Principles of Antimicrobial Use Flashcards
What are the 4 key steps in the systematic approach to antimicrobial use?
- Confirm presence of infection [INDICATION]
- Identification of pathogens [INDICATION]
- Selection of antimicrobial and regimen [REGIMEN]
- Monitor response [MONITORING]
Step 1: Confirm presence of infection
What are the parameters to consider?
- Risk factors: disruption of the protective barriers of the innate system , immune function, age, alteration in normal flora that promotes overgrowth of microorganisms due to use of antibiotics or uncontrolled blood sugar
- Subjective (symptoms): localized and systemic
- Objective (signs):
Vital signs
fever >= 38
Hypotension <100mmHg
Tachypnea RR >22bpm
Tachycardia HR>90bpm
Change in mental status (Glasgow coma scale)
Lab test
Elevated/depressed WBC (4-10 X 10^9 /L)
Incr neutrophils (45-75%)
Incr CRP (<10mg//L, in infection >40mg/L)
Incr ESR (more utility for bone and joint infection)
Incr procalcitonin
Radiological imaging
Tissue changes, collections, abscess, obstruction
- Site of infection
Step 1: Confirm presence of infection
Why is procalcitonin more useful than CRP?
It is more specific for bacterial infection and can reflect severity of infection, used to supplement clinical assessment, guide initiation and discontinuation of antibiotics
Initiation cut off: <0.25ug/L, if stricter <0.5ug/L
*antibiotic is strongly discouraged when PCT <0.25ug/L
Discontinuation: <0.25ug/L OR decrease by >= 80% from peak conc. given <0.5ug/L
Step 1: Confirm presence of infection
When is a second PCT conc. obtain? (1st one obtain in early stage of episode)
6-12h later
Step 1: Confirm presence of infection
Other than bacteria infection, Procalcitonin may also be elevated in:
- ESRF (since it is cleared by the kidneys)
- Traumatic brain injury (TBI)
Step 2: Identification of pathogens, indication for antibiotic
Cultures should be obtained before administering antimicrobial because follow-up cultures are less reliable. Why is this so?
Follow up cultures may not reflect initial causative organisms
Follow up cultures can cause false negative
Step 2: Identification of pathogens, indication for antibiotic
What is the difference between pathogen, coloniser, and contaminant?
Pathogen: organism capable of invading host tissue, elicit host response, can be acquired from environment or due to normal flora invading other tissues
Coloniser: presence of normal flora or pathogenic organisms without eliciting host response
Contaminants: presence of microorganism acquired during collection/processing of host specimen, no host response
=> proper collection and handling of specimen is impt (e.g., take midstream urine, draw blood after proper disinfection)
Step 2: Identification of pathogens, indication for antibiotic
Mixed growth is often due to ________
Colonization
Not likely to be pathogen since good ecology still present, unlikely for one to cause infection
E.g., mixed growth of skin commensals + gram-negative bacilli
*gram-negative bacilli likely represent superficial colonisation or post-antibiotic flora
Step 2: Identification of pathogens, indication for antibiotic
What are some considerations to determine if its a pathogen?
Is it usually found at the site
Is it single huge inoculum or mixed growth
Is it isolated from multiple cultures/specimens
Any signs of invasion of the tissue
Signs and symptoms
Epidemiology, likelihood of causing disease
Step 3: Selection of antimicrobial regimen
What to consider?
- Empiric, definitive (culture-directed), or prophylaxis
- Which agent, route, dosing, duration
- Consider organism, host, drug factors
Step 3: Selection of antimicrobial regimen
Empiric therapy is based on ______, while definitive therapy is based on ________
Empiric: clinical presentation of likely site, likely susceptibility (antibiogram, drug spectrum of activity), consider pt risk factor for MDR pathogens (e.g., recent antibiotic use)
Definitive: based on susceptibility (culture and AST results)
Step 3: Selection of antimicrobial regimen
What are some organism factors?
- Identify organism
- Susceptibility/resistance of the infecting organism
- Assess need for combination therapy
Step 3: Selection of antimicrobial regimen
For combination therapy, we look at the time-kill curve (log10 CFU over time) of the drugs to determine indifference, synergy, and antagonism. (and choose synergy)
Explain these.
Indifference: combi shows no diff in time to kill
Synergy: combi shows decrease in time to kill, more effective
Antagonism: combi is less effective than single drug
Step 3: Selection of antimicrobial regimen
When might we consider using combination therapy (advantages)?
To achieve synergistic bactericidal effect
To extend spectrum of activity:
- to cover all resistant strains of the organism esp when no 1 agent has susceptibility close to 100% (for empiric)
- when it is a polymicrobial infection (empiric/definitive)
To prevent development of resistance
- for combinations against M. tuberculosis and HIV (since they multiply quickly, and develop resistance at faster rate)
Step 3: Selection of antimicrobial regimen
What are some disadvantages of combination therapy?
- incr risk of toxicity + allergic reaction
- incr risk of DDI
- incr cost
- selection of MDR bacteria (incr selection pressure)
- incr risk of superinfections (CDAD, fungal)
Step 3: Selection of antimicrobial regimen
What are some host factors that can affect selection of antimicrobial regimen?
