ANTIMICROBIAL

DRUGS

Iwan Dwiprahasto
Department of Pharmacology and Therapy
Faculty of Medicine GMU
Why do young children have more
illness?
Infection can result from sharing towels, dishes, or from
handling contaminated objects. Indirect contact or skin to
skin contact can also result in the spread of an illness.
Sometimes an illness is passed to others by a carrier, or a
person who has been infected by a germ but does not look or
feel sick. This person may carry the germ in their nose, throat,
or stomach. They can pass the germ to others by coughing,
sneezing, or by not washing their hands properly.
 Your hands carry many germs
even if you cant see them.

Many people dont wash their

hands because they look clean.

As you can see this is not

Light patches indicate always the case.
germs carried on the
hands
Some examples of contagious bacterial diseases
are:

strep throat

Impetigo

pertussis (whooping cough)

bacterial conjunctivitis (pink eye)

Antibiotics Work
Some contagious viral infections include:
varicella (chicken pox)

rubella (German measles)

the common cold

hepatitis

mumps

infectious mononucleosis

rubeola (measles)

Antibiotics Dont Work

 Antimicrobial therapy
When the balance between the microorganism and
the host tilts in the direction of the microorganism

the bodies normal defenses cannot prevent or

overcome the disease

When this occurs we turn to chemotherapy.

Chemotherapy is the
treatment of disease
with chemicals taken
into the body.
chemotherap
Drugs for chemotherapy
eutic agents

antimicrobial Chemotherapeutic agents

used to treat infectious
drugs diseases are called

they must act within the host

 Terminology
Antimicrobial drugs are chemotherapeutic drugs

Some
Some antimicrobials
antimicrobials are are called antibiotics
synthetic drugs

they are produced

they are synthesized
naturally by bacteria
in the laboratory.
and fungi.
 Introduction

No effct Infection
 Emerging Pathogens
Healthcare associated: Community Acuired
Infections (HAI) Infections:
MRSA HIV
MRSE Foodborne diseases
VRE Malaria
VISA PR Strept pneumo.
ESBL producing Gm-ve Hepatitis B & C
organisms E. coli 0157:H7
Multidrug resistant Lymes disease
Acinetobacter Legionnaires disease
MDR-TB Pathogens of
bioterrorism

Center of Disease Control, USA

 What are the consequences ?

Morbidity

Increase Mortality

Financial cost

Increasing antibiotic
resistance
 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
Principles of Anti-infective Therapy

Identifying the infecting organism

Having information of its

antimicrobial susceptibility (or
potential susceptibility)

Consider Host factors that will

impact on choice on antimicrobial
The classification of antimicrobial drugs

Antibacterials

Antiviral

Antimicrobials Antifungal

Antiprotozoal

Anthelmintics
 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.

 Antimicrobial therapy

When the balance between the microorganism and the

host tilts in the direction of the microorganism

the bodies normal defenses cannot

prevent or overcome the disease

we turn to chemotherapy

the treatment of disease with chemicals taken into the body

The following criteria should be used to evaluate
chemotherapeutic agents
It should demonstrate selective toxicity for
the microbe, but not the host (most are
actually somewhat toxic to the host).

It should not produce hypersensitivity

reactions in most hosts

It should penetrate body tissues rapidly and

be retained for an adequate time

Microbes should not readily develop

resistance to it.
 An Ideal Antimicrobial

Quick acting

Water Few side

soluble effects

Broad Quick kill

spectrum in of the
action pathogen
 Antimicrobial therapy

The problem with broad spectrum antimicrobials

much of the normal flora of the host is destroyed

may allow certain normal flora which, may be

resistant to the antimicrobic, to flourish and cause an
opportunistic infection

superinfection
 Antimicrobial drugs

bacteriocidal bacteriostatic

kill the bacteria simply prevent the

growth of the bacteria

effective when host the hosts own defenses of

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

Penicillin
Aminoglycosides
Bactericidal Cephalosporin
Cotrimoxazol
Isoniazid
Rifampicin
Erithromycin (high conc)
Vankomisin
 Antibiotic susceptiility testing (in vitro)

