Oct 10,

2015

Antimicrobial
Therapy
Objectives
To treat infection
To prevent
infection

Timing of use
Empirical use
Specific use

Site of infection
Function of organ
Immune status
Other physiologic
and disease
states
Allergy history

Pathog
en

Identification
of organism
Susceptibilit
y - MIC

Hos
t

Dru
g

Spectrum of
agent
PD
PK
Route of
administration
ADRs

Effect bacteriostatic and

bactericidal drug on
growth of bacteria in
vitro

Antimicrobial
pharmacokineti

ntibacterial PD : killing modes

Mode of killing

Representatives Goal of
Regimen

Conc.dependent

Aminoglycosides
Fluoroquinolone
Metrodinazole

Maximize conc.

Time dependent

Pennicillins
Cephalosporins
Aztreonam
Azithromycin
Tetracyclin
Streptogramin
Vancomycin

Maximize
exposure time

Time above MIC levels

Maximize conc.
and time

AUC24/MIC

Time and conc.

dependent

Parameters
Correlating With
Clinical Efficacy
Ratio of Cpeak to MIC

Reasons why bacteria show selective toxicity at

various
sites
Site of action
Reasons for selective
Examples of
toxicity
Bacterial cell wall
synthesis

Bacterial protein
synthesis

Folic acid synthesis

Nucleic acid
metabolism

Membrane

antimicrobials active at
this site
The bacterial cell is bounded
-lactam agents ;
by a wall composed of
penicillin, cephalosporins
peptidoglycan, whereas
and carbapenems
mammalian cells lack this
Glycopeptides ;
Vancomycin and
Telcoplanin
Protein synthesis in bacteria is Macrolides
by the 70s ribosome : that in
Tetracycline
mammalian (or other
Chloramphenical
eukaryotic) cells is by the 80s Aminoglycosides
ribosome
Folic acid synthesis in bacteria Sulphonamides
and in higher organisms
Trimethroprim
differs radically.
Nucleotide synthesis and
Quinolones
polymerization is similar in
Rifampin
bacteria and mammals, and
Metrodinazole
drugs that affect these
processes often have toxicity
for mammals
Some are used but the
Amphotericin B (an

Drugs Affecting Bacterial

Cell Wall synthesis

irreversible binding to penicillin binding proteins

(PBPs) or transpeptidases
bactericidal
time dependent

-lactamase
PBPs

Evolution of Penicillins
Natural penicillins
Pen G, V

Antistaphylococcal
pennicillins
cloxacillin
dicloxacillin

Aminopennicillins
Ampicillin
Amoxicillin

Antipseudomonal penicillins
Carbenicill
in
ticarcillin
piperracilli

Cephalosporins

Carbapenems

cilastatin

P.aeruginosa

actam- -lactamase inhibitors (BLBLIs)

Generic name
Amoxycillin +
Clavulanic acid
Ampicillin +
Sulbactam
Sulfamicillin
(AmpicillinSulbactam ester
form)
Cefoperazone (
antipseudomonal
cephalosporins) +
Sulbactam
Piperacillin (
antipseudomonal
penicillin) +
Tazobactam

Trade name
Augmentin

Routes
Oral, IV

Unasyn

IV

Unasyn

Oral

Sulperazone

IV

Tazocin

IV

Glycopeptides

Vacomycin

outer membrane

porin
Red man syndrome
(ototoxicity)

aminoglycosides

Anti-bacterials affecting
protein synthesis

 Broad spectrum

Time-dependent

***

bacteriostatic

Resistance
- 3
1) pump
Macrolides
2) esterase cladinose, desosamine
Macrolide ring (Enterobacteriaceae)
-
1 2
*** 3) Modification of ribosome binding site
ribosome
- Methylation : methyl ribosome

- Macrolides

- Lincosamide Lincosamide

ribosome Macrolides
- Streptogramin B
MLS type B (Macolides Lincosamide

Macrolides

Erythromycin
Roxithromycin
Clarithromycin
Azithromycin
Medicamycin
Spiramycin
Telithromycin

Lincosamide

Lincomyci
Clindamycin
n
- Lincosamides inhibit trans-peptidation step
(peptidyltransferase- enzyme)
at(-)P-site

of
50S ribosome
Lincosamides

- Bacteriostatic
porin LPS

- Time-dependent
Narrow spectrum Macrolides
- Gram (+)
- Anaerobes (only Clindamycin)

Bacteroides fragilis, Clostridium

perfringens, C.tetani, C.difficilePregnancy

Tetracyclines

Inhibit bacterial protein synthesis

30S subunits ribosome
Bacteriostatic
Time-dependent, concentrationenhanced (with PAE)
- Broad spectrum
Resistance
- pump
Tet(K, AE, M)
- pump
- Tet(K) in staphylococci (only Tetracycline)
- Tet(AE) in gram -ve (except Tigecycline)
- Production of protein that interfere with
tetracycline binding to ribosome
- Tet(M) in gram +ve (except Tigecycline)
- Enzymatic inactivation

