ANTIMICROBIAL DRUGS

Iwan Dwiprahasto
Department of Pharmacology and Therapy
Faculty of Medicine GMU
 The anti-infective drugs
• Anti-infective agents are drugs that are
designed to act selectively on foreign
organisms that have invaded and infected the
body
Anti-infective drugs
1. Antibacterials

2. Antifungals

3. Antiprotozoals

4. Antihelminthics

5. Antivirals

6. Antimycobacterial
 • Chemotherapeutic
antimicrobial agents used to
drugs treat infectious
diseases

they must act within the host

 Introduction

No effect Infections
 What are the consequences ?

Morbidity

Increase Mortality

Financial cost

Increasing antibiotic
resistance
Emergence of Antimicrobial Resistance
Infection
Exposure to Drug treatment
occurs and the
bacteria occurs is used
bacteria spread
 Emergence of Antimicrobial Resistance
Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

New Resistant Bacteria
 Selection for antimicrobial-resistant Strains

Antimicrobial
Resistant Strains Exposure Resistant Strains
Rare Dominant
 Spectrum of antimicrobial activity

Narrow spectrum Broad spectrum

affect only Gram- affect both Gram-

positive cells or only positive and Gram-
Gram-negative cells negative cells

The normal flora is affected, too.

 An Ideal Antimicrobial

Quick acting

Water Few side

soluble effects

Broad Quick “kill”

spectrum in of the
action pathogen
 Antimicrobial drugs

Bacteriocidal Bacteriostatic

Simply prevent the growth of

Kill the bacteria the bacteria

Effective when host The host’s own defenses of

phagocytosis and antibody
immune system is production will destroy the
compromized bacteria
No antimicrobial Tetracycline
agent
Fucidic acid
Sulfonamida
Chloramphenicol
PAS
Lincomycin
Erithromycin (Low conc)
Bacteriostatic
Clindamycin

Penicillin
Aminoglycosides
Bactericidal Cephalosporin
Cotrimoxazol
Isoniazid
Rifampicin
Erithromycin (high conc)
Vankomisin
 ka
T1/2
Cl

Cmax Max TC

MBC Min TC
K el
MIC

Tmax
Predictor of Efficacy: Pharmacokinetics/Pharmacodynamics
Parameter
PK/PD
• T>MIC
• Peak/MIC
• AUC/MIC 24 jam
 Antibiotic susceptiility testing (in vitro)

Minimum inhibitory concentration (MIC)

the lowest drug concentration that prevents visible
microorganism growth after overnight incubation

Minimum bactericidal concentration (MBC)

the lowest concentration of antibiotic required to kill a
particular bacterium
 PK/PD profiles: prediktor of bacterial eradication

Peak/MIC T > MIC AUC/MIC 24 jam

• Aminoglycosida • Beta lactam • Azithromycin

• Erythromicin • Quinolon
• Clindamycin • Vancomisin
• Linezolid
 PK/PD

Antibiotic concentration (ug/ml)

8

Time above MIC : Drug A

6 Drug A
Drug B
Drug B
4
Proportion of dosing
interval when plasma 2 B
concentration is above B
MIC
0 A Time

Time above MIC

 PK/PD

AUC/MIC Area under the curve over MIC

concentration
Antibiotic
Ratio AUC/MIC
PEAK

Peak/MIC MIC

Ratio peak plasma

over MIC
Time
 Aminoglycoside Pharmacodynamics in Vivo
Initial serum peak level Died Survived
< 5mcg/ml 21% 79%
>= 5mcg/ml 98% 2%

Fluoroquinolone Pharmacodynamics vs S. Pneumoniae

24h-AUC/MIC ratio Microbiological Response

< 33.7 (64%)
> 33.7 (100%)
Ambrose et al, Antimicrob Agents Chemo 10: 2793,
2001
 Therapeutic PK/PD
Activities Antibiotics
goals Parameter
Type I Aminoglycosides
Maximize its AUC/MIC-
Concentration-dependent Daptomycin
blood 24 jam
killing & Prolonged Fluoroquinolones
concentration Peak/MIC
persistent effects Ketolides

Carbapenems
Type II Cephalosporins Maximize its
Time-dependent killing & Erythromycin duration of T>MIC
Minimal persistent effects Linezolid exposure
Penicillins
Azithromycin
Type III
Clindamycin
Time-dependent killing & Maksimize its 24h-
Oxazolidinones
Moderate to prolonged amount/dose AUC/MIC
Tetracyclines
persistent effects.
Vancomycin
How antimicrobials act?
Fig. 13-2