Minimum inhibitory concentration (MIC)

Lowest concentration that results in
inhibition of visible growth

Minimum bactericidal concentration (MBC)

Lowest concentration that kills 99.9%

of the original inoculum
How antimicrobials act?
Peptidoglycan synthesis
Fig. 13-2

Antibiotics classification
Resistance to beta lactams - Gram-negative bacteria
Cross-linking of peptidoglycan
D-cycloserin

Vancomycin
Bacitracin

Cephalosporin
Penicillin
Imipenem
Aztreonam
 Cell wall synthesis DNA replication
Cycloserine Quinolones
Bacitracin Nitroimidazoles
Beta lactams
Glycopeptides DNA

Folic acid Asam Folat

mRNA Rifampicin
metabolism
Asam Folat
50 50 50
Trimetoprim 30 30 30
Sulfonamid
Ribosomes

Cell membrane Protein synthesis

Polymixins Aminoglycosides
PABA
Macrolides
Lincosamides
Amphenicols (50S)
Tetracyclines (30S)
Structural characteristics of a bacterial cell
 1

Agents that either inhibits the synthesis of or disrupt

bacterial cell wall through enzyme activation

Examples: penicillins 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
 Site of infection

Bacterial Community/hospital
factors acquired

Details about the host (age, underlying

disease, predisposing factor)
 Bacteria by Site of Infection

Mouth Abdomen Upper respiratory

Peptococcus E. coli, Proteus S. pneumoniae

Peptostrepto- Klebsiella H. influenzae
coccus Enterococcus M. catarrhalis
Actinomyces Bacteroides sp S. pyogenes
 Bacteria by Site of Infection

Skin/Soft Bone and

Meningitis
Tissue joint
S. aureus S. Aureus S. Pneumonia
S. pyogenes S. Epidermidis N. Meningitidis
S. epidermidis Streptococci H. Influenzae
Pasteurella N. Gonorrhoeae Group B. Strep
Gram Negatif rods E. Coli
Listeria
 Bacteria by Site of Infection

Lower Respiratory Lower Respiratory

Urinary Tract
(Community) (hospital)
S. pneumoniae K. pneumoniae E. coli
H. influenzae P. aeruginosa Proteus
K. pneumoniae Enterobacter sp Klebsiella
Legionella Serratia sp Enterococcus
Mycoplasma S. aureus Staph.
Chlamydia saprophyticus
Infection Bacterials Antibiotics of choice

Meningitis N. meningitidis Benz

H. influenzae Chloramphenicol
Acute follicular tonsilitis S. pyogenes Benzilpenisi
Amoxycillin
Acute Otitis media S. pyogenes Amoxycillin
Sinusitis S. pyogenes Amoxcycillin
S. pneumoniae Amoxycillin
H. influenzae Amoxcycillin
Pneumonia S. pneumoniae Benz
M. pneumoniae Erythromyci
Endokarditis S. viridans Benzilpenisi
S. faecalis gentamicin
Pyelonefritis E. coli Amoxycillin
Urinary tract Infection E. coli Amoxycillin
Wound dan abscess S. aureus Flucl
Osteomyelitis S. aureus Flucloxacillin
Septic Arthritis S. aureus Flucl
Infection Bacterials Antibiotics of
choice
Trachoma Chlamydiae Tetracyclin
Non specific Urethritis Chlamydiae Tetracylin
Septicaemia E.coli
Acute Pyelonephritis Klebsiella Gentamicin
Pyelonephritis E. coli Co-trimoxazole
Urinary tract infection E. coli Co-trimoxazole
Biliary tract infection Enterobacter Gentamicin
Proteus Gentamicin
Ps. Aeruginosa Gentamicin +
ticarcillin
Intraabdominal infections Bacteroides spp Metronidazole
e.g. liver abscess
pelvic inflamm dis
cholangitis
peritonitis
Typhoid fever Salmonella typhi Chloramphenicol
The bacterial, host, and drug factors that must be
considered when selecting antibiotic therapy
Bug factors Host factors Drug factors
Activity against
Identity of pathogen(s) Site of infection
pathogen(s)
Susceptibility of Ability to get to site of
Allergies
pathogen infection
Potential for drug
Renal function
interaction
Dosing frequency (for
Hepatic function
outpatient)
Taste (for liquid
Neutropenia
formulation)
Stability at different
Digestive tract function temperature (liquid
formulation)
Other underlying
Cost
diseases