- %F
Ca2+ , Mg2+ , Fe2+ ,
Zn2+ , Al3+
-
Doxycycline
-
- tetracyclines


- 1st gen half life
4
3
- 2nd gen 3rd gen half life doxy
2 tige
-

Chloramphenicol

Fusidic acid

Mupirocin

Linezolid

Spectinomycin

 conc.-dependent

Derived from Streptomyces genus :___mycin

- Streptomycin
- Kanamycin
- Neomycin
- Tobramycin
Derived from Micromonospora spp.:___micin
- Gentamicin
- Neltimicin
Semisynthetic aminoglycosides
- Amikacin

- gram negative aerobic bacteria

-


- aminoglycosides anaerobic bacteria
- PAE (

MIC
)
- IM IV,
topical ( , ointment) ,

-

GI tract
-

Neomycin
- ototoxicity

CSF
irreversible


- nephrotoxicity reversible

dose
--
toxic

aminoglycosides
penicillins

aminoglycosides
-

Anti-bacterials affecting
genetic materials

Sulfonamides

sulfonamides
dihydropteroate synthase
bacteriostatic

dihydrofolate
reductase inhibitors

Trimethoprim
synergist
bactericidal
broad
spectrum
Sulfadiazin
Sulfamethoxazole
e

Resistance
- Overproduction of PABA (
PABA ) ***
- Modification of target enzymes (plasmidencoded)
-Pharmacokinetics
Impair permeability
-

-

- albumin 100%
- Metabolism Acetylation (major)
Glucoronidation (minor)
-

Adverse reactions
- sulfonamides

lipophilic
sulfonamides


-
Kernicterus

-

sulfonamides
- Sulfonamides
G6PD
deficiency
- Pregnancy category C

Silver sulfadiazine = SSD

Dihydrofolate reductase
inhibitors

Sulfamethoxazole + Trimethoprim
- sulfonamides + dihydrofolate reductase
inhibitors
- 2 PK
Trimethoprim
- half life 9 11 hrs
-
-

- tissue
- Co-trimoxazole Tab, Syr, IV
- bactericidal
- Urinary filtration and tubular
secretion
-

-
PCP

-
sulfonamides

folate
- trimethoprim selective enz


enz

-
folic acid

ulfadiazine + Pyrimethamine
- half life 96 170 hrs
Pyrimetha
- 3 5 regimen mine

-
- protozoa
- Toxoplasmosis
Malaria selective
enz
- pyrimethamine folic acid
trimethoprim
- pyrimethamine add folic acid

- folic acid folinic acid

Quinolones

Bactericidal - Concentration



divalent cations Ca2+,

-


Urinary tract infections (UTIs)
Respiratory tract infections (URIs and
LRIs)
Skin and skin structure infections
(SSSIs)
Sexual transmitted diseases (STDs)
Gastrointestinal infections
(gastroenteritis)

Septicemia


tissue

Tuberculosis (TB)

 urine

Moxifloxacin
50-60 %

2 (Short half
life): Norfloxacin, Ofloxacin,
Ciprofloxacin, Rufloxacin, Prulifloxacin,
Sitafloxacin

2 (Long half life):
Levofloxacin, Moxifloxacin

Adverse reactions
-

-

!
-
G6PD
- Arthropathy warning!! 18

- fluoroquinolones enz CYP1A2
- Quinolones

Pregnancy category C

Metronidazole
-
-

Anaerobes
- Clostridium sp, P.acne

Nitrofurans Nitrofurantoin

Nitrofurazone

Nitrofuroxazide, Furazolidone

Antimycobacterial Drugs
Mycobacterium tuberculosis
Aerobic bacillus, high cell wall content of
high MW lipid, acid-fast staining
generation time 15 20 h
First line
Isoniazid, rifampicin, pyrazinamide,
ethambutol, streptomycin
Second line
Ethionamide, p-aminosalicylic acid (PAS)
Amikacin, kanamycin, capreomycin
Cycloserine
Moxifloxacin, gatifloxacin

Isoniazid
INH isonicotinic acid hydrazide
prodrug active metabolite
catalase-peroxidase
(KatG)

mycolic acid



CSF 20 100%
N-acetylation

300 mg/d
ADR
Hepatitis
Peripheral neuropathy

Rifampin

rifabutin, rifapentine

DNA-dependent RNA polymerase
potent enzyme inducer



CSF
600 mg/d

, ,
()

Pyrazinamide

phagolysosome

(pH 5.5)
PZA pyrazinoic acid (active
form)






***

Ethambutol
enz. Arabinosyl transferase

arabinoglycan





Retrobulbar neuritis (
)