Antibiotics classification
Formulary issues in the Use of Antibiotics

Formulary issues

Specific indications
Patient population
Cost issues
Resistance issues
Overall applicability to the institution
Antibiotic control
 Inhibitors of cell wall synthesis

ß-Lactam antibiotics Other Antibiotics

Penicillins Cephalosporins Carbapenem Monobactams

Penicillin G
1st 2nd 3rd 4th Imipenem/
Aztreonam
Generation Generation Generation Generation Cilastatin
Penicillin V

Methicillin
Cefazolin Cefaclor Cefixime Cefepime

Nafcillin
Cefadroxil Cefamandol Cefoperazone

Oxacillin
Cephalexin Cefonicid Cefotaxime
Cloxacillin

Dicloxacillin
Cephalothin Cefmetazole Ceftazidime

Ampicillin Cephapirin Cefotetan Cefizoxime

Amoxicillin
Cephradine Cefoxitin Ceftriaxone
Carbenicillin

Ticarcillin
Cefuroxime Moxalactam

Piperacillin

Mezocillin
 1

Agents that either inhibits the synthesis of or disrupt

bacterial cell wall through enzyme activation

Examples: penicillins and cephalosporins

Agents that act on microbe cellular membrane, causing

internal compartment leaks

Examples: amphotericin B, polymixin

 3 4
Agents that inhibit protein Agents binding to the 30S
synthesis, through ribosomal ribosomal unit, inhibiting
disruption protein synthesis

Examples: the
Examples: chlorampenicol, aminoglycosides such as
erythromycin garamycin and gentamycin
 5 6
Agents that inhibit specific
Agents that alter the synthesis
metabolic activity of the
or metabolism of nucleic acids microbe

Examples: rifampin, nalidixic

Examples: sulfonamides
acid
 7
Agents that bind to viral enzymes
preventing DNA synthesis, thus
preventing viral replication

Examples: acyclovar, vidarabine

 Bacteria are still survive
Drug tolerant after antibiotics treatment

>
Bacteria are able to
Drug destroying destroy antibacterial
Resis- activities (penisilinase)

tance
Genetic From chromosome
>
Related to bacteria which
Non-genetic is not multiplicating
 Bacterial resistance test

Example: ampicillin
Sensitive: Intermediate
Inhibition Zone ≥ 14 mm
Resistance: Susceptible
Inhibition Zone ≤ 11 mm
Resistant
 1st Generation
Penicillin
2nd
Cephalo- Generation
sporins
3rd Generation

Beta-lactam
4th Generation
antibiotics

Imipenem
Inhibitors of Carbapenem
Cell Wall meropenem
Synthesis Monobactam

Vancomycin
Other
antibiotics
Bacitracin

Clavulanic acid
Beta-
lactamase Sulbactam
inhibitors
Tazobactam
 Antimicrobials

1. Sulfonamides

2. Penicillins

3. Cephalosporins and Related Antibiotics

4. Tetracyclines, Macrolides, and Lincosamides

5. Fluroquinolones and Aminoglycosides

6. Miscellaneous Anti-infectives

7. Antitubercular Drugs 108

 Penicillins

O
S CH3
R C NH CH CH C
CH3
O C N CH COOH

B-lactam ring

Common nucleus
 1. PENICILLIN
Wide therapeutic margin

Less effective for Gram (-)

Mostly destroyed by beta lactamase

Widely distributed in the body (esp. pleura, peritoneal,

sinovial fluid)

High concentration in urine

CSF < 1% (normal) & 5% (inflammed)

Underlying enterohepatic cycle (high concentration in gall

bladder)
 1. PENICILLIN

Activity Example
Active against Gram (+), destroyed by
betalactamase Penisilin-G

Stable in gastric Penisilin V, ampicilin,

juices amoxyciilin, cloxacilin

Active against Gram (+), resistance to

staphylococ producing betalactamase Meticilin, nafsilin

Active against Gram (+) & (-), destroyed by

betalactamase Ticarsilin, carbenisilin
 1. PENICILLIN

Activity Example
Narrow spectrum, sensitive to Penisilin-G, benzatin penisilin,
beta-lactamase prokain penisilin, penisilin V

