General Principles of Infectious Disease

Mohammad Aljawadi PharmD, Msc, PhDSalha jokhab, MSC

Clinical Pharmacy Department King Saud University

PHCL 430

Objectives

Recall foundational principles of microbiology, pharmacology, pathophysiology, & immunology in the treatment of infectious diseases

Recognize predisposing conditions leading to the development of infection and preventative measures

Objectives Cont’d

Describe physical findings, lab etc used in the diagnosis of infection and monitoring of response to therapy

Name and differentiate the 3 primary uses of antibiotics

Explain the use of patient data to optimize initial and subsequent antibiotic therapy

Outline

Microbiology Laboratory Tests to direct

antimicrobial pharmacotherapy Antibiotic Introduction Systematic Approach in selecting an

antibiotic

Pharmacotherapy of Infectious Diseases General Principles Why do we care?

Major cause of morbidity & mortalityAccounts for billions $ a year world

wideInpatient & Outpatient prescriptions

1/3 of hospital budgets• 14 of the top 100 hospital drugs• Major % of outpatient prescriptions

Why does it happen ?

We share the world with potential pathogens

Exposure to a virulent pathogenBrucella, Malaria, HIV, Tb, STD’s, H1N1

Public health measures are not followed likeHand washingVaccination Vector controlAvoiding contact

Factors predisposing to infection Alteration in normal flora Disruption of natural barriers Age Immunosuppression secondary to:

Malnutrition Underlying disease drugs

Microbiology

Microorganisms

Gram-positive (Cocci, Bacilli) Aerobic Anaerobic

Gram-negitive (Cocci, Bacilli) Aerobic Anaerobic

Aerobic Microorganisms

Gram-positive cocci

Staphylococcus aureus Staphylococcus epidermidis Streptococcus (groups A, B, C, G) Streptococcus bovis Streptococcus pneumoniae Streptococcus viridans group Enterococcus faecalis E. faecium

Gram-positive Bacilli

Cornyebacterium Listeria Bacillus

Gram-negative cocci Moraxella (Branhamella) catarrhalis Neisseria gonorrhoeae Neisseria meningitidis

Aerobic Microorganisms

Gram-negative bacilli

Enterobacteriaceae Citrobacter Enterobacter Escherichia coli Klebsiella Proteus Salmonella Shigella Serratia marcescens Yersinia Providencia stuartii

Acinetobacter Campylobacter Haemophilus

influenzae Helicobacter pylori Pseudomonas

aeruginosa Legionella spp Stenotrophomonas

(Xanthomonas) maltophilia

Anaerobic Microorganisms

Gram-positive cocci

Peptococcus Peptostreptococcus

bacilli Clostridia

C.perfringens C. difficile C. tetani C. botulinum

Propionibacterium acnes

Gram negitive Bacilli

Bacteroides fragilis Prevotella Fusobacterium

Miscellaneous microorganisms

Chlamydiae C. pneumoniae C. trachomatis

Mycoplasmas M.pneumoniae

Spirochetes Treponema pallidum Borrelia burgdorferi

Rickettsiae Mycobacteria

Mycobacterium tuberculosis Mycobacterium avium

intracellulare Viruses (Hepatitis,

Influenza, HIV) Fungus (Candida,

Aspergillus) Protoza

Normal flora

The human body contains a vast variety of microorganisms that colonize body systems. These organisms occur naturally in the tissues of the host and provide some benefits , including:

defense by occupying space competing for essential nutrients with pathogenic

bacteria stimulating cross-protective antibodies suppressing the growth of potentially pathogenic

bacteria and fungi

The effect of Antibiotics on normal floraPharynx

oral thrush

Intestine pseudomembranous colitis Colonization with resistant organisms

Laboratory Tests to direct antimicrobial pharmacotherapy

Laboratory tests associated with the presence of an infection NONSPECIFIC TESTS

White blood cell count and differential 4500 and 10,000 cells/mm3

Other tests the erythrocyte sedimentation rate (ESR) the C-reactive protein concentration,

they are elevated in an inflammatory process but do not confirm the presence of infection because they are often elevated in noninfectious conditions, such as collagen-vascular diseases and arthritis.

Large elevations in ESR are associated with endocarditis, osteomyelitis, and intra-abdominal infections.

 TNF alpha found in patients with serious infections.

Laboratory Identification of pathogens Direct examination(gram-positive, gram-negative, gram-variable,

bacillus, or cocci). Microscopic examination Gram stain

Cultures

Microscopic examination

wet-mount specimen preparations can provide valuable information regarding potential pathogens. Sputumbronchial aspirates scrapings of mucosal lesionsurinary sediment.

