General principles of infectious disease
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General Principles of Infectious Disease. November 2011 Lobna Al Juffali,MSc. Objectives. Recall foundational principles of microbiology, pharmacology, pathophysiology, & immunology in the treatment of infectious diseases

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General principles of infectious disease

General Principles of Infectious Disease

November 2011

Lobna Al Juffali,MSc


Objectives

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

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

Outline

  • Microbiology

  • Laboratory Tests to direct antimicrobial pharmacotherapy

  • Antibiotic Introduction

  • Systemic Approach in selecting an antibiotic


Pharmacotherapy of infectious diseases general principles

Pharmacotherapy of Infectious Diseases General Principles

  • Why do we care?

    • Major cause of morbidity & mortality

    • Accounts for billions $ a year world wide

    • Inpatient & Outpatient prescriptions

      • 1/3 of hospital budgets

      • 14 of the top 100 hospital drugs

      • Major % of outpatient prescriptions


Why does it happen 1

Why does it happen? 1

We share the world with potential pathogens

  • Exposure to a virulent pathogen

    • Brucella, Malaria, HIV, Tb, STD’s, H1N1

  • Public health measures are not followed like

    • Hand washing

    • Vaccination

    • Vector control

    • Avoiding contact


Factors predisposing to infection

Factors predisposing to infection

  • Alteration in normal flora

  • Distruption of natural barriers

  • Age

  • Immunosuppression secondary to:

    • Malnutrition

    • Underlying disease

    • Hormones

    • drugs


Microbiology

Microbiology


Microorganisms

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


    Aerobic microorganisms1

    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

    Aerobic Microorganisms


    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

    Anaerobic Microorganisms


    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

    Miscellaneous microorganisms


    Normal ora

    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 flora

    The effect of Antibiotics on normal flora

    Pharynx

    • oral thrush

      Intestine

    • pseudomembranous colitis

    • Colonization with resistant organisms


    Laboratory tests to direct antimicrobial pharmacotherapy

    Laboratory Tests to direct antimicrobial pharmacotherapy


    Laboratory tests confirming the presence of infection

    Laboratory tests confirming the presence of infection

    • NONSPECIFIC TESTS

      • White blood cell count and differential

    • 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 intraabdominal infections.

      •  TNF alpha found in patients with serious infections.


    Laboratory identification of pathogens

    Laboratory Identification of pathogens

    • Direct examination

      (gram-positive, gram-negative, gram-variable, bacillus, or cocci).

      • Microscopic examination

      • Gram stain

  • Cultures


  • Microscopic examination

    Microscopic examination

    wet-mount specimen preparations can provide valuable information regarding potential pathogens.

    Sputum

    bronchial aspirates

    scrapings of mucosal lesions

    urinary sediment.


    Gram stain

    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

    Other staining Techniques

    • For Fungi

      • India ink

      • potassium hydroxide (KOH)

      • Giemsa stains

    • ForMycobacterierium tuberculosis or atypical mycobacteria

      • Ziehl-Neelsen stain for acid-fast bacilli


    Cultures

    Cultures

    • Isolation of the etiologic agent by culture is the most definitive method available for the diagnosis and eventual treatment of infection.

    • Every effort should be made

      • to avoid contamination.

      • Time(perish from air or dry)

      • Transport media

      • Source of specimen should be recorded


    Diagnosis of infection using immunologic methods serology testing

    Diagnosis of Infection using immunologic Methods(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

      • Legionellapneumophila.

