PRINCIPLES OF ANTIBIOTIC USE

MSc. BPharm. Nguyen Nhat Thien Tu

Email: nnttu@medvnu.edu.vn
 Objectives
➢ Understand the definition of antibiotics, antibiotic classification and antibiotic
resistance mechanisms
➢ Understand the principles of using antibiotics in the treatment of infectious diseases
 Lecture content
1. Overview of antibiotics and antibiotic resistance
2. Priciples of antibiotic use in the treatment of infectious diseases
 Definition
▪ Antibiotics are antibacterial substances produced by microorganisms that inhibits or kills
other microorganisms
▪ Nowadays, the term "antibiotics" has been expanded to include even synthetic
antibacterial agents such as sulfonamides and quinolones

Antibiotic usage guidelines (Ministry of Health, 2015)

Oxford Handbook of Infectious Diseases and Microbiology (2021)
 Antibiotic discovery
▪ In 1928, Alexander Fleming discovered penicillin
▪ In 1941, penicillin was first used in treatment

Alexander Fleming
(1881-1955)
 Antibiotic classification
Antibiotics are classified by several ways:
➢ On the basis of chemical structure
➢ On the basis of mechanism of action
➢ On the basis of antibacterial activity
https://www.compoundchem.com/2014/09/08/
 Mechanism of action
▪ Inhibition of cell wall synthesis
▪ Inhibition of protein synthesis
▪ Inhibition of nucleic acid synthesis
▪ Disruption of cell membrane

Review on Antibiotics and their Positive and Negative Impact on Health (2021)
 Bacteriostatic antibiotics vs Bactericidal antibiotics

Bacteriostatic antibiotics Bactericidal antibiotics

suppress the growth of bacteria
→ rely on an intact immune system to
clear the infection
Ex: macrolid, tetracyclin, clindamycin,
chloramphenicol
kill the bacteria
Ex: beta-lactam, vancomycin, aminoglycosid,
fluoroquinolone, daptomycin
https://basicmedicalkey.com/principles-of-antimicrobial-chemotherapy-2/
Antibiotic Resistance
 What is antibiotic resistance?
Antibiotic resistance occurs when microorganisms change over time and no longer
respond to medicines → making infections harder to treat and increasing the risk of
disease spread, severe illness and death.

https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
 MDR – XDR - PDR

➢ MDR (Multi-Drug Resistance): defined as non-susceptible to at least 1 agent in at

least 3 antimicrobial classes (không nhạy cảm với ít nhất 1 KS trong ≥ 3 nhóm KS
được thử)
➢ XDR (Extensive Drug Resistance): defined as non-susceptible to at least 1 agent
in all but one or two available classes (không nhạy cảm với ít nhất 1 KS của tất cả
các nhóm nhưng còn nhạy với ≤ 2 nhóm)
➢ PDR (Pan Drug Resistance): defined as non-susceptible to all agents in all
antimicrobial classes (không nhạy cảm với tất cả kháng sinh của tất cả các nhóm)
 Antibiotic resistance
Intrinsic resistance (natural resistance): resistance that is inherently or naturally
possessed by bacteria.
Ex: E.coli has natural resistance to vancomycin → large molecular size → inability to
penetrate the outer bacterial membrane

Acquired resistance: the changes in the genetic material of a bacteria, through 2

processes:
1) Vertical gene transfer: resistance genes are passed down to daughter cells through
cell division
2) Horizontal gene transfer: acquisition of resistance genes from another organism
(through conjugation, transduction, or transformation)
https://www.niaid.nih.gov/research/antimicrobial-resistance-causes
 Antibiotic resistance mechanisms

▪ Alteration of drug target

E.g. modify PBP (penicillin-binding proteins)
→ resistance to β-lactam
▪ Production of enzyme that inactivates
antibiotic
E.g. β-lactamase break β-lactam ring
▪ Alteration of metabolic pathways
E.g. resistance to sulfonamide, trimethoprime
▪ Limiting uptake of a drug
▪ Efflux pumps

Mutuku, C., World J Microbiol Biotechnol 38, 152 (2022)

Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics. Antibiotics 2022
Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet (2019)
Deaths attributable to AMR every year by 2050

The Review on Antimicrobial Resistance, Jim O'Neill (2014)

 Factors contributing to antibiotic resistance

Patient-related factors Drug-related factors

- Poor adherence - Availability of antibiotic
- Self-medication - Counterfeit and substandard
- Lack of awareness and drugs -> sub-optimal blood
knowledge concentration

Prescriber-related factors Other factors

- Inappropriate prescribing - Lack of access to clean water
- Overuse of antibiotics - Poor sanitation
- Extensive agricultural use
- Lack of enforcement of
legislation
Without urgent action, we are heading for a post-antibiotic era

https://www.cdc.gov/drugresistance/pdf/11-2013-508.pdf
https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
 PRINCIPLES OF ANTIBIOTIC USE

