Fundamentals of Infectious Disease

Normal flora (resident flora)

microorganisms usually found on/in the human body

Colonization (transient flora)

microorganisms found on/in body for a period of time but are not considered normal flora as they are acquired from environment or other hosts

Pathogen

microorganism that can cause disease in a host; can be acquired or from host’s own flora

Does the presence of microorganisms mean there is an infection?

no, just because something grows doesn’t mean there is an infection; infection occurs when there is damage

What are the three characteristics that increase likelihood of infection?

• size of inoculum

• virulence of pathogen

• effectiveness of host defenses (most important)

Innate Immune System

First line of defense against pathogens. Non-specific response that includes physical barriers (skin, mucous membranes), phagocytic cells (neutrophils, macrophages), and antimicrobial proteins (complement, cytokines). Rapid response, but lacks memory.

Adaptive Immune System

The part of the immune system that responds to specific pathogens. It recognizes, attacks, and remembers invaders to provide long-term protection against future infections. It involves B cells, which produce antibodies, and T cells, which directly destroy infected cells. The adaptive immune system is highly specialized and can adapt to new threats. Slower to activate vs innate immune system.

Can identifying and correcting deficiencies in a patients immune system reduce risk of infection?

yes, if properly identified and corrected (when possible) can decrease risk

Characteristics of normal flora

• changes over space and time

  • acquire from environment, so if different environments it changes

• capable of causing infection if defenses fail

• protects against infection

  • produced toxins - keeping other bacteria away

  • competes for nutrients and binding sites

  • stimulates low-level activation of host immune system

Important normal flora in nasopharynx

• Pneumococci

• Staphylococcus aureus (not everyone but enough)

• Haemophilus influenzae

• Staphylococcus epidermidis

Important normal flora in oral cavity

• Candida

• Anaerobes (excluding Bacteroides)

Important normal flora on skin

• Candida

• Staphylococcus aureus (some people)

• Propionibacterium

• Staphylococcus epidermidis

Important normal flora in gut

• Enterococci

• Candida

• Enterobacterales

• Anaerobes (including Bacteroides)

Antimicrobial

natural, semisynthetic or synthetic substance that destroys or inhibits the growth of microorganisms (includes activity against bacteria, viruses, fungi and protozoa)

Antibiotic

substances produced by or derived from microorganisms (includes activity against bacteria only)

antimicrobials

All antibiotics are ______________, but not all ______________ are antibiotics.

Susceptible

if a microorganism is likely to be harmed or killed by an antimicrobial agent at normal doses

Resistant

if a microorganism is able to withstand the effects of an antimicrobial agent at normal doses

For a microorganism to be resistant, why must it withstand at normal doses to be considered resistant?

must be normal doses, because it will eventually be susceptible at a large dose, but this is not manageable to treat a human as there would be adverse reactions

Intrinsic resistance

inherent ability of a species to oppose activity of a particular agent because of its structural or functional characteristics

Acquired resistance

a strain or subpopulation of a species gains the ability to oppose activity of an agent to which it was previously susceptible (can occur through horizontal gene transfer or random mutation)

Selective pressure

microbes not killed by antimicrobials (due to resistance from mutation or gene transfer) survive and multiply, leading to the emergence of strains that are partially or fully resistant to antimicrobial treatment

Collateral damage

normal flora unintentionally harmed by antimicrobial therapy

Superinfection

second infection superimposed on an earlier one by a pathogen that is resistant to antimicrobial therapy previously used, generally by opportunistic pathogens

Opportunistic pathogen

microorganism that usually does not cause infection but can do so in vulnerable individuals (e.g. immunocompromised)

5 guiding principles of antimicrobial stewardship

1. use leads to resistance in patients AND communities

2. antibiotic-resistant organisms are harder to treat

3. antimicrobials are a shared resource (resistant strains can spread)

4. cannot develop new drugs fast enough

5. if cannot conserve, will risk entering a “post-antibiotic era”

Only use antimicrobials when necessary and then ensure to use the…

…right drug at the right dose for the right amount of time

3 golden rules of antimicrobial stewardship

1. limit collateral damage

2. avoid unnecessary use

3. use shortest duration for effectiveness possible

Does not completing your course of antibiotic treatment cause resistance?

no, this is a myth, median duration of therapy is usually too long and every extra day is associated with measurable harm. Patients should be advised to contact their clinician when they are feeling better, to see if stopping is reasonable.

Step 1: Inflammatory response to infection

pro-inflammatory mediators released by damaged and phagocytic cells in the area; causing local symptoms of inflammation (erythema, warmth, edema and pain)

Step 2: Inflammatory response to infection

if local inflammatory reaction not contained, mediators spill into bloodstream; causing systemic symptoms of inflammation (fever, tachycardia, tachypnea, leukocytosis, bandemia)

• does NOT mean bacteria has spread into bloodstream

Bandemia

increased levels of immature WBC released into bloodstream (left shift)

Step 3: Inflammatory response to infection

if systemic inflammatory reaction not contained, it may become dysregulated; causing uncontrolled vascular permeability leading to decreased organ perfusion with or without hypotension = sepsis

Sepsis

a life-threatening organ dysfunction caused by a dysregulated host response to infection

Step 4: Inflammatory response to infection

if sepsis progresses, patient can develop shock and multisystem organ failure which has a mortality rate of >40%

Does evidence of systemic inflammation mean pathogens have spilled into bloodstream?

no, just because there is systemic inflammation does not necessarily mean there is a systemic infection. A patient can have bacteremia without a fever and can have a fever without bacteremia.