Narrow spectrum, resistance to Meticilin, oxacylin, nafsilin,

beta-lactamase kloksasilin, dikloksasilin

Broad spectrum aminopenisilin Ampicilin, amoxycillin

Extended spectrum, Ticarsilin, carbenisilin,

antipseudomonas piperasilin
 1. PENICILLIN

ADVERSE EVENT

immediate: skin rash,

anaphylactic, wheezing
HipersensitivitY

Delayed: erythema, serum

sickness syndrome

interstitial nephritis, haemolytic anemia ,

netropenia, pansitopenia, eosinofilia, drug fever,
vaskulitis
PENICILLIN-G

Unstable in acid environment

After I.m, peak concent 15-30 mnt, and
decline
(t 1/2): 30 mnt

Serum & tissue concentration

• Up to 12 hrs (300.000 unit)
• Up to several days (2,4 million unit)

10% are eliminated via glomerular filtration, 90%

via tubular secretion
Benzatin penicillin (1 mol penisilin + 2 mol
amonium base): in plasma up to 15-30 days
 Narrow spectrum, sensitive to beta-lactamase
benzatin prokain
Penisilin-G, penisilin V
penisilin, penisilin,

• coccen Gram (+),

Effective for: • Neisseria, and
• Gram (-) anaerob,

Weakneses • Destroyed by beta-lactamase.

• For Infection by pneumococcus,

penicillin G (0,6 – 5
streptococcus, meningococcus, and
million Unit) i.m.
gonococcus:
 Narrow spectrum, sensitive to beta-lactamase
benzatin prokain
Penisilin-G, penisilin V
penisilin, penisilin,

severe infection, • penicilin G, every 4 – 6 hours, infusion,

mild infection • penisilin V per oral, 500mg every 6

(pharyngitis, sinusitis,
and otitis media): hours (5 days).

Pharyngitis due to Strept • penicillin V, 500 mg every 6 hours for

beta-hemolyiticus group 10 days, or
A: prophylaxis for RHD • benzathine penisilin G, i.m 1,2 million
or glumorulonephritis unit, (duration several weeks).
 Extended spectrum, antipseudomonas
Ticarcilin, carbenisilin, piperacilin

Carbenisilin
• DOC for Pseudomonas aeruginosa
and ticarcilin:

• carbenisilin 12-30 gr/day iv or

Sepsis due to • ticarsilin 200-300 mg/kg BB/day
pseudomonas • Combined with Gentamicin 5-7 mg/kg
BB/day i.m
 PK/PD
(Pharmacokinetic/Pharmacodynamics)

The β-lactams are “time-dependent” killers

The effect is directly proportional to the amount of
TIME the concentration of the antibiotic at the site
of infection is ABOVE the MIC of the organism.

The β-lactams are BACTERIOCIDAL… (at

therapeutically attainable levels)
“Time Dependant”

H Derendorf
PENICILLINS
Penicillin G
Penicillin V
Methicillin
Nafcillin
Oxacillin
Cloxacillin
Dicloxacillin
Ampicillin
Amoxicillin
Carbenicilin
Ticarcilin
Piperacillin
Mezlocillin
Azlocillin
ANTIBIOTICS WHICH INHIBIT BACTERIAL PROTEIN SYNTHESIS

Chloramphenicol

Tetracycline

Erythromycin

Streptomycin
 MACROLIDE

• Inhibit bacterial protein synthesis

• Bound to 50S ribosome sub unit, preventing

prolongation of peptide chain

• Bacteriostatic or bactericidal (higher concentration)

• Antibacterial effect increased in neutral pH or

alkaline
 Pharmacokinetics: Erythromycin base

• incomplete but adequate from intestine

• Inactivated by gastric HCL, hence given as Enteric
Absorption coated tablets or ester (stearate, ethyl succinate )
• Food delays absorption

• Not metabolized and actively secreted in bile (major

Metabolism route of excretion)

Excretion • Only 2-5 % is excreted in active form in urine

• Widely distributed into most tissues, except the brain and

CSF
Distribution • Cross the placental barrier
• Protein binding: 70- 80 %
• Half – life approx. 1.6 hr
 Azithromycin: Pharmacokinetics
• Rapidly absorbed from GIT
Absorption
• Food delays absorption

• Widely distributed (extensive tissue distribution

Distribution ), except CSF
• Protein binding 51%

• Undergo some hepatic metabolism (inactive)

Metabolism
• Biliary route is the major route of elimination

• Only 6% is excreted unchanged in the urine

Excretion
• Half- life approx. 3 days

Advantage over • Once daily dosing

erythromycin &
clarithromycin • No inhibition of cytochrome P- 450
Indications for erythromycin

Alternative to penicillin in allergic pts (Staph. aureus, S.

