Principles of Antimicrobial Use

Key principles of antimicrobial use include:

Empirical antibiotics are those given to cover likely organisms, rather than given in response to a known pathogen.

Inappropriate or delayed antibiotic use ↑ morbidity and mortality.

Sensible prescribing
Appropriate sourcing and prescription of cultures
Antimicrobial characteristics
- Minimum inhibitory concentration
- Kill characteristics
- Post-antibiotic effect
Treatment failure
Dose adjustment

Prescribing

Principles:

Administer antibiotics without delay
Choice of empirical antimicrobial should be based upon:
- Site of infection
- Community or hospital-acquired
- Local microbiome
  Understanding of the hospital or intensive care units antibiogram.
- Patients previous microbiology results
The narrowest-spectrum drug should be used
Ideally empirical spectrum can be narrowed after 3 days.
Drugs eliminate susceptible organisms, at the cost of significant side-effects
- Provide huge evolutionary advantage to resistant strains
- Promote overgrowth of non-susceptible organisms
  - Including fungi
Monotherapy is preferable to combination therapy
Exceptions include:
- Achieving adequate empiric cover
- Treatment of polymicrobial infections with known sensitivities
- Antibiotic synergy
  - Neutropaenic sepsis
  - Known bacteraemia
  - High (>25%) mortality
Clinical response should be used to guide therapy
- In vitro sensitivity does not equate with clinical effectiveness
- In vitro resistance is a better predictor than sensitivity
A >7 day course is rarely indicated
- Prolonged courses are associated with significant adverse effects
- Exceptions include:
  - Immunosuppressed patients
  - Osteomyelitis
  - Infective endocarditis
  - Complicated bacteraemia
    Require longer therapy and have ↑ mortality. Indicated by:
    - CNS involvement
    - Septic emboli
    - Multiple infected regions
    - Recurrent infection
An adequate dose should be given
Under-dosing leads to resistance.
Serum levels of toxic antibiotics should be monitored for both toxicity and efficacy
Recognise patients with augmented renal clearance, and ↑ dose accordingly

Factors Influencing Antibiotic Choice
Category	Factor	Examples
Patient	Age	Weight-based dosing
	Allergies	Presence Significance
	Metabolic function	↓ Renal clearance Renal failure Augmented renal clearance Dialysis Pregnancy High CO state ↓ Hepatic clearance Altered clearance Extracorporeal circuits Plasma exchange Haemoperfusion
	Pregnancy	Teratogenesis Tetracyclines, chloramphenicol, sulfonamides. Lactation
	Immunocompetence	Immunosuppression Transplantation Steroid use Vaccination status Asplenia Chemotherapy Radiotherapy Malignancy Malnutrition
	Genetic	G6PD Nitrofurantoin, fluoroquinolones, cotrimoxazole, sulfamethoxazole, primaquine.
Epidemiological	Travel	Regional geography Known outbreaks Seawater Vibrio vulnificus.
	Occupational	Abattoir workers Coxiella burnetii Cattle farmers Brucella sp.
	Recreational	IVDU Pets Birds Psittacosis. Cats Toxoplasmosis. Bushwalking Tick-borne illnesses.
	Therapeutic	Recent antimicrobial use Drug interactions
Disease	Clinical	Clinical urgency Differential diagnosis Likelihood of diagnosis
	Infection	Source control Controlled Uncontrolled Uncontrollable Persistent bacteraemia Duration of therapy Clinical response to existing therapy
	Organism	Resistance patterns Local antibiogram Life-cycle Particularly for parasites, which may only be vulnerable at certain stages.
Drug	Pragmatic	Cost Availability Available routes of administration
	Pharmacokinetics	Bioavailability Absorption Penetration CSF Organ affinity Organ aversion
	Pharmacodynamic	Bactericidal vs. bacteriostatic Synergism TB.