❑ Use antibiotic in patients with bacterial infection

❑ Appropriate antibiotic selection
❑ Appropriate antibiotic combination
❑ Dosage of antibiotics
❑ Apply PK/PD parameters to optimize antibiotic therapy
❑ Choose the appropriate route of administration
❑ Duration of antibiotic therapy
1. Use antibiotic in patients with bacterial infection
❖ Only use antibiotics when there is suspicion of infection or definitive evidence
of infection
❖ Misuse, inappropriate, or overuse of antibiotics
▪ Increase antibiotic resistance
▪ The risk of ADR
▪ Increase treatment costs
Clinical symptoms
 Lab examinations and imaging tests

▪ White blood cell (WBC), Neutrophil (NEU)

▪ C-reactive protein (CRP), procalcitonin (PCT)
▪ Imaging tests: X-rays, CT Scan, MRI, Ultrasound
▪ Microbiological tests:
+ Stain and examine under a microscope
+ Culture and sensitivity (Antibiogram)
+ Molecular diagnostics
Sample is obtained from the body area likely to contain pathogens (blood, sputum, urine,
stool, tissue or fluid from a wound…)
Note: Samples should be obtained before starting antibiotic therapy
+ S: sensitive
+ I: intermediate
+ R: resistant
 2. Appropriate antibiotic selection

Empiric antibiotic Definitive antibiotic

therapy therapy

Diagnosis Culture and

susceptibility
test results
available
2. Appropriate antibiotic selection

Empiric therapy
Choice of agent:
▪ Cover all microorganisms suspected of causing the infection
▪ Consider factors:
+ Site of infection
+ Local susceptibility
+ Patient-related factors
+ Drug-related factors
Fernández L. et al, Antibiotics 2021
Staphylococci (Staphylococcus aureus)
Streptococci (Streptococcus pyogenes)
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas
Enterococci
Staphylococci
Drug-related factors

▪ Drug's safety
▪ Ability to reach the sites of infection:
+ Reach the infection target and achieve therapeutic concentration
+ Some tissues/sites that are difficult to penetrate or have impaired blood supply (CNS
infections, bone and joint infections, abscesses,…)
 Patient-related factors

▪ Age
▪ Renal and hepatic function
▪ Pregnancy and lactation
▪ History of allergy or intolerance
▪ Immune system status
▪ Comorbidity
▪ Risk factors of MDR (multidrug resistant) organisms
 Age
➢ Age-related changes in bacterial pathogens:
For example, bacterial meningitis varies with age:
+ Neonates: Group B Streptococcus; Listeria monocytogenes
+ Adults: Streptococcus pneumoniae; Neisseria meningitidis
+ Elderly individuals: Streptococcus pneumoniae; Listeria monocytogenes
➢ Note that some antibiotics should not be used in young children (quinolones and
tetracyclines)
➢ Age-related changes in liver and kidney function:
Reduced kidney function in preterm neonates, neonates, and the elderly
 Patient-related factors

▪ Age
▪ Renal and hepatic function
▪ Pregnancy and lactation
▪ History of allergy or intolerance
▪ Immune system status
▪ Comorbidity
▪ Risk factors of multidrug-resistant (MDR) organisms
 Risk factors of MDR organisms

▪ Treatment for ≥ 5 days at healthcare facilities within 90 days

▪ Administered IV antibiotics within 30 days
▪ Prolonged corticosteroid use
▪ Concurrent chronic conditions (diabetes, cirrhosis, end-stage renal disease with
dialysis, immunodeficiency,...)
▪ Patients with bone marrow or organ transplants, granulocyte count reduction due to
chemotherapy
▪ Age > 60
▪ Contact with multidrug-resistant bacterial carriers

Guidelines for diagnosis and treatment of Covid-19, Ministry of Health (2023)

2. Appropriate antibiotic selection
Definitive therapy
▪ After identifying the pathogen and susceptibility result is available
▪ Antibiotics with the narrowest spectrum → effective against the identified pathogens
 3. Rational antibiotic combination

➢ Only use combination antibiotic therapy when necessary

➢ Purpose of antibiotic combination:
▪ Extending antibacterial spectrum → infections caused by multiple bacteria.
E.g. ceftriaxone + metronidazole for treating intra-abdominal infections
▪ Enhance antibacterial effect
▪ Prevent the emergence of drug-resistant bacterial strains (e.g., for tuberculosis
treatment)
3. Rational antibiotic combination
➢ Additive effect: (1 + 1) = 2
➢ Synergistic effect: (1 + 1) > 2
➢ Antagonistic effect: (1 + 1) < 2
3. Rational antibiotic combination