Concomitant medication

Pregnancy

Desired route of
administration
 Antibiotic Spectrum of Activity

No antibiotic is effective against all microbes

 Systematic Approach for Selection of
antimicrobials
Selection of
Confirm the Identification of presumptive Monitor
presence of the pathogen (see therapy therapeutic
infection Chap. 103) considering every response
infected site
Collection of
Careful history infected material Clinical
and physical assessment
Host factors

Stains
Signs and
Laboratory tests
symptoms
Serologies

Drug factors Assessment of

Predisposing
Culture and therapeutic
factors
sensitivity failure
 Sulfonamides

Penicillins

Cephalosporins and Related

Antibiotics

Tetracyclines, Macrolides, and

Antimicrobials Lincosamides

Fluroquinolones and Aminoglycosides

Miscellaneous Anti-infectives

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 (+),
Penisilin-G
destroyed by betalactamase

Stable in gastric Penisilin V, ampicilin,

juices amoxyciilin, cloxacilin

Active against Gram (+),

resistance to staphylococ Meticilin, nafsilin
producing betalactamase

Active against Gram (+) & (-),

Ticarsilin, carbenisilin
destroyed by betalactamase
 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 juta 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
Penicilin-G, benzatin penicilin, procain penicilin, penicilin V

Effective for: coccen Gram (+), Neisseria,

and Gram (-) anaerob,

Destroyed by beta-lactamase.

Infection by pneumococcus,
streptococcus, meningococcus, and
gonococcus: penicillin G 0,6 5 million
Unit (0,36-3 gr) i.m.
Narrow spectrum, sensitive to beta-lactamase
Penicilin-G, benzatin penicilin, procain penicilin, penicilin V

penicilin G: every 4 6 hours, infusion, severe

infection.

For mild infection (pharyngitis, sinusitis, and otitis

media): penisilin V per oral, 1 gr/hari, 4 times/day
(5 days).

Pharyngitis due to Strept beta-hemolyiticus

group A: prophylaxis for RHD or
glumorulonephritis
penicillin V, 4 x 500 mg 10 days, or
benzathine penisilin G, i.m 1,2 million unit,
(duration several weeks).
 Extended spectrum, antipseudomonas
Ticarcilin, carbenisilin, piperacilin

Carbenisilin and ticarcilin:

DOC for Pseudomonas aeruginosa

Sepsis due to pseudomonas:

Combined with
carbenisilin 12-30 ticarsilin 200-300
Gentamicin 5-7 mg/kg
gr/day iv or mg/kg BB/day
BB/day i.m
Penicillins and Cephalosporins
O
S CH3
R C NH CH C H C
CH3
O C N CH COOH

Penicillin nucleus
B-lactam ring

O
S
R C NH CH C CH2 O

O C N C CH2 O C
C
CH3

Cephalosporin nucleus
2. CEPHALOSPORIN

Mostly parenteral.

Widely distributed in the body, only

a few penetrate CSF

High concent in urine: for UTI.

Concent in Gall bladder is much

higher than plasma
2. CEPHALOSPORIN

Cefoperazon and Ceftriaxon are

excreted via gall bladder

1st Generation esp active against

Gram (+)

3rd Generation esp active against

Gram (-), weaker effect towards
staphylococcus,
Pharmacokinetics parameter of cephalosporin
CEPHALOSPORIN Oral i.v. T1/2 (hrs)
st
1 GENERATION
Cefalotin - Yes 0,5
Cefazolin - Yes 2,0
Cefalexin Yes - 1,0
Cefradin Yes Yes 0,5
Cefadroxil Yes - 1,5
Cefachlor Yes - 1,0
2nd GENERATION
Cefamandol - Yes 0,7
Cefuroxim Yes Yes 1,7
Cefoksitin - Yes 3,5-4,0
Cefotetan - Yes 0,8