pyogens, S.pneumoniae or T.pallidum )

Diphtheria & whooping cough – drug of choice

Legionnaires disease- drug of choice

Pneumoniae ( M. pneumoniae ) – children

Chlamydia trachomatis
Erythromycin

Derived from • Streptomyces erythreus

• Esp. active against mycoplasma,

chlamydia and treponema
• DOC for C diphteriae, M. pneumoniae, E.
Activities hystolitica & Chlamydia
• Available as estolat, stearat, etilsuccinate,
base

Elimination • Eliminated via hepatic metabolism

• in inflammed meninges: 25% blood

CSF concent concent
 Erythromycin

Children: • estolate is better absorbed

• estolate is not recommended (causing

Adult:
cholestatic hepatitis)

Oral dose: • 250-500 mg every 6 hours per day

Child dose: • 30-50 mg/kgBW/day divided into 4 dose

 AZITHROMYCIN

Compared to erythromcin: more stable in acid environment

37% dose are absorbed, affected by food, t-max: 2 hours

Low serum concent, high tissue concent

Reaching therapeutic level in lung, genital, liver

High concent in phagocytes, macrophage and fibroblast cells

Streptococcal pharyngitis/tonsilitis
Indication

Acute exacerbation of Chronic Bronchitis

Pneumonia due to S. pneumoniae/H. influenzae
Uncomplicated skin infection due to S. aureus, S. pyogenes
Urethritis & cervicitis due to C. trachomatis
Antimicrobic inhibition of protein synthesis
TETRACYCLINE
Inhibits bacterial protein synthesis

Bound to 30S ribosome sub unit,

preventing the formation of peptide
chain

Between 2 meals

+ milk, antacide, metal will form chelating

agent

Widely distributed

CSF concent: 10% serum

In bone and teeth could bind calcium

Children < 8 yrs, discolorisation of teeth,

enamel hypoplasia
TETRACYCLINE

From streptomyces species.

Good absorption in GI tract.

Esp bacteriostatic,

efektive for Gram (+) aerob coccen,

riketsia, chlamydia, and treponema.
 Tetracycline

Intermediate
Short acting Long acting
acting

Absorption

Oxytetracycline 58% Demeclocylin 66% Doxicyclin 93%

Tetracycline 77% Minocyclin 95%
Half lives

Oxytetracycline 9 hrs Demeclocilin 12 hrs Doxicyclin 18 hrs

Tetracycline 8 hrs Minocyclin 16 hrs
 Tetracycline

Indication
• Infection esp due to M. pneumoniae
• Acute exacerbation of chronic bronkitis
• Acute diarrhoea due to shigella, Vibrio cholerae
• Acne (low dose 250-500mg), inhibits proliferation of
Corynebacterium acnes

Adverse events
• Nausea, vomites
• Stomatitis
• Depressed bone growth
• Teeth discoloritation esp during formation of permanent
teeth
• 1st Trimester pregnancy should be discouraged
 Chloramphenicol
• blocks 50S ribosome, preventing peptide bond
formation.
 CHLORAMPHENICOL

Streptomyces species

Broad spectrum

Induce bone marrow aplasia

Difusion to bacterial cell, bound to 50S ribosome sub

unit, preventing formation of peptide chain

Bacteriostatic • S. aureus & enterobacteriaceae

Bactericidal • H. influenzae, S. pneumoniae, N. meningitidis

CHLORAMPHENICOL

Pharmacokinetics
• Good absorption
• iv 25-50mg/kgBW, serum concent < oral
• Distribution: CSF, CNS
• Metabolism: conjugated by glucoronic acid

• typhoid (S . typhi)
DOC for
• Eye infection

• 2-3g atau 30-50mg/kgBW/day (divided in 4 doses),

Dose:
• 2-3 weeks to prevent relapse

Second
line: • Meningitis: H influenzae
 CHLORAMPHENICOL

Contraindication:

• leukopenia, trombositopenia,
severe anemia
• Pregnancy
• Prematurity/ < 2 weeks

Adverse event:

• Bone marrow suppression

• Grey baby syndrome
 AMINOGLYCOSIDE

Mechanism of • Bound to 30S subunit ribosome:

preventing formation of peptide
action chain

Pharmacokinetics
• Poor absorption in GI tract.
• Only available parenterally (except neomisin)
• Low concent in tissue and CSF
• Narrow therapeutic margin
• Highest concent: renal cortex, endolymphe and
perilymphe of middle ear