Gram stain

Using crystal violet and iodine Cerebrospinal fluid (CSF) in cases of suspected meningitis, on urethral smears for venereal diseases, on abscess or effusion specimens. Sputum They are helpful in identifying organisms that

may not grow on culture and which otherwise would be missed.

Other staining Techniques (FYI) For Fungi

India ink potassium hydroxide (KOH) Giemsa stains

For Mycobacterierium tuberculosis or atypical mycobacteriaZiehl-Neelsen stain for acid-fast bacilli

Cultures

Isolation of the etiologic agent by culture is the most definitive method available for the diagnosis and eventual treatment of infection. (Discriminating Test)

Every effort should be made

To take it before initiation of therapy To avoid contamination. Time(perish from air or dry) Transport media Source of specimen should be recorded

Diagnosis of Infection using immunologic Methods (FYI)(serology testing) Antibody and antigen Detection

detected easily during acute infection Immunofluorescence,

cytomegalovirus, respiratory syncytial virus, Latex agglutination

meningococcal capsular antigens in CSF of patients suspected of having bacterial meningitis

Legionella pneumophila. Enzyme-linked immunosorbent assay (ELISA)

HIV,

Susceptibility The minimum inhibitory concentration MIC is

defined as the lowest antimicrobial concentration that prevents visible growth of an organism after approximately 24 hours of incubation in a specified growth medium.

The minimum bactericidal concentration MBC is is defined as the lowest concentration of drug

that kills 99.9% of the total initially viable cells (representing a 3 log CFU/mL or greater reduction in the starting inoculum).

It is used in assessing the treatment of more severe infections, such as endocarditis and osteomyelitis

Susceptibility

Susceptible (S) Clinical success can be expected if treated

with usual doses Intermediate (I)

Clinical success may be possible if High doses of antibiotic are used Antibiotic concentrates at the site of infection Combination of synergistic agents are used

Resistant (R) Treatment failure is expected

Qualitative antimicrobial susceptibility Testing Disc diffusion assay

Other Susceptibility testingE test

Pharmacology

The Primary uses of antibiotics

1. Prophylaxis Medical Surgical

2. Empiric

Treat likely / suspected pathogens (usually up to 72 hours)

3. Definitive

Treat known / confirmed susceptible pathogen Use the most effective, least toxic, narrowest

spectrum, and most cost effective agent (Drug of Choice)

Classification Of Antibiotic

Pharmacodynamic

Bacteriostatic Inhibits growth at all concentrations

above MICRequires intact immune system for

killingAvoid in life-threatening diseases statesStill may be a drug of choice if no other

options

Pharmacodynamic Cont’d

Bacteriocidal: Kills MO above MIC, Kills above MBC

Dose Dependent Killing (Peak to MIC) Aminoglycosides and Quinolones “once daily” aminoglycosides

Time Dependent Killing (Time Above MIC) Beta-Lactams Tetracyclines

POSTANTIBIOTIC EFFECT is the persistent suppression of an organism’s

growth after a brief exposure to an antibiotic A PAE equal to or greater than 1 hour has been

demonstrated for most antibiotics against gram-positive bacteria.

As a general rule, antibiotics that inhibit DNA or protein synthesis (e.g., quinolones and aminoglycosides) demonstrate significant PAEs against gram-negative organisms.

POSTANTIBIOTIC EFFECT The primary clinical application of the PAE is to

allow for less frequent administration of antimicrobials while still maintaining adequate antibacterial activity

(e.g., extended-interval aminoglycoside administration).

Pharmacokinetics (ADME)

AbsorptionMany antibiotics are IV only or PO onlyOthers have excellent oral

bioavailability safer / outpatient treatment

DistributionMany sights of infection are not easily

reached by antibiotics Central nervous system, lung, bone

Metabolism / EliminationsHepatic: drug interactions via CYP 450

Inhibitors: Macrolides, Azoles Inducers: Rifampin Both: Protease inhibitors

Renal: dose adjustment with dysfunction

Elderly, critically ill

Pharmacokinetics (ADME)

Special concerns regarding antibiotics

TIMING OF COLLECTION OF SERUM SAMPLES  Peak and/or trough concentrations are monitored

routinely for only a select few antimicrobials(e.g.,aminoglycosides and vancomycin)

It is crucial to ensure that the antimicrobial’s administration time and serum sample time(s)are recorded

