

Srinakharinwirot University

Rational based on facts or reason and not on emotions

or feelings having the ability to reason or think about

things clearly

Patients receive medications appropriate to their clinical needs, in doses that meet their own individual

requirements, for an adequate period of time, and at the lowest cost to them and their

community. (WHO, 1985)

Morbidity / mortality / adverse reaction Stimulate inappropriate patient demand Waste of resources Medicine stock-out Increased treatment cost Loss of patient confidence in the health

system

The most important weapons for the treatment of many infectious diseases caused by bacteria.

Interference with patient’s normal flora Selection of drug resistant organisms

People often have very rational reasons for using

medicines irrationally.

Pressure/complaint from patient Peer pressure Cost saving??? (omit diagnostic test) Inappropriate promotion Profit motives

Lack of knowledge, skills Lack of independent information Unrestricted availability of antibiotics Overwork of health personnel

Patients receive medications appropriate to their clinical needs, in doses that meet their own individual

requirements, for an adequate period of time, and at the lowest cost to them and their

community. (WHO, 1985)

Rational thinking

Virus + no pathogen identified ~ 80% Group A Streptococcus + (Gr C, G) ~ 15%

▪ No evidence of beta-lactam resistance Other bacterial pathogens ~5%

▪ Chlamydophila pneumoniae▪ Mycoplasma pneumoniae▪ Arcanobacterium haemolyticum▪ Corynebactrium diphtheriae▪ Fusobacterium necrophorum▪ Neisseria gonorrheae▪ Treponema pallidum▪ Francisella tularensis

For diagnosis of Group A Streptococcal infection History of fever Tonsillar exudates Tender anterior cervical adenopathy Absence of cough

Presence of all 4 variable -> PPV 40-60%Absence of all 4 variables -> NPV > 80%

Hospital antibiotic policies National antibiotic policies Essential drug list Guidelines

http://newsser.fda.moph.go.th/rumthai/

Bacterial toxin Vomit No ATB

Annual Epidemiological Surveillance Report 2007

Diarrhea: 1,433,230 cases Dysentery: 19,026 cases (1.3%)

Shigella 0.3%

Prescribe ATB only if

▪ Fever

▪ Bloody diarrhea / RBC, WBC in stool exam

▪ Beware of EHEC O157:H7 ▪ HUS

▪ No ATB

ATB choice▪ norfloxacin

2 days of ATB prophylaxis

http://newsser.fda.moph.go.th/rumthai/userfiledownload/asu15dl.pdf

Community settings In-Hospital settings

Use of antibiotics to treat

▪ Non-infectious disease

▪ Antibiotic-unresponsive infectious disease

▪ Virus

▪ Fungus

▪ Bacterial colonization

Use of antibioitcs for persistent fevers.

Suboptimal empirical therapy Inappropriate combination therapy Dosing and duration errors Mismanagement of antibiotic failure

▪ Persistent fever

▪ Clinical failure.

Prophylaxis Empiric Specific

Obvious bacterial infection?

▪ Characteristic clinical findings

Urgent?

▪ Non urgent situation

▪ Subacute bacterial endocarditis

▪ Chronic osteomyelitis

▪ Urgent

▪ Acute endocarditis

▪ Meningitis.

Have appropriate clinical specimens been obtained?

▪ Staining

▪ Culture

Which organisms are most likely

▪ Type of focal infection

▪ Community vs nosocomial

▪ Prior colonization.

3 main factors Etiologic agents Antibiotic-related factors Patient-related factors

Indentification of the infecting organism

▪ Staining

▪ Culture; aerobe, anaerobe,

Determination of susceptibility

▪ Method?

▪ Local data?

▪ Antibiogram.

Infect Dis Clin N Am 1995;9:483–95.

Conc > MBC

MBC > Conc > MIC

Persistent antimicrobial effect

Regrowth!!

Adequate host defense?

Concentration-Dependent + Bactericidal Action + Prolonged PAE

▪ eg aminoglycoside

Time-Dependent + Bactericidal Action

▪ eg betalactam

Bacteriostatic + moderate to prolonged PAE▪ eg azithromycin

Host factors

▪ Previous allergic reaction?

▪ Age

▪ Genetic; G6PD deficiency, hemoglobinopathy?