3rd GENERATION
Cefotaxim - Yes 1,0
Ceftizoxim - Yes 1,8
Ceftriaxon - Yes 6-8
Moxalactam - Yes 2,0
Cefiksim Yes - 3-4
Ceftazidim - Yes 1,6- 2
Cefoperason - Yes 2,0
 Cephalosporins

Numerous
1st. / 2nd. / 3rd. / 4th
compounds in this
generations class of drugs

Most commonly used

Common -lactam
antibiotics in many
ring compound parts of the world.

Mechanism of action similar

to penicillin: interferes with Overall good safety
synthesis of the
peptidoglycan component of profile
the bacterial cell wall.
 1st. Generation Cephalosporins

Eg. cefazolin, cephalexin

Active against Gm +ve cocci

Moderately active against community

acquired E.coli, M. catarrhalis, Proteus
mirabilis (indole ve)

Other enterbactericeae: unpredictable

Poor activity against MRSA, PRSP &

enterococci
 1st. Generation Cephalosporins
Clinical Uses:

Skin & soft tissue infections

Strept pharyngitis (Penicillin still drug of choice)

Community acq. UTI (SMX-TMP: > effective &

cheaper)

Cefazolin: prophylactic antibiotic for surgical procedures

involving implants & clean + clean comtaminated procedures
 1st Generation Cephalosporin
Skin infect, resp tract infect, urinary tract infect.

Surgical pophylaxis for cardiac surgery or prosthetic implant in

orthopaedic surgery.
Cefalotin is not absorbed orally, painfull via i.m. recommended i.v.
Very short half live, rarely used.

Cefazolin (i.m./ i.v)., widely distributed, does not penetrate CSF

Clearence through glomerular filtration & tubular secretion, is not

metabolized.

Cefalexin, Cefadroxil, and cefradin: oral absorption: good

They are not metabolized, eliminated through glomerular filtration &

tubular secretion.

Dose adjustment is required in renal failure.

2nd. Generation Cephalosporins

Eg. cefuroxime, cefprozil, cefaclor*

Significantly activity against

H. influenzae, M. catarrhalis, P. mirabilis, N. gonorrhoea

activity against
Staph. & nonenterococcal strept

activity against some enterobactericeae eg.

klebsiella spp., salmonella, shigella.

(cefaclor: poor activity generally to

enterobactericeae)
2nd Generation Cephalosporin

Drugs

Cefamandole
Cefuroxime
Cefoksitin
Cefotetan
2nd Generation Cephalosporin
Common characters
More active on gram-negative bacteria

Less active on gram-positive bacteria

More stable to -Lactamase produced by gram-

negative rods

Some are effective on anaerobes

No effect on P. aeruginosa

Less renal toxicity

2nd. Generation Cephalosporins
Clinical Uses:
Gram-negative bacteria infections: first choice
Anaerobic infections
CAP (Community acquired pneumoniae)
Epiglotitis, Sinusitis
Uncomplicated UTI
Meningitis (3rd. Gen cephalosporins preferred)
 3rd. Generation Cephalosporins

ceftriazone, cefotaxime, cefoperazone,

Example ceftazidine

Main
distinguishing Good activity against Gm-ve bacilli.
feature:
Potent activity against Strept pneumoniae
Activity: including those with relative penicillin
resistance.

non-antipseudomonal &
2 groups: antipseudomonal (ie. cefoperazone,
cefpodoxime & ceftazidine)

Lacks activity enterococci, MRSA, highly resistant PRSP,

Stenotrophomonas, Acinetobacter (variable
against: sensitivity)
 3rd. Generation Cephalosporins
Clinical uses:

Serious infections caused by Gm ve bacilli (due to

the superior activity against GNB that are resistant to
other -lactam antibiotics.)

