3. ANTI-MICROBIAL AGENTS 2
Inhibitors of cell wall synthesis
β-lactams
Penicillins
Benzyl penicillin
IV / IM
Depot
preparation
Acid resistant β-lactamase resistant Broad spectrum Extended
spectrum
Pharmaco-
kinetics
- hydrolyzed by gastric
acidity → parenteral
- distributed to infected CSF
- cross placenta
- renal excretion → fall in
blood conc.
“Probencid blocks renal
excretion”
Procaine
24hr
Benzathine
1month
IM
Penicillin v
acid stable →
Oral
Nafcillin → IV
Oxacillin IV
Cloxacillin Oral
Dicloxacillin Oral
Ampicillin
Amoxicillin
(more complete absorption
ans less incidence of diarrhea
than ampicillin and not
affected by food )
→ Oral
- absorbed from gut
Ticarcillin
Piperacillin
Spectrum Gram +ve
Gram –ve
Non β-lactamase
Gram +ve
Gram –ve
Non β-
lactamase
Gram +ve
Gram –ve
Non β-lactamase
Staphylococci “producing
β-lactamase”
All Gram +ve
No Gram -ve
Penicillin resistant
streptococci
Gram -ve
Gram –ve
rods
Pseudomonas
aeruginosa
Uses Drug interactions :
1- Probenecid : inhibit
secretion & ↑ plasma level
2- oral contraceptive pills :
the effect is lost and
unintended pregnancy √
- Benzathine
for
prophylactic
uses only
as rheumatic
fever
Minor infections β-lactamase producing
organisms
cellulitis ,osteomyelitis,
endocarditis ,bacteria
from MSSA
Not MRSA
1- UTI, RTI
2- meningitis
3- salmonella ( ampicillin )
4- HP Pylori ( amoxicillin )
Meningitis – syphilis – gonococcal infections (prophylaxis) – pneumococcal infections streptococcal infections – bacterial pneumonia
Disadvantages1- 1- short duration
2- 2- instable in acid
3- 3- destroyed by β-lactamase
Penicillinase hydrolyzes it to
penicillioic acid (inactive)
4- 4- narrow spectrum
1- poor
bioavailablity
2- frequent dosing
“4-6 times/day”
3- destroyed by
β-lactamase
4- narrow
spectrum
narrow spectrum
destroyed by β-lactamase destroyed by
β-lactamase
Side effects 1- hypersensitivity → anaphylactic shock 3- Ampicillin → GIT distress
2- complete cross allerginicity between individual penicillins 4- diarrhea 5- Neurotoxicity 6- Hematologic toxicity
β-lactamase inhibitors:
- clavulinic acid + amoxicillin → Augmentin oral / IV
- Sulbactam + ampicillin → Unasyn Oral /IV/IM
- Ticarcillin / calvulante → Timentin IV
- Piperacillin / Tazobactum → Zosyn IV/IM
4. ANTI-MICROBIAL AGENTS 3
β-lactams Non β-lactams
Cephalosporins Carbapenem
s
Monobactam Glycopeptides
1st 2nd 3rd 4th 5th Meropenem,
Ertapenem
Primaxin;
(imipenem-
clistatin)
Aztreonam Vancomycin
Cephazolin true : Cefaclor ,
cefuroxime
cephamycin :
cefotetan ,
cefoxitin
Ceftriaxone Cefepime ceftaroline
Pharmaco-
kinetics
many of them must be administrated parenterally because of their poor oral absorption
* No cross
resistance with
other drugs
Parenteral
* No cross
reactivity
- Not well absorbed
→ IV injection
- Well distributed
- excreted unchanged by
kidney
Oral for GIT infections
“clostridium difficile colitis”
Excreted unchanged by the kidney
CSF X CSF X CSF √ CSF √
Spectrum
Pseudomonas
Gram +ve ---------------------decreasing-------------------------->
Gram –ve bacilli ---------------increasing-------------------------->
gram +ve and –
ve and
anaerobes
no MRSA
Ertapenem :
pseudomonas
- Gram –ve
including
psuodomonas
Gram +ve including MRSA
Anaerobes +++
Indole +ve proteus
Anaerobes
Indole + ve proteus
Anaerobes
Indole +ve
proteus
gram + ve
MRSA
VRSA
VISA
β-lactamase resistance -------------increasing------------------->
X X X
except ceftazidime
& cefoperazone
√ X √
Uses 1- 1- surgical prophylaxis
2- 2- urinary tract infections
(uncomplicated)
(Penicillin/sulphonamide resistant)
1- Meningitis & gonorrhea 1- complicated
skin and soft
tissue infection
infections due to
resistant Gram –
ve organism
1- hospital
acquired
meningitis
2- intra-
abdominal
infections
3- complzicated
skin and soft
tissue infections
1- hospital
acquired
pneumonia
2- intra-
abdominal
infections
3- sepsis
4- skin and soft
tissue infections
1- MRSA
2- staphylococcal enterocolitis
&Pseudomembranous colitis
“caused by clostridium difficile”
3- In combination with:
- 3rd
gen. ceph. → meningitis
- Penicillin resistant
- gentamycin → enterococcal
endocarditis
- penicillin allergic patient
3- uncomplicated