▪ Sulfonimide, dapsone

▪ Pregnancy

▪ Renal and hepatic function

▪ Site of infection.

Which agent?

▪ Choice of the Proper Antibiotics

Combination?

▪ Different mechanisms.

Most infections in immunocompetent hosts can be treated with a single agent.

Combinations may provide broad-spectrum coverage than single agent can

Disadvantage Antagonism Cost Adverse reaction

▪ Which one? .

Initial therapy / empirical treatment

▪ High rate of resistance

▪ At least one of the agents would be active

▪ Often possible to switch to a single drug

Polymicrobial infections Prevention of the emergence of resistance

organism

▪ For P. aeruginosa -> controversy.

Antimicrobial synergism

▪ Endocarditis

▪ Enterococcal

▪ Prosthetic valve

▪ Prosthesis infection? .

Which agent?

▪ Choice of the Proper Antibiotics

Combination?

▪ Different mechanisms

How to assess effectiveness?

▪ Clinically

▪ Bacteriologically

Treatment modification.

Clinical worsening? Clinical improvement?

▪ De-escalation

▪ What if culture positive for MDR organism? .

Adequate? -> adequate coverage of resistance pathogen(s)

▪ Broad spectrum agent?

Appropriate?

▪ Agent

▪ Dosing and interval

▪ Tissue penetration

▪ Drug interaction.

Principles Use broad spectrum early

▪ Consider clinical context/setting

▪ Local susceptibility patterns

▪ Hx of colonization with resistant organism?

Optimize dose and duration De-escalation/streamlining.

Skin and soft tissue infections

▪ Including diabetic foot

Community-acquired pneumonia

▪ Caution in severe CAP

Community onset intraabdominal infection Community-acquired bacterial meningitis.

Adapted from Paterson DL. CID 2008; 47(S1): S14

Hospital acquired pneumonia (HAP/VAP) Fever in neutropenic patients Fever in critically ill patients.

Glycopeptide

▪ Vancomycin

▪ Teicoplanin

▪ Telavancin

Daptomycin Linezolid Tigecycline Streptogramin

Fusidic acid TMP/SMX Clindamycin Rifampin Fosfomycin Ceftobiprol.

Slow bacterial killing Poor tissue penetration Rising MICs for MRSA Inadequate dosing.

Suspected catheter infection History of known colonization of MRSA or

other penicillin/cephalosporin resistance gram positive pathogen

▪ Discontinue if cultures negative for these pathogens after 3-4 days

Gram positive lab data?

▪ Consider clinical setting.

VSSA MIC < 2 mg/L VISA MIC 4-8 mg/L VRSA MIC > 16 mg/L hVISA MIC 1-4 mg/L

▪ Subpopulation MIC > 4 mg/L > 1 in 106CFU /ml

*Disk testing is not reliable*

An AUC/MIC ratio of ≥400 has been advocated as a target to achieve clinical effectiveness with vancomycin.

Am J Health-Syst Pharm. 2009; 66:82-98

Minimum serum trough concentrations should always be maintained above 10 mg/L

▪ To avoid development of resistance

To generate the target AUC:MIC of 400 the minimum trough have to be at least 15 mg/L

▪ For pathogen with an MIC of 1 mg/L

Trough should be obtained just prior to the next dose at steady-state condition

▪ Just before the forth dose.

Am J Health-Syst Pharm. 2009; 66:82-98

Extended spectrum beta-lactamase

▪ E. coli, K. pneumoniae, K. oxytoca, Proteus mirabilis

Capable to hydrolize

▪ All penicillins

▪ All cephalosporins

▪ All monobactam

Cefoxitin is stable to this enzyme Inhibited by clavulanic acid.

Risk factors Prior hospitalization Prior antibiotics use

▪ 3rd generation chephalosporin

▪ Quinolone

Prior colonization Prolonged hospitalization.

Carbapenems -> most reliable Fluoroquinolones Tigecycline Aminoglycosides Colistin.

Serratia Pseudomonas Indole-positive Proteus Citrobacter Enterobacter Morganella Acinetobacter Providentia.