If pseudomonas infection is suspected: ceftazidine is

the option from this class. (cefoperazone,, has little
role in such clinical setting)

Ceftazidine + AMG: option for febrile neutropenia

 Overuse of 3rd. generation
cephalosporins
Has been linked to Extended spectrum -lactamase
producing organisms eg. Klebsiella, E. coli

Rahal et al. JAMA2008:280;14:1233-7

Also linked to MRSA

Washio et al. Pub Health 20077;111:187-190
 3rd Generation Cephalosporin

Ceftizoxim,
nosokomial respiratory tract, urinary tract, skin
Ceftriaxon, & infection, osteomyelitis, and meningitis (penetrate CSF).
cefotaxim:
long half live (6-8 hrs, once/day)
is not metabolized, 60% are excreted through gall bladder,
Ceftriaxon: Dose adjustment might be needed in hepatic and renal
disfunction.

is eliminated via gall bladder (75%) and

Cefoperason
kidney (25%).

is absorped orally,
Cefixim
half live: 4 hours.
3rd Generation Cephalosporin
Common characters
Much more active on gram-negative bacteria

To gram-positive bacteria: third<second<first

Stable to extended -Lactamase produced by

gram-negative bacteria

Effective on anaerobes and P.aeruginosa

No renal toxicity

Penetrating body fluids and tissues well

 Fourth- generation cephalosporins

Example: Character: Clinical uses:

Cefpirome, Enhanced infections
cefepime, antimicrobial caused by
cefclidin activity organisms that
Stable to are resistant to
ESBLs third-
(extended generation
spectrum beta cephalosporins
lactamase)
More activity
on gram-
positive cocci
 Side effect of cephalosporins

Allergic effect
Gastrointestinal reactions
Renal toxicity
Other : bleeding
Other -Lactam drugs
 Cephamycins
Cefoxitin
Similar to second-generation
cephalosporins
More activity on anaerobes

-Lactamase resistant

High concentration in CSF

Treatment of mixed anaerobic and
aerobic infections
 Carbapenems

The most important antimicrobial agents

in 1990s

Wide spectrum and high activity

Resistant to most -Lactamase (including

ESBLs and cephalosporinase)
 Carbapenems
Thienamycin

Imipenem

Carbapenems Imipenem-cilastatin:tienam

Meropenem

Panipenem
-Lactamase inhibitors

Clavulanic acid
Sulbactam
tazobactam
 -Lactamase inhibitors

Weak antimicrobial action

Protect -lactams from
inactivation by -lactamase
Synergism
Compound preparation
 Monobactams
Aztreonam, carumonam

No effect on Gram (+) bacteria and anaerobes

High activity on gram-negative bacteria

No cross-allergic reaction with penicillin

Penicillin-allergic patients tolerate well

Low toxIcity
 VANCOMYCIN

Bacterial cell wall synthesis inhibitor.

Is not absorbed in GI tract, i.m, painfull.

Reaching various body fluid: gall bladder,

pleura, pericard, peritoneum, and synovial
fluid; penetrate inflammed meninges.

Dose adjustment is required in patient

with renal disfunction.
TEICOPLANIN & BACITRACIN

Teicoplanin: i.m / Very long half live,

per oral, 50-100 hrs

To attain steady
Reaching various
state: bigger initial
body fluid,
dose.
TEICOPLANIN & BACITRACIN

Bacitracin can not be given parenterally, very

toxic, only available topically.
 Vancomycin & Teicoplanin

Severe infection esp staphylococcus

For MRSA

Vancomycin: pneumonia, endocarditis,

emphysema, osteomyelitis, surgical site infection
Oral: particularly enterocolitis pseudomembranose
due to C. difficile
 Adverse Events
Vancomycin

Painfull at Erythema, Nephrotoxic if given

Ototoxic injection hipotension, concurrently with
site chest pain aminoglycoside

Nephrotoxic if reaching systemic

Bacitracin
circulation
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
 Erythromycin
from Streptomyces erythreus

Esp. active against mycoplasma, chlamydia and treponema

DOC for C diphteriae, M. pneumoniae, E. hystolitica & Chlamydia

Available as estolat, stearat, etilsuccinate, base

Eliminated via hepatic metabolism

CSF concent in inflammed meninges: 25% blood concent

Children: estolate is better absorbed

Adult: estolate is not recommended (causing cholestatic hepatitis)

Oral dose: 4 x 250-500 mg 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
H3C
N CH3
H3C OH
OH

OH C ONH2
OH O OH O
TETRACYCLIN
E 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.