Synergistic effect
✓ Trimethoprim – Sulfamethoxazole
✓ Aminoglycoside – Beta lactam
✓ Beta lactam - Beta lactamase inhibitor
E.g. Amoxicillin - acid clavulanic,
ampicillin-sulbactam, ticarcillin - acid
clavulanic, piperacillin-tazobactam,…
3. Rational antibiotic combination
Inappropriate antibiotic combination

▪ Antagonistic effects
E.g. erythromycin – clindamycin, tetracyclin - penicilin
▪ Increased treatment costs
▪ Increased the risk of ADR
3. Rational antibiotic combination

Antagonism in 80% and indifferenence in 20%

3. Rational antibiotic combination
Antibiotic combinations in the following cases:
▪ Patients infected with multiple bacterial pathogens
▪ Patients infected multidrug-resistant bacteria
▪ Empiric therapy for severe infection, immunocompromised patients
▪ Specific infections such as tuberculosis, leprosy, endocarditis...
 4. Dosage of antibiotics
Dosage of antibiotics depends on:
▪ Age
▪ Weight
▪ Liver and kidney function
▪ Severity of the disease
TDM (Therapeutic drug monitoring): Highly toxic antibiotics, the therapeutic range is
narrow (vancomycin, aminoglycosides) → monitor drug levels to avoid toxicity and
ensure therapeutic efficacy
Uptodate 2023
Apply PK/PD parameters to optimize antibiotic therapy

3 main PK/PD indices:

▪ T > MIC
▪ Cmax/MIC
▪ AUC0-24/MIC
 Post-
PK/PD
Category antibiotic Antibiotics Optimal dosing strategies
indice
effect (PAE)
Carbapenems
Optimizing T > MIC
Cephalosporins
No or very (increasing dosing frequency,
Penicillins T > MIC
short PAE extending the infusion time,
Time- using ER formulations)
dependent
killing Azithromycin Optimizing amount of drug
Clindamycin (increasing dose, increasing
Prolong PAE AUC0–24/MIC
Tetracyclines dosing frequency, or
Vancomycin extending the infusion time)
Aminoglycosides
Concentration- Fluoroquinolones
Prolong PAE Cmax/MIC, Optimizing concentration
dependent Daptomycin
AUC0–24/MIC (increasing dose)
killing
 Beta - lactam

T > MIC ~ 40-70%

Grupper M. et al. Clin Microbiol Rev. 2016

Nguyễn Hoàng Anh. Tiếp cận dược lâm sàng trong sử dụng kháng sinh trong nhi khoa
Nguyễn Hoàng Anh. Tiếp cận dược lâm sàng trong sử dụng kháng sinh trong nhi khoa
Nguyễn Hoàng Anh. Tiếp cận dược lâm sàng trong sử dụng kháng sinh trong nhi khoa
Strategies for optimize beta-lactam dosing:
▪ Multiple time a day
▪ Extended infusion (over 2 to 4 hours)
▪ Continuous infusion (over the entire dosing interval)
▪ Use extended-release formulation
Drawbacks of continuous infusion/extended infusion strategies:
▪ Inconvenience for patients
▪ Workload for nurses
▪ Intravenous line access
▪ Drug stability
▪ Compatibility with coadministered intravenous drugs

Patients with risk of drug-resistant pathogens or with severe infections

 inactive

Nguyễn Hoàng Anh. Tiếp cận dược lâm sàng trong sử dụng kháng sinh trong nhi khoa
 Post-
PK/PD
Category Antibiotic Antibiotics Optimal dosing strategies
indice
Effect (PAE)
Carbapenems Optimizing T > MIC
No or very Cephalosporins (increasing dosing frequency,
T > MIC
short PAE Penicillins extending the infusion time,
Time- using ER formulations)
dependent
killing Azithromycin Optimizing amount of drug
Clindamycin (increasing dose, increasing
Prolong PAE AUC0-24/MIC
Tetracyclines dosing frequency, or extending
Vancomycin the infusion time)
Concentration- Aminoglycosides Cmax/MIC,
Prolong PAE Fluoroquinolones Optimizing concentration
dependent AUC0-24/MIC (increasing dose)
killing Daptomycin

Aminoglycoside: Cmax/MIC ~ 8-10

 Aminoglycosid

Traditional dosing
+ Amikacin: 5 mg/kg Q8h
+ Tobarmycin, Gentamicin: 3 to 5
mg/kg/day divided Q8h

High - dose extended-interval

dosing
+ Amikacin: 15-20 mg/kg once daily
+ Tobramycin, Gentamicin: 5-7 mg/kg
once daily

Pediatr Infect Dis J 2011;30: 338–339

Aminoglycosid

Advantages of high-dose extended-interval dosing:

▪ Reduces the risk of ototoxicity and nephrotoxicity
▪ Ease of administration and serum concentration monitoring
▪ Reductions in administration and monitoring-related costs
 5. Route of administration
▪ Oral route (PO): convenience, safety, and cost-effectiveness → mild infection,
outpatient
▪ Parenteral route:
• severe/life-threatening infections, tissues that are difficult to penetrate (meningitis,
endocarditis,...)
• inability to take/absorb oral medications (severe vomiting or diarrhea, intestinal
obstruction, post-operative ileus,...)
• poor oral bioavailability: some drugs are poorly absorbed if given PO
→ Switching to oral antibiotics (if possible)
Cunha BA. Antibiotic essentials. 14th ed (2015)
Criteria for switching from IV to PO antibiotics

Decision 5631/QD-BYT
6. Assessment of response to treatment

▪ Clinical assessment: symptoms and signs (eg, a decrease in fever, cough,

tachycardia, confusion,…)
▪ Lab values and imaging tests:
+ Decreasing WBC, NEU, CRP, procalcitonin
+ Microbiological parameter (sepsis)
+ Imaging tests: X-rays, CT Scan, MRI, Ultrasound (eg; decrease in the size of an
abscess, chest radiography,…)
Bassetti, M., Intensive Care Med 44, 2018
 7. Duration of antibiotic therapy
Depend on type of infection, the severity of an infection, and response to treatment

Type of infection Duration of antibiotic therapy

Complicated urinary tract infection 7-14 days

Uncomplicated cystitis (women) 3-5 days

Community-acquired pneumoniae 7-10 days

Osteomyelitis 4-6 weeks

Endocarditis 4-6 weeks

USE OF PROPHYLACTIC ANTIBIOTICS
 DEFINITION

Surgical prophylactic antibiotics are antibiotics used before/during/after surgery to

prevent infections at the surgical site
 Surgical site infection (SSI)
▪ Surgical wound infections develop when microorganisms enter the wound through
the dermal incision
▪ Organisms causing SSI can come from 2 causes:
+ Endogenous (from the patient’s normal flora)
+ Exogenous (healthcare workers' hands, air, surgical instruments,…)
Type of surgery Common pathogens
Cardiac surgery Staphylococcus aureus, staphylococci coagulase (-)
GI surgery Enterobacteriales, anaerobes, enterococci
Orthopedic surgery S. aureus, staphylococci coagulase (-)
Head and neck surgery Staphylococcus aureus, streptococci spp., oral
anerobes
Gynecological Surgery Enterobacteriales, anaerobes, enterococci, group B
streptococcus
Do all surgeries require prophylactic antibiotics?
Surgical wound classifications

ACS-NSQIP surgical wound classifications

 Không nhất thiết dùng
KSDP (trừ cấy ghép
vật liệu nhân tạo)

Là đối tượng chính

của KSDP

Chỉ định kháng sinh

điều trị

Hướng dẫn phòng ngừa nhiễm khuẩn vết mổ 2012 (Bộ Y tế)
Principles of prophylactic antibiotic use

1 Indication

2 Selection

3 Dosing - Route

4 Timing

5 Duration
 Selection
Antibiotic agent should be:
(1) active against the pathogens most likely to contaminate the surgical site
(2) favorable pharmacokinetic profile
(3) safe
(4) low cost
Cefazolin → the drug of choice for prophylaxis in most surgical procedures because of:
➢ Spectrum of activity against organisms commonly encountered in surgery
➢ Desirable duration of action
➢ Safety and low cost
https://www.ashp.org/surgical-guidelines (2013)
 Dosing
▪ Dosage → to maintain drug concentration throughout the operative period
▪ A single-dose prophylaxis is usually sufficient
▪ Additional doses can be given:
+ Duration of the procedure (> 2 half-life of the antibiotic)
+ Significant blood loss occurs during surgery (> 1,5L – adult; > 25ml/kg – peadiatric)

Route of administration
Antimicrobial prophylaxis can be administered through a variety of routes (eg, oral,
topical, IV, IM) → IV is favored → quickly achieve high concentrations in the
bloodstream and tissues
 Timing
▪ Within 60 minutes before the surgical incision
▪ Some agents (fluoroquinolones and vancomycin) require administration over 1-2
hours → the administration of these agents should begin within 120 minutes
before surgical incision
Additional dose
(the duration of
procedure > 2 x T1/2
of antibiotic, significant
blood loss occurs
during surgery

≤ 60m
before skin Operation
incision Incision
 Duration
▪ Do not use prophylactic antibiotics for more than 24 hours after surgery (except for
cardiac surgery → 48 hours)

Additional dose
(the duration of
procedure > 2 x T1/2
of antibiotic, significant
blood loss occurs
during surgery

≤ 60m
before skin Operation Do not use
incision Incision > 24 hours
THANK YOU!
Email: nnttu@medvnu.edu.vn