Does an infection have to progress through steps 1-4 of the inflammatory response?

no, the progression of the infection is dependent on virulence, size of inoculum, effectiveness of therapies and most importantly - baseline health status of patient.

How to identify if antimicrobial is indicated?

• confirm the presence (or likelihood) of infectious syndrome

  • local features of inflammation

  • systemic features of inflammation

  • diagnostics

Signs and symptoms or systemic inflammation

• Heart rate >100bpm

• Respiratory rate >20bpm

• fever or <36C

• systolic BP <100 or >20 decrease - because not enough blood to perfuse

  • may not need to physically check, look for dizziness etc.

• very high or very low WBC or >10% bands

Gram-stain and morphology of S. aureus

• gram-positive

• cocci clusters

• coagulase positive

Gram-stain and morphology of S. pneumoniae

• gram-positive

• cocci chains or pairs

• alpha-hemolytic

Gram-stain and morphology of S. pyrogenes

• gram-positive

• cocci chains

• beta-hemolytic

Gram-stain and morphology of N. gonorrhoeae

• fuchsia = negative

• cocci

Gram-stain and morphology of E. coli and Klebsiella

• fuchsia = negative

• bacilli

• lactose fermenter

• negative oxidase

Gram-stain and morphology of Pseudomonas

• gram-negative

• bacilli

• non-lactose fermenter

• positive oxidase

Gram-stain and morphology of Proteus

• gram-negative

• bacilli

• non-lactose fermenter

• negative oxidase

Gram-stain and morphology H. influenzae and M. catarrhalis

• fuchsia = negative

• coccobacilli

Important factors of interpreting microbiological data

• can optimize therapy with data

• accurate interpretation is essential

• false negatives

  • insufficient volume

  • fastidious organism

  • drawn after antibiotic admin

• false positives

  • collection technique

  • storage and transportation

What are the reasons “just-in-case” prescribing occurs?

• lack of diagnostic certainty

• fear of result if infection not adequately treated

• perception that antimicrobial therapy is benign (“what’s the worst that can happen? diarrhea?” - people do not have same thought process for chemo)

Empiric therapy

when therapy is given without definitive knowledge of if or what the infection is. Is unavoidable in some circumstances and tends to be more broad treatment. Requires educated gues as to pathogens that are present.

Targeted therapy

when therapy is given when are aware of type of infection and susceptibility. Tends to be more narrow and less collateral damage.

Under what circumstances is empiric therapy given?

when definitive microbiology is not available or impractical (e.g. cannot sample bottom of lungs for someone with pneumonia), or when there is a serious infection and delay in therapy would result in poorer outcomes

What questions do you need to ask when deciding on an empiric antimicrobial: what could the pathogen be?

1. what does the literature say are common pathogens for this infection?

2. are there any types of exposure that could have caused it?

3. reasons for increase or decrease suspicion of a certain pathogen? (immunizations, previous cultures, exposure to hospital setting)

4. is there potentially resistance? consider population based and individual risk

5. do I have to cover all potential pathogens? risks for over or under treating

What do you need to ask to see if antibiogram is applicable to patient?

• How recent?

• How many isolates included?

  • <30 is unreliable

• What patients did the lab service?

  • outpatient, LTC, ICU

• What type of isolates were submitted?

What questions do you need to ask when deciding on an empiric antimicrobial: what antimicrobial is effective?

1. is the agent likely to be effective against the pathogen?

2. will the agent penetrate to the site of infection?

3. what does the evidence say about this pathogen? (might not have evidence)

What are 2 buzz words that are myths when talking about antibiotic efficacy?

“superbug” and “strong” antibiotic - both do not exist

Is penetration related to the route of administration?

no, there is no route of administration that will penetrate “more”. Being able to penetrate is based on the absorption to the site of the infection.

What factors need to be considered to determine safety of antimicrobial agent for a patient?

• Age

  • extremes have unique PK-PD issues

• Allergies

• Pregnancy

  • concern for patient and fetus

• Comorbidities

  • can change PK

  • need altered doses

• Routes of administration

  • ability to swallow,

  • increase risk with parenteral

• collateral damage

  • unavoidable, but can it be minimized

What factors need to be considered for patient adherence to antimicrobial agent?

not generally an issue because short term therapy

• cost

• duration

• dosage form (might need suspension and not available)

• interactions

• palatability

• ongoing monitoring (vancomycin)

• frequency of administration

Time-dependent agents

efficacy correlates with percent time that the concentration at the site of infection is greater then MIC (e.g. B-lactams)

if dose isn’t taken on time, then concentration drops below threshold and antibiotic is no longer working anymore

Concentration-dependent

efficacy correlated with ratio of peak concentration at the site of infection to MIC (e.g. aminoglycosides)

just need a very high peak, and doesn’t matter if at some point gets to zero at some point