Short acting Intermediate acting Long acting

Oxytetracycline Doxyciclin
Demeclosilin
Tetracycline Minosiklin
 TETRACYCLIN
E

Short acting Intermediate acting Long acting

A b s o r p s i on

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

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

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

DOC typhoid (S. typhi)

Dose: 2-3g atau 30-50mg/kgBW/day (divided in 4
doses), 2-3 weeks to prevent relapse
Meningitis: H influenzae (second line)
Eye infection
 CHLORAMPHENICOL

Contraindication:
leukopenia,
trombositopenia, severe
anemia
Pregnancy
Prematurity/ < 2 weeks
Adverse event:
Bone marrow suppression
Grey baby syndrome
 AMINOGLYCOSIDE

MECHANISM OF ACTION

Bound to 30S subunit ribosome: preventing formation

of peptide 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
 AMINOGLYCOSIDE

ADVERSE EVENTS

Ototoxic (t1/2: 5-6times higher than plasma:

vestibular damaged
Gentamycin, streptomycin: vestibular
Amikacin, kanamicin, neomicin: auditory function
Nephrotoxic (8-26% renal function impairment,
reversible.
Neomisin: topical only
AMINOGLYCOSIDE
Nephrotoxicity
of
aminoglycoside
Ototoxicity of aminoglycoside
Gentamycin

Ps. Aeruginosa, E.coli, Proteus,

Staphylococcus

+ penicillin for septicaemia due to Gram (-)

Good concent in cornea and humor aqueous:

topical

Increase nephrotoxicity if given concurrently

with cephalosporin or diuretics

Inactivated if given concurrently with

carbenicilin, penicillin, cefalexin
METRONIDAZOL

Bactericidal for T. vaginalis, G. lamblia, E.

hystolitica
Active against anaerobic bacteria: Bacteroides sp,
Clostridium

PHARMACOKINETICS

Well absorbed in GI tract

Distributed to all body fluid, pleura, vagina, CSF,
breast milk
Is metabolised in liver, excreted via kidney
 CLINICAL USE OF METRONIDAZOLE

Trichomoniasis Amoebiasis Giardiasis

2 gr. Single dose OR 3x250 mg, 5 days 3x250 mg, 5 days

3x250 mg, 7 days Child: 3x5mg/kgBB
+ partner

ADVERSE EFFECT

Alcohol intolerance: nausea, vomit,

Gastrointestinal symptom: nausea, vomits
Peripheral Neuropathy with high dose administration
SULFA AND
TRIMETOPHRIM
 TRIMETOPRIM

Antibacterial spectrum = sulfametoksazol

20-50 more poten than sulfonamid
High concentration: prostate and vaginal fluid
For the treatment of UTI & prostatitis
Adverse event

megaloblastic anemia, leukopenia,

granulocytopenia
 COTRIMOKSAZOL
(trimetoprim + sulfametoksazol

Greater antibacterial effect

Expand antibacterial spectrum
1 trimetoprim + 20 sulfametoksazol
Indication: UTI

Adverse event:

Erythema, nausea, vomit

megaloblastic anemia, leukopenia, trombositopenia
Haemolytic anemia in patient with G-6PD deficiency
 Fluoroquinolones
Novel group of synthetic antibiotics developed in
response to growing resistance

Agents available today are all structural derivatives

of nalidixic acid

The fluorinated quinolones (FQs) represent a

major therapeutic advance:
Broad spectrum of activity
Improved PK properties excellent bioavailability, tissue
penetration, prolonged half-lives
Overall safety