Strong inducer (and substrate)

▪ Benzylpenicillin, ampicillin, cefazolin

Strong inducer (stable for hydrolysis)

▪ Imipenem

Intermediate inducer (stable for hydrolysis)

▪ Meropenem

Weak inducer (and substrate)

▪ 3rd generation cephalosporin, piperacillin

Weak inducer (more stable)

▪ cefepime.

Serratia Pseudomonas Indole-positive Proteus Citrobacter Enterobacter Morganella Acinetobacter Providentia

Avoid 3rd generation cephalosporin

Choice: Quinolones,

carbapenems cefepime.

Pleomorphic gram negative coccobacilli Multidrug resistance Local data

▪ Prevalence/indidence

▪ Choice of antibiotic

▪ Sulbactam containing drug

▪ Tigecycline

▪ colistin.

Urinary tract infection/pyelonephritis

▪ Cefoperazone?

▪ Moxifloxacin?

Prostatitis

▪ Quinolones

▪ TMP/SMX.

Central Nervous System

▪ Beta-lactam/Beta-lactamase inhibitor?

▪ Amoxicillin/Ampicillin

▪ Piperacillin?

▪ Clavulanate/Sulbactam/Tazobactam?

▪ Aminoglycoside?

▪ Clindamycin?

▪ Colistin?

▪ Tigecycline? .

Hepatobiliary▪ Ciprofloxacin

▪ Piperacillin

▪ Ampicillin Lung/pneumonia

▪ Daptomycin?▪ Inhibited by pulmonary surfactant

Bone and Joint▪ Tigecycline?▪ Low concentration in bone .

Intracellular pathogen?

▪ Salmonella

▪ Legionella.

Only antibiotic? Other measures?

▪ Abscess -> drainage

▪ Foreign body

▪ Prosthetic joint

▪ Shunt

▪ Intravenous line.

Avoid

ESBLs

▪ Cefoxitin?

AmpC

▪ 3rd gen Cephalosporin? .

Staphylococcus aureus Resist to erythromycin Susceptible to clindamycin? erm gene? .

erm gene (erythromycin ribosomal methylase)

Inducible clindamycin resistance

Stenotrophomonas and carbapenems Enterococcus and cephalosporin

It is not effective against Pseudomonas aeruginosa Providencia sp Morganella morganii Proteus sp.

Proteus Providencia Serratia Edwardsiella Neisseria Moraxella catarrhalis Helicobacter pylori Brucella Chryseobacterium

indologenes

Burkholderia cepacia Elizabethkingia

meningoseptica Some strains of

Stenotrophomonas maltophilia

Aeromonas Vibrio Prevotella Fusobacterium.

Rather than route of administration, it’s more important to think in terms of

▪ Antibiotic spectrum

▪ Bioavailability

▪ Tissue penetration

Risk of nosocomial infection

▪ Septic phelebitis.

Patients able to take oral medications should be swith to PO equivalence therapy, unless

▪ critically ill

▪ Endocarditis

▪ Staphylococcus aureus bacteremia

Doxycyline, metronidazole, amoxicillin, TMP/SMX, levofloxacin, linezolid

▪ Food-drug interaction.

Interaction with quinolones and doxycycline

▪ magnesium or aluminum antacids

▪ sucralfate

▪ products containing calcium, iron, or zinc

Subtherapeutic antibiotic level.

Present with prolonged fever / FUO

▪ Infectious

▪ Non infectious

▪ Connective tissue disease

▪ Malignancy

Fever despite antibiotics

▪ Drug fever?

▪ Undrained source?

▪ Wrong dose? .

Drugs Factitious

▪ Healthcare personel Disorder heat

hemostasis▪ CNS

Hematoma Blood transfusion Endocrine:

▪ Hyperthyroidism,

▪ Adrenal insuffciency

▪ Pheochromocytoma

Atrial myxoma Cyclic neutropenia Gout Pulmonary embolism Tissue infarction Habitual hyperthermia

▪ Exaggerated circadian rhytm.

Only antibiotic? Other measures?

▪ Abscess -> drainage

▪ Foreign body

▪ Prosthetic joint

▪ Shunt

▪ Intravenous line.

Overuse and misuse of antibiotics have favored the growth of resistance organisms

It’s more important to reassess the patient than to add additional antibiotics.