Samples ideally should be obtained after steady state is achieved

Combination therapy

SynergyCombination of the two antibiotic is significantly

greater than the sum of activity of either agent alone

Antagonism combination may result in activity that is worse

than either agent alone indifferent or additive.Combination activity that is neither synergistic nor

antagonistic

Aminoglycosides

Serum conc. Has been linked to clinical response and nephrotoxicity

once-daily versus multiple daily aminoglycoside dosing

Vancomycin vancomycin has been associated with oto- and

nephrotoxicity in humans, most of these reports occurred with

older, impure formulations of the drug with extremely high concentrations

uncommon with contemporary dosing regimens

or when vancomycin was combined with known nephrotoxic agents.

continuous infusions versus intermittent regimens

Systematic Approach for Selection of Antimicrobials Confirm the presence of infection

Careful history and physical Signs and symptoms Predisposing factors

Identification of the pathogen Collection of infected material Stains Serologies Culture and sensitivity

Selection of presumptive therapy considering every infected site

Host factors Drug factors

Monitor therapeutic response Clinical assessment Laboratory tests Assessment of therapeutic failure

CONFIRMING THE PRESENCE OF INFECTIONWhite Blood Cell Count (WBC)

The number of leukocytes (WBC) in the blood is often an indicator of disease. 4000 and 10,000/mm3

An increase in the number of leukocytes over the upper limits is called leukocytosis

A decrease below the lower limit is called is called leukopenia.

Most infections result leukocytosis because of the mobilization of granulocytes and/or lymphocytes to destroy invading microbes.

WBC count

The WBC count can become elevated in response to a number of noninfectious causes: Stress inflammatory conditions such as rheumatoid

arthritis leukemia in response to certain drugs (e.g.,

corticosteroids).

White blood cell Classification

Main targets % Diagram Type

BacteriaFungi

40% - 60%

Neutrophils Granulocytes(polymorphonuclear leukocytes)in allergic reactions 0.5% -

1% Basophils

parasitesin allergic reaction

1% - 4% Eosinophils

Viral infectionsTuberculosis

20%- 40%

Lymphocytes Agranulocytes (mononuclear leucocytes) phagocytosis 2% -8% Monocytes

phagocytosisstimulation of immune cells that respond to the pathogen.

Macrophages

antigen-presenting cell (APC) that activates T lymphocytes.

Dendritic cell

Neutrophils

In response to infection, they leave the bloodstream and enter the tissue to interact with and phagocytize offending pathogens.

Mature neutrophils sometimes are referred to as segs because of their segmented nucleus, which usually consists of two to five lobes.

Immature neutrophils lack this segmented feature and are referred to as bands.

Neutrophils

During an acute infection, bands are released from the bone marrow into the bloodstream at an increased rate, and the percentage of bands (usually 5%) may increase in relationship to mature cells.

The change in the ratio of mature to immature cells is often referred to as shift to the left because of the way the cells were counted by hand with a microscope and charted from immature to mature cells.

Neutropenia

Is when the neutrophil counts decreases less than 500cells/mm3 occurs in : cancer patients taking chemotherapy. elderly severe cases of sepsis

Leukocytosis is a normal host defense to infection and is an important adjunct to antimicrobial therapy. Leukocytosis does not occur in neutropenic patients

Lymphocytes

Two functional types lymphocytes are the T cell, which is involved in cell-mediated immune the B cell, which produces antibodies involved in

humoral immunity. Lymphocytosis frequently is associated with

acute viral infections such as Epstein-Barr virus infection (mononucleosis) cytomegalovirus infection rarely with unusual bacterial infections (i.e., Brucella

spp. infections).

Pain and Inflammation Pain and inflammation may accompany infection

and are sometimes manifested by swelling, erythema, tenderness, and purulent drainage.

Easly detected insuperficial infections or infections of the bone or joint.

Deep –seated infections –must examine tissues/ fluids (sputum,CSF,urine)

May be absent in neutropenic hosts

Fever

Normal body temperature 36.7 to 37 ˚C Single oral temp >38.3˚ C or 38.0 ˚C over at least 1 hour Rectal Temp - subtract 0.6˚ C (1 F) Ear or Axillary - add 0.6˚ C (1 F)

False positive: Fever is a manifestation of many disease states other than

infection. Drug-induced fever.

False negative: Medications: aspirin, and other antipyretics,

corticosteroids.