    • Enzyme-linked immunosorbent assay (ELISA)

      • HIV,


    Susceptibility

    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


    Susceptibility1

    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


    Quantitative antimicrobial susceptibility testing

    Quantitative antimicrobial susceptibility Testing

    • The minimal inhibitory concentration (MIC)

    • The MIC quantitatively determinates in vitro antibacterial activity.

      determined via

      • the macrotube dilution method

      • 96-well microtiter plates

      • Solid agar


    Macrotube dilution method

    Macrotube Dilution Method


    96 well microtiter plates

    96-well Microtiter Plates


    Qualitative antimicrobial susceptibility testing

    Qualitative antimicrobial susceptibility Testing

    Disc diffusion assay


    Other susciptability testing e test

    Other Susciptability testingE test


    Pharmacology

    Pharmacology


    The primary uses of antibiotics

    The Primary uses of antibiotics

    • Prophylaxis

      • Medical

      • Surgical

  • Empiric

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

  • 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

    Classification Of Antibiotic


    Pharmacodynamic

    Pharmacodynamic

    • Bacteriostatic

      • Inhibits growth at all concentrations above MIC

      • Requires intact immune system for killing

      • Avoid in life-threatening diseases states

      • Still may be a drug of choice if no other options


    Pharmacodynamic cont d

    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


    Postantibiotic effect

    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 effect1

    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

    Pharmacokinetics (ADME)

    • Absorption

      • Many antibiotics are IV only or PO only

      • Others have excellent oral bioavailability

        • safer / outpatient treatment

    • Distribution

      • Many sights of infection are not easily reached by antibiotics

        • Central nervous system, lung, bone


    Pharmacokinetics adme1

    Pharmacokinetics (ADME)

    • Metabolism / Eliminations

      • Hepatic: drug interactions via CYP 450

        • Inhibitors: Macrolides, Azoles

        • Inducers: Rifampin

        • Both: Protease inhibitors

      • Renal: dose adjustment with dysfunction

        • Elderly, critically ill


    Special concerns regarding antibiotics

    Special concerns regarding antibiotics


    Timing of collection of serum samples

    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

    Combination therapy

    Synergy

    Combination 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

    Aminoglycosides

    • Serum conc. Has been linked to clinical response and nephrotoxicity

    • once-daily versus multiple daily aminoglycoside dosing


    Vancomycin

    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

    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 infection

    CONFIRMING THE PRESENCE OF INFECTION

    • Fever

      • Normal body temperture 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)

        • Axillary - add 0.6˚ C (1 F)

    • Fever is a manifestation of many disease states other than infection.

    • Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition.


    Confirming the presence of infection1

    CONFIRMING THE PRESENCE OF INFECTION

    White 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

    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

    White blood cell Classification


    Neutrophils

    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 segsbecause of their segmented nucleus, which usually consists of two to five lobes.

    • Immature neutrophils lack this segmented feature and are referred to asbands.


    Neutrophils1

    Neutrophils

    • During an acute infection, bands are released from the bone marow 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

    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

    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., Brucellaspp. infections).


  • Pain and inflammation

    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


    Identification of the pathogen

    IDENTIFICATION OF THE PATHOGEN

    • Infected body materials must be sampled before the starting of antimicrobial

    • Blood culture (acutely ill/febrile patient)

    • less accessable 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 pathogen1

    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 ofpoorsampling 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

    SELECTION OF PRESUMPTIVE THERAPY

    • Host Factors

    • Antibiotic Factors


    Host factors

    HOST 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

    Antibiotic Factors

    • Empiric vs directed Antimicrobial therapy

    • Criteria for selecting Antimicrobial Therapy


    Antibiotic factors1

    Antibiotic Factors

    • 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 factors2

    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 factors3

    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 factors4

    Antibiotic factors

    B.Criteria for selecting Antimicrobial Therapy

    • Efficacy (clinical, bacteriologic)

    • In Vitro Microbiology activity (Susceptibility and resistant)

    • Pharmacokinetics

    • Pharmacodynamics

    • Adverse Effects

    • Drug interactions


    Antibiotic factors5

    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

    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

    FAILURE OF ANTIMICROBIAL THERAPY

    • Failures Caused by Drug Selection

    • Failures Caused by host Factors

    • Failures caused by Microorganisms


    Failures caused by drug selection

    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

    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

    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

    Pharmacists Role

    • Patient Care

      • Empiric treatment selection

      • Optimization of therapy

        • Agent selection & dosing regimen

      • Drug Interactions (prevent & manage)

      • Adverse Drug Events (prevent, detect & manage)


    Pharmacists role1

    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)


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