skin and soft
tissue infections
3- Respiratory
tract infections
4- cephamycin :
mixed aerobic and
anaerobic
infections of skin
and soft tissues ,
intraabdominal
and gynecological
2- upper and
lower RTI
3-pyelonephritis
4- skin and soft
tissue infections
2-serious
nosocomial
infections
3-complicated
UTI
2- community
acquired
pneumonia
Disadvantages 1- Hypersensitivity:
- cross allerginicity between drugs
- partial cross allerginicity w/ penicillin
- avoid in patients with history of anaphylaxis to penicillin
2- GIT upset & bleeding disorders
3- eliminated by the kidney so adjusted dose in renal dysfunction except cefatriaxone
and cefoperazone execreted in the bile and used in renal insufficiency.
4- Super-infection
5- Hospital-acquired clostridium difficile colitis
6- All cross the placenta
1- increase risk
of neurotoxicity
contraindicated
in Epilepsy
**ADV: no
cross reactivity
with penicillin
allergy
1- Ototoxicity & nephrotoxicity
2- irritation leading to phlebitis
@ site of injection
3- Histamine release → Red
Man syndrome prevented by
slow infusion
4- Chills & fever
5. ANTI-MICROBIAL AGENTS 4
Inhibitors of protein synthesis
Drug interaction with tetracycline:
1- Antacids, dairy products & iron.
2- Penicillin
3- Loop diuretics
30s Subunit inhibitors
Aminoglycosides Tetracycline
Neomycin Gentamycin Streptomycin Minocycline- doxycycline
Pharmaco-
Kinetics
• Poorly absorbed when oral (highly polar drugs )
• Cleared unchanged in the kidney
o Well absorbed orally except tigecycline
o Well distributed[placenta/milk]
o Eliminated by kidney or bile [doesn't accumulate in renal failure]
o Doxycycline & minocycline cross BBB
• Min plasma protein binding, tissue level
in CSF, NOT crossing meninges
Oral, topical Parenteral Parenteral
Spectrum Gm +ve, Gm-ve Mycobacterium TB 1) Gm +ve, Gm-ve
2) Anaerobic pathogen , chlamydia
3) Spirochetes [cholera/syphilis& H.pylori] & malaria
Gm-ve including pseudomonas
May be combined with B- lactam E.X: penicillin to extend spectrum to
Gm +ve
Uses 1) Oral:
- Elective bowel
surgery (Hepatic
coma
2) Topical:
- Skin& wound
infection D.t
Gm+ve staph
- Injection into joints,
pleura, tissue
spaces
Severepseudomon
as, Enterobacter
infections resistant
to Abs. as in:
- Septicemia
- pneumonia
1) Spectinomycin:
In acute Gonorrheal
infection as IM
injection
1) Drug of choice in Atypical : chlamydia , spirochetes
2) Cholera. Entamoeba Histolytica
3) Acne: topical & systemic
4) Combination to treat H.pylori ….AACE Pylori1
5) Prostatis & meningococcal carrier & malaria
tigecycline:
1- staphylococci &streptococci ( MRSA & VRE)
2- anaerobes
3- gram –ve except : pseudomonas
Adverse
effects
1) Nephrotoxicity: shouldn't be used with diuretics or
vancomcyin[+kanamycin]
2) Ototoxicity: auditory [KON] Vestibular divisions of 8th
cranial
nerve[SGT] high peak of plasma conc. levels accumulate in
peri& endolymph of ear irreversible with other ototoxic drugs as
diuretics
3) Neuromuscular blockade(neurotoxicity)
1- GIT disturbance& chelating of Ca+
2- Deposition in bone, teeth[ yellowing, hypoplasia, growth]
3- Liver toxicity
4- Kidney toxicity[ renal tubular acidosis " Fanconi Syndrome"]
5- Ototoxicity: vestibular reactions as [N, V& Vertigo] in
minocycline &deoxycycline
6- Superinfection with candida albicans [affect flora, immune
defense]
7- Photosensitivity
****تجميعه
- Toxicity: nephro, oto, hepato
- Chelating: GIT, Bone, teeth
- Sensitivity: IV, IM, photo
+ superinfection with candida
4) Hypersensitivity :
with topical
neomycin
5) Fetal risk
Contra
indications
Pregnancy 1- Renal impairment
2- Pregnancy, lactation
3- Children under 8 years
6. ANTI-MICROBIAL AGENTS 5
50s Subunit inhibitors
Macrolides, ketolides Clindamycin Chloramphenicol
Erythromycin Clarithro
-mycin
azithromycin Telithrom-
ycin
Pharmaco-
Kinetics
- Gluconate: acid
unstable[parenteral]
- Estolate: acid
resistant[oral]
✓placenta CSF
- Accumulate in
macrophages
- Metabolized : liver
- Excreted: bile
[no renal adjustment]
taken on empty stomach
*Methyl-
ated form
* stable in
gastric
acidity
* oral
*
increased
by eating
- absorbed orally
- food
bioavailability
- CSF
- in phagocytic cells
- 1/2 life = 2-4
days.