Microbial Cultures

Microbiological specimens should be obtained before commencing antimicrobials
- Prevents false-negative cultures
- Immediate Gram stain may guide therapy
Interpretation of cultures depends on the site:
- Sterile sites:
  - Include blood, urine, CSF
  - Cultured organisms are significant and indicate infection
  - Usually only one organism cultured, which is the causative organism
- Non-sterile sites:
  - Usual commensal organisms are expected
  - Diagnosis of infection is clinical
    Exception is cultured organisms that are definitively not commensal:
    - Legionella
    - TB
  - Microbiological results guide treatment
Gram negative organisms become dominant with hospital admission
The hallmark of an intravascular device infection (including CLABSI) is a continuous bacteraemia

True bacteraemia (or fungaemia) should be assumed with culture of:

S. Aureus
E. Coli
Candida

An antibiogram is a summary of the local antimicrobial susceptibilities of different pathogens, and is important to determine choices for antimicrobial agent for both empirical therapy, and prior to receiving sensitivity data.

Drug Properties

Minimum Inhibitory Concentration

The MIC is the lowest concentration of antimicrobial that will inhibit visible growth of an organism after overnight incubation. The MIC is:

Reported as μg/mL
A lower MIC indicates ↑ efficacy.
Easily performed
Usually automated, and therefore reproducible
Affected significantly by:
- Incubation time
  ↑ MIC with ↑ time.
- Concentration of bacteria in sample
  ↓ MIC with ↓ concentration.
Not a perfect surrogate for in vivo efficacy
- Other factors besides MIC determine antibiotic effect
- Antibiotic tissue concentration (at site of disease) may be higher or lower than sampled serum concentration

Kill Characteristics

Antibiotics can effect bacterial genocide in three broad ways:

Time-dependent killing
Efficacy dependent on the time that antibiotic concentration exceeds MIC, but not by how much.
- Occurs when the drug only works at a particular point in the bacterial life cycle
  e.g. Preparation for cell division.
- Threshold effect
  - Maximal effect reached at some proportion (usually 40-70%) of the dosing interval
    Drug concentrations do not have to be continuously over MIC.
  - Affected by tissue penetration
    Time over MIC is important only in the tissue where the infection is, which may not be in blood (where we measure concentrations).
- Lend themselves to dosing by infusion
  - Benefits (at steady-state) include:
    - ↓ Mortality compared to intermittent dosing
    - ↑ Time above MIC, which should ↑ efficacy and ↓
    - ↓ Peak concentration, which generally ↓ toxicity
    - ↓ Nursing workload
  - Disadvantages include:
    - ↓ Concentration gradient driving diffusion into tissues
    - Most drugs are not pure time-dependent killers, and ↑ concentration still results in some ↑ efficacy
    - MIC is not known in early stages of treatment
    - Requires continuous use of a lumen
  - May ↓ ventilator days without clear evidence of mortality benefit, with greatest effect seen in the critically ill
- Examples include:
  - β-lactam
  - Carbapenems
  - Linezolid
Concentration-dependent killing
Efficacy dependent on how much antibiotic concentration exceeds MIC, but not by how long for.
- Occurs when drug affects some critical component of bacterial infrastructure
- Greater effect with greater dose
- Examples include:
  - Aminoglycosides
  - Metronidazole
  - Fluoroquinolones
Time and concentration-dependent killing
Efficacy dependent on both time over MIC and concentration above MIC.
- Occurs for drugs which prevent synthesis of components for cell division
  - ↑ Concentration results in ↑ inhibition of relevant components
  - ↑ Time results in affecting a greater number of bacteria
    As they won’t all divide at the same time.
- Examples include:
  - Fluoroquinolones
  - Azithromycin
  - Glycopeptides

Post-Antibiotic Effect

The post-antibiotic effect describes bacterial killing that persists after the concentration falls below MIC. Post-antibiotic effects:

Are an idiosyncratic feature of some agents
Usually where the drug binds strongly to some part of the bacteria.
Are strongest generally for drugs with concentration-dependent killing

Treatment Failure

Antibiotic treatment failure may occur due to:

Wrong bug
- Not susceptible
  - Viral
  - Fungal
  - Parasitic
- Not infection
Wrong drug
- Resistant organism
- Poor penetration to infected tissue
- Bacteriostatic antagonism
  Administration of a bacteriostatic antibiotic may ↓ efficacy of a bacteriocidal antibiotic, as cell division cannot be interrupted if it does not occur.
Wrong dose
- Too small
- Too infrequent
- Too short
Wrong route
- Inadequate oral absorption
Source control
- Incomplete surgical resection
- Inadequate sputum clearance

Dose Adjustment

Pharmacokinetic Changes in Critical Illness
Characteristic	Increased With	Decreased With
Peak Target Concentration	↓ Protein binding ↑ Free drug fraction. ↑ Penetration into target tissue	↓ Gut absorption ↑ V_D Oedema ↑ distribution of water-soluble agents. ↓ Penetration
Half-life	Renal dysfunction Hepatic dysfunction Particularly sepsis. ↓ Metabolism	RRT Enzyme induction

Renal Failure

Adjusting antibiotic administration in renal failure is to avoid toxicity as efficacy is unaffected by impaired renal clearance. Drugs may require:

In general:

Interval-adjustment:
- Aminoglycosides
- Fluoroquinolones
- Glycopeptides
Dose or Interval adjustment:
For drugs not particularly toxic in overdose either can be chosen, although interval adjustment is cheaper.
- Beta-lactams
- Carbapenems

Dose adjusted
- Best for both:
  - Time-dependent killing
    Time above MIC determines efficacy, but amount above MIC doesn’t.
  - Concentration-dependent toxicity
- Maintains time above MIC, with ↓ dosing to avoid progressively ↑ drug levels when amount given exceeds amount cleared
Interval adjusted
- Best for both:
  - Concentration-dependent killing
    Peak concentration should be 8-10 times MIC, but the time above MIC doesn’t effect efficacy.
  - Concentration-dependent toxicity
- Maintains the high peak concentration required for killing, but minimises concentration at other times

Renal Replacement Therapy

Dose adjustment on RRT is similar to renal failure. In general, drugs can require:

No adjustment
Administration is unchanged due to:
- Small free drug fraction
  - High V_D
  - Highly protein bound
- Hepatically cleared
- Cleared by filtration
  CRRT replicates glomerular filtration reasonably well, but not other forms of renal clearance.
Interval adjustment
- Actively transported drugs
  Renal clearance by tubular secretion is not replicated by CRRT, and so interval adjustment needed to ↓ toxicity.
Dose adjustment
- Renally reabsorbed drugs
  Drugs that are usually reabsorbed by the tubule undergo increased clearance in the kidney, and therefore require ↑ dose on RRT.

Key Studies

FABLED (2019)
- Adults in the ED with suspected severe sepsis
- Multi-centre (7) diagnostic cohort study
- 2 sets of blood cultures taken before antibiotics via separate venepuncture
- 1-2 sets of cultures taken 30-240 minutes after antibiotics
- Significant ↓ in positive cultures post antibiotics
  - ~30% positive pre-antibiotic, compared to ~20% positive post-antibiotic
    RRR ~33%.
  - More pronounced ↓ in positive post-antibiotic cultures if organism was sensitive to antibiotic used
    RRR ~50%.
  - Positive post-antibiotic cultures were associated with ↑ time to positivity, suggesting ↑ bacterial burden
Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock (2024)
- β-Lactam antibiotics are commonly used as first-line agents in sepsis, and their bactericidal activity is related to time-above MIC
- A series of RCTs comparing intermittent dosing to continuous infusion have been performed
  These include BLING-II, MERCY, and BLING-III.
- Meta-analysis was strongly suggestive of ↓ 90-day mortality with the use of an intermittent infusion

90-Day Mortality of Continuous vs. Intermittent Antibiotic Infusions

References

Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
Cheng MP, Stenstrom R, Paquette K, et al. Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis. Ann Intern Med. 2019;171(8):547-554. doi:10.7326/M19-1696