Disadvantages: resistance, expense

 Fluoroquinolones
Mechanism of Action

Unique mechanism of action

Inhibit bacterial topoisomerases which are necessary for

DNA synthesis
DNA gyrase removes excess positive supercoiling in the DNA helix
Primary target in gram-negative bacteria
Topoisomerase IV essential for separation of interlinked daughter
DNA molecules
Primary target for many gram-positive bacteria

FQs display concentration-dependent bactericidal

activity
 Fluoroquinolones

Mechanisms of Resistance
Alteredtarget sites chromosomal
mutations in genes that code for DNA
gyrase or topoisomerase IV
most important and most common
Altered cell wall permeability
decreased porin expression
Expression of active efflux transfers FQs
out of cell
Cross-resistance occurs between FQs
 The Available FQs

1. Norfloxacin (Noroxin) - PO
Older FQs
2. Ciprofloxacin (Cipro) PO, IV

1. Levofloxacin (Levaquin) PO, IV

Newer FQs 2. Gatifloxacin (Tequin) PO, IV
3. Moxifloxacin (Avelox) PO, IV
 FQs Spectrum of Activity

Gram-positive older agents with poor

activity; newer FQs with enhanced
potency
Methicillin-susceptible Staphylococcus aureus
Streptococcus pneumoniae (including PRSP)
Group and viridans streptococci limited activity
Enterococcus sp. limited activity
 FQs Spectrum of Activity

Gram-Negative all FQs have excellent

activity (cipro=levo>gati>moxi)
Enterobacteriaceae including E. coli,
Klebsiella sp, Enterobacter sp, Proteus sp,
Salmonella, Shigella, Serratia marcescens,
etc.
H. influenzae, M. catarrhalis, Neisseria sp.
Pseudomonas aeruginosa significant
resistance has emerged; ciprofloxacin and
levofloxacin with best activity
 FQs Spectrum of Activity
Anaerobes
only trovafloxacin has adequate activity against
Bacteroides sp.

Atypical Bacteria
all FQs have excellent activity against atypical bacteria
including:
Legionella pneumophila - DOC
Chlamydia sp.
Mycoplasma sp.
Ureaplasma urealyticum

Other Bacteria
Mycobacterium tuberculosis, Bacillus anthracis
 Fluoroquinolones
Pharmacology

Remark
Concentration-dependent bacterial killing AUC/MIC (AUIC)
correlates with efficacy
Absorption
Most FQs have good bioavailability after oral administration
Cmax within 1 to 2 hours; coadministration with food delays the
peak concentration
Distribution
Extensive tissue distribution prostate; liver; lung; skin/soft tissue
and bone; urinary tract
Minimal CSF penetration
Elimination renal and hepatic;
not removed by HD
 Fluoroquinolones
Adverse Effects
Gastrointestinal Nausea, vomiting, diarrhea, dyspepsia
5%
Headache, agitation, insomnia,
Central Nervous
System dizziness, rarely, hallucinations and
seizures (elderly)
Hepatotoxicity
LFT elevation (led to withdrawal of
trovafloxacin)
Phototoxicity More common with older FQs (halogen
(uncommon with
current FQs) at position 8)

Variable prolongation in QTc interval

Cardiac
Led to withdrawal of grepafloxacin,
sparfloxacin
 Fluoroquinolones
Adverse Effects

Articular Damage

Arthopathy including articular cartilage damage,

arthralgias, and joint swelling
Observed in toxicology studies in immature dogs
Led to contraindication in pediatric patients and
pregnant or breastfeeding women
Risk versus benefit
Other adverse reactions: tendon rupture, dysglycemias,
hypersensitivity
 Fluoroquinolones
Drug Interactions

Divalent and trivalent cations ALL FQs

Zinc,Iron, Calcium, Aluminum, Magnesium
Antacids, Sucralfate, ddI, enteral feedings
Impair oral absorption of orally-administered
FQs may lead to CLINICAL FAILURE
Administer doses 2 to 4 hours apart; FQ first
Theophylline and Cyclosporine - cipro
inhibition of metabolism, levels, toxicity
Warfarin idiosyncratic, all FQs