- Excreted: bile
tissue>serum
- Linosamides
- CSF
- Penetrate bone
- Metabolized in
liver
- Excreted in bile
- Rapid absorbed orally
- ✓placenta ✓CSF
- Metabolized by liver by
conjugation with glucuronic acid
- Excreted by bile
Spectrum = benzyl penicillin [gm+]
+ Staph, Corynebacteria
+ Atypical [mycoplasma, legionella&
chlamydia]
- No anaerobic
strept
staph
Chlamydia
influenza [gm-ve
cocci]
*Resistant
strains to
other
macrolides
= Erythromycin
+anaerobic
+ MRSA
1) Gm +ve, Gm-ve
2) Aerobes, anaerobes
3) Atypical: rickettsia
So ( broad spectrum)
Uses 1) Drug of choice in
Corynebacteria diphtheria
2) Chlamydia[neonatal,
ocular &genital]
3) Community acquired
pneumonia
by[mycoplasma,
Chlamydia&
pneumococci]
4) Penicillin allergy
with[strept, staph]
5)Pro-kinetic before
endoscopy or to advance
feeding tubes
mainly
against
H.influen-
zae &
h.pylori
1- atypical infection
.
2-pelvic infection
,urethritis
,cavities
[by chlamydia &
gonococci
3-community
acquired pneumonia
, sinusitis , street
throat inf. In
pemicillin allergic
patients
**Resp.
tract
infections
1) Intra-abdominal as
peritonitis and
intra-abdominal
abcess caused by
anaerobic
2) Osteomyelitis
3) Acne vulgaris (
topical gel )
topical in treatment of eye infection
drops and oinements
Adverse
effects
1) GIT upset: motility, N,
V, Anorexia
2) Liver toxicity : Estolate
form cause acute
cholestatic hepatitis
3) QT prolongation :
arrhythmia
4) Drug interaction:
- Liver enz. & warfarin
metabolism cause
accumulation
- Serum con. Of digoxin
by eliminating intestinal
flora that inactivate it
normally
inhibit
hepatic
metabolis
m
No drug
interaction
Not affect liver enz.
high risk of
hepatoxicity .
1- Hypersensitivity
2- Impaired liver
function
3- Pseudomonas
colitis D.t over
growth of
clostridium difficile
1- Bone marrow suppression: aplastic
anemia [CBC monitoring is a must]
2- GIT Disturbance
3- Grey baby Syndrome:
- underdeveloped conjugation enzymes
glucuronic acid and break O2 in blood
leading to:
- Hypoxia: fetal
- Cyanosis: bluish discoloration
- Vascular collapse
** treated by: O2 ventilation
4- DRUG INTERACTION:
[HEPATIC ENZ. INHIBITORS] so
Serum con.
Contra
indications
Liver toxicity “CYTP450” ---- ----- ----- Liver toxicity 1- Pregnancy, lactation
2- Children under 2 years
3- CYTP450
7. ANTI-MICROBIAL AGENTS 6
New protein synthesis inhibitors:
1- streptocramins: quinupristin / dalfopristin:
- VRSA & VRE
2- linezolid:
-Inhibit the initiating process in protein synthesis
-MAO inhibitor
-VRSA
Adverse effects:
1- thrombocytopenia
2-serotonin syndrome ( with serotonin increasing drugs)
8. ANTI-MICROBIAL AGENTS 7
Inhibitors of Nucleic acid function/synthesis,
Inhibitors of bacterial metabolism & bacterial cell membrane.