IDENTIFICATION OF THE PATHOGEN Infected body materials must be sampled before

the starting of antimicrobial

Blood culture (acutely ill/febrile patient)

Less accessible fluids or tissues are obtained when needed to assess localized Signs & Symptoms

e.g Aspiration of infected fluids (sputum, blood, urine, spinal fluid in meningitis, joint fluid in arthritis). Abscesses and cellulitic areas.

Avoid contamination

IDENTIFICATION OF THE PATHOGEN A positive culture may represent

Colonization :bacteria are present at the of infection site but are not actively causing infection

Contamination : a result of poor sampling

techniques or inappropriate handling of specimens

Infection: Invasion by and multiplication of pathogenic microorganisms in a bodily part or tissue, which may produce subsequent tissue injury and progress to overt disease through a variety of cellular or toxic mechanisms.

SELECTION OF PRESUMPTIVE THERAPY Host Factors Antibiotic Factors

HOST FACTORS (Patient-related factors)When evaluating a patient for initial or empiric therapy, the

following factors should be considered: Severity of the disease Allergy or history of adverse drug reactions Age of patient and weight Pregnancy Metabolic abnormalities Renal and hepatic function Concomitant drug therapy Concomitant disease states Site of infection

Antibiotic Factors (Drug-related factors) Empiric vs directed Antimicrobial

therapy Criteria for selecting Antimicrobial

Therapy

Antibiotic Factors

A. Empiric vs. directed antimicrobial therapy 1. Microorganisms likely to cause infection Body site (CSF, urine,blood,etc.) Knowledge of normal flora Knowledge of most likely pathogen from history

and physical exam

Antibiotic factors

2. Anticipated antimicrobial susceptibility pattern

Local patterns (hospital-wide versus specific patient care areas ICU)

Hospital versus outpatient isolates Large scale studies from the literature Published Guidelines

Antibiotic factors

3.Is combination Antimicrobial therapy necessary?

Why do we combine? Expand spectrum ß-Lactam & macrolide in CAP Prevent resistance INH & Rifampin for TB Enhance Killing (Synergy)

1 + 1 = 3 ß -Lactam + Aminoglycoside vs Gram

Negative Rod Avoid Antagonism

Static with cidal (Penicillin & Tetracyclines)

Antibiotic factors

B. Criteria for selecting Antimicrobial Therapy1. Efficacy (clinical, bacteriologic)2. In Vitro Microbiology activity (Susceptibility and

resistant)

3. Pharmacokinetics4. Pharmacodynamics5. Adverse Effects 6. Drug interactions

Antibiotic factors

B. Criteria for selecting Antimicrobial Therapy

7. Cost Acquisition cost Administrative (Supplies, personnel

,storage/inventory) Monitoring Costs (TDM, additional lab tests) Costs of toxicity Costs of poor clinical results Total cost of care

MONITORING THERAPEUTIC RESPONSE Clinical assessment

Physical examination (fever) Non invasive techniques (x-ray, scans)

Laboratory tests Cultures-Follow-up to previously positive

cultures WBC count Therapeutic drug mointoring

(efficacy/toxicity)

FAILURE OF ANTIMICROBIAL THERAPY

Failures Caused by Drug Selection

Failures Caused by host Factors Failures caused by

Microorganisms

Failures Caused by Drug Selection inappropriate selection of drug, dosage, or route of

administration.

Malabsorption of a drug product because of GI disease (e.g., short-bowel syndrome)

drug interaction (e.g., complexation of fluoroquinolones with multivalent cations resulting in reduced absorption)

Accelerated drug elimination (cystic fibrosis ,burns, or during pregnancy)

poor penetration into the site of infection. (CNS, the eye, and the prostate gland).

Failures Caused by Host Factors

Immunosuppression (e.g., granulocytopenia from chemotherapy, AIDS).

the necessity for surgical drainage of abscesses foreign bodies (e.g. orthopedic hardware,

prosthetic valve) and/or necrotic tissue.

If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.

Failures Caused by Microorganisms the development of drug resistance

during therapy. Primary resistance (intrinsic

resistance of the pathogens) acquisition of resistance during

treatment .

Pharmacists Role

Patient CareEmpiric treatment selectionOptimization of therapy

Agent selection & dosing regimenDrug Interactions (prevent & manage)Adverse Drug Events (prevent, detect &

manage)

Pharmacists Role

Organizational P&T

Formulary management Committee and Day to Day monitoring

Medication Use Evaluation Appropriateness…

ADE (including drug interactions) Infection Control

Tracking resistance outbreaks and trends Prevention (surgical prophylaxis and vaccines)