- age (dosing, prevalence of organism, antibiotic CI in children)
- G6PD deficiency (cotrimoxazole, sulfonamide, nitrofurantoin)
- history of allergies and ADRs (consider cross-reactivity as well)
- pregnancy or lactation (safety of drug in pregnancy or fetus, changes in PK of antibiotics)
- renal or hepatic impairment (dose adjustment, toxicity)
- immune function status
- severity of illness
- recent antimicrobial use (in last 6 months, risk factor for drug resistant organism)
- healthcare associated risk factors
Step 3: Selection of antimicrobial regimen
Cross reactivity of penicillins and other B-lactams is due to allergic rxn between B-lactams with similar R1 side chain.
Give examples of B lactams with common shared R1 side chain.
Amoxicillin, Ampicillin, Cephalexin
(Cephalexin cannot be used with the aminopenicillins)
Cefepime, Ceftriaxone
Ceftazidime, Aztreonam
Step 3: Selection of antimicrobial regimen
Which B lactam has no shared side chain?
Cefazolin
Step 3: Selection of antimicrobial regimen
What are some drug factors that can affect selection of antimicrobial regimen?
- spectrum of activity
- reach site of infection (e.g., able to penetrate CSF to treat CNS infections)
- bactericidal vs bacteriostatic (bactericidal when MBC is within one 2 fold dilution of MIC)
- PK-PD
- route of administration (site and severity, IV vs Oral)
- side effects (ADRs and infirect effects such as superinfection, collateral damage - development of resistance against other antibiotics - fluoroquinolone cause resistance to 3rd gen cephalosporin)
- drug interactions
- duration of use (specify review or stop date)
- cost
Step 3: Selection of antimicrobial regimen
How is PK-PD used to predict outcomes?
Use serum conc. (PK profile) and MIC to predict clinical outcome:
If conc. dependent: Cmax/MIC ratio
Optimise: Cmax 8-10x MIC
e.g., aminoglycoside (also has PAE), fluoroquinolones
If time dependent with no PAE/with short half-life: %T above MIC
Optimise: 40-70% of dosing interval above MIC
e.g., B-lactams
If time dependent with PAE/with long half-life: AUC24h/MIC ratio
Optimise overall drug exposure, AUC = (F . Dose) / CL
e.g., vancomycin
Step 3: Selection of antimicrobial regimen
PK-PD drug factor, what is PAE?
Post antibiotic effect - ability of antimicrobial agent to persistently suppress bacterial growth even at low conc.
Step 3: Selection of antimicrobial regimen
Why are conc. dependent antibiotics dosed at larger dose at extended intervals?
Maximize efficacy while limiting toxicity
Allow downtime that prevent adaptive resistance
Lower cost
If PAE - drug can still have effect at low conc.
Step 3: Selection of antimicrobial regimen
What is Hartford nomogram used for?
Use conc. of sample drawn 6-14h after administration to determine the dosing interval for TDM of conc. dependent antibiotics.
Step 3: Selection of antimicrobial regimen
How should dosing for aminoglycoside be calculated?
Aminoglycoside is hydrophilic, follows water
Hence,
Use TBW if TBW =< 130% IBW
Use AdjBW if TBW > 130% IBW, in order to deduct additional adipose tissue weight
AdjBW = 0.4 (TBW - IBW) + IBW
Step 3: Selection of antimicrobial regimen
ORAL route of administration is preferred unless:
- Absorption problem (e.g., GI pathology)
- Oral not available
- High tissue conc. required (e.g., endocarditis, meningitis, bone/joint)
- Urgent treatment
- Non-compliance
Step 3: Selection of antimicrobial regimen
Drug factors
What are some drug interactions based on PK interactions?
A:
- impaired absorption of tetracycline/fluroquinolone due to divalent/trivalent cations => form non-absorbable chelates
- antacid and PPI decrease absorption of itraconazole, isoniazid, ethambutol
- erythromycin has prokinetic effect (motilin agonist) can reduce absorption of other drugs
M:
- CYP450 inhibitors: macrolides, azoles, isoniazid
- CYP450 inducers: Rifampicin
- Substrates, metabolised by CYP450: Voriconazole, Terbinafine, Metronidazole
E
- Probenecid inhibits tubular secretion of penicillins, increase penicillin conc. (prolong its effect)
Step 4: Monitor response
What are the 2 treatment goals?
- Achieve therapeutic response
- Resolution of symptoms and signs
- Microbiological clearance
- Absence of complications/progression - Minimal adverse drug reactions
Step 4: Monitor response
Why is clinical response evaluate after 48-72h?
Give antibiotic adequate time to work before evaluation
Step 4: Monitor response
When should therapy be modified?
- When empiric not effective (escalate to broader spectrum)
- When AST available (de-escalate to narrowest spectrum possible)
- When response satisfactory (switch from IV to oral, consider stopping)
- When response unsatisfactory (re-evaluate)
Step 4: Monitor response
What are some possible reasons for unsatisfactory response?
- inappropriate diagnosis (non-infectious cause)
- inappropriate choice of agent, resistance to agent
- subtherapeutic conc. (due to non-compliance, DDI, improving renal function)
- collections or abscess
- impaired host defense
- superinfection
- toxicity of drug
What are the 3 main principles of Antimicrobial use to achieve improved pt outcomes?
- Narrowest Spectrum
- Individualized dosage
- Shortest duration
Daptomycin is not used for ______ as it is inactivated by _______
Not used for pneumonia, inactivated by lung surfactants
*Daptomycin: gram positives inlcuding MSSA, MRSA, VRE, Strep
*NOT used for Strep pneumoniae