A-Inhibitors of nucleic acid
function/synthesis
(Fluroquinolones)
B-Inhibitors of bacterial metabolism
Co- trimoxazole (trimethoprim +sulphamethoxazole)
Pharmaco-
kinetics
-Well absorbed orally
-well distributed in CSF , Placenta ,Milk
-renally excreted unchanged
400 mg sulphamthoxazole”inhibit DHF synthesis”+80mg
trimethoprim”inhibit DHF reductase”➔ reduced minimum inhibitory
concentration
-Well absorbed orally
-Well distributed
-Renally excreted
Spectrum 1st
: nalidixic acid : gram –ve
2nd
: ofloxacin, Cipro , norfloxacin : mainly gram -ve
3rd
: levofloxacin : gram –ve and ↑ gram +ve and
atypical organisms
4th
:moxifloxacin : same as 3rd
Gm +ve: less used
gm –ve: less used
not peudomoas
Uses 1-GIT : typhoid , paratyphoid ➔ drug of choice
ciprofloxacin
2- UTI: even if multidrug resistence.
3- Gonorrhea ➔ ciprofloxacin , ofloxacin
4- Respiratory tract. & resistant inta-abdominal .
1- Complicated UTI and prostatitis .
2- Community acquired MRSA skin infections
3- Traveler’s diarrhea
Adverse
effects
1- GIT reaction : N V D
2- Tendon damage and rupture.
3- CNS reactions : insomnia , seizures , headache.
4- Abnormal liver function test.
5- Skin rash “ photosensitivity”
6- CYP450 inhibition :increase conc. Of warfarin.
1- Hematologic: BM depression (aplastic anemia) – acute hemolytic anemia
( methomoglobinemia / hemolysis in G6PD)- agranulocytosis-
thrombocytopenia. ↓ folic acid
2- Renal : crystaluria, prevented by :
- increase fluid intake
- Keep urine Ph alkaline by NaHco3
3- GIT upset: N V
4- (megaloblastic anemia)
5- Allergy: skin rash – drug fever – urticarial, Steven Johnson’s syndrome
6- Drug interactions:
a- displace bilirubin formation (kernicterus)
b- drugs from plasma binding proteins : oral hypoglycemic ,
anticoagulants.
Contra
indications
1- Growing children up to 18 years (cartilage
damage – arthropathy)
2- Pregnancy – lactation
3- CNS disorders or epilepsy.
1- Pregnancy – lactation , Children under 2 years.
2- Patients with impaired renal function.
3- Patients eith preexisting blood dyscrasias or BM suppression
2- Metronidazole :
used in :
1-anaerobic gram +ve & -ve bacteria & clostridium difficle
2-treatment of choice in pseudomonas colitis
3-H.bacter pylori
4- antiprotozoal : giardia , trichomonas , E. histolytica
c- inhibitors of bacterial cell membrane.
colistin …. Very toxic
polymixin antibiotic
gram –ve including pseudomonas
9. ANTI-MICROBIAL AGENTS 8
Anti-Viral Chemotherapy
Anti-herpetic Anti-retroviral Anti-influenza Anti-hepatitis
Acyclovir (IV, tablets, cream, eye ointment ,syrup)
Action: nucleoside analogue need 3 phosphorylations
steps the first by virus-specific thymidine kinase
then host inhibits DNA synthesis by 2 mechanisms:
1- Competitive inhibition with deoxy GTP for
DNA polymerase &<<< to DNA template
irreversible complex.
2- Chain termination following incorporation.
Nucleoside reverse
transcriptase inhibitor:
Zidovudine,.tenofovir
&lamivudine .
Inhibit RNA → DNA.
nNRTI,PI, fusion
inhibitors , integrase
inhibitor , CCR5
antagonist
HAART: highly active
retroviral therapy : 2
NRTIs with NNRTI,PI
or Integrase inhibitor
factors affect HAART
drugs choice :
1- associated
comorbidities
2- adverse effects
3- drug- ( drug –food)
interactions .
4-pregnancy
NRTI zidovudine -
lamivudin
NNRTI nevirapine
PI liponavir / ritonavir
Goals of therapy :
1- ↓morbidity due to
infection, ↑ survival
2-improve quality of life
3-restore &preserve
immunologic function
4- suppress viral load
5- prevent vertical
transmission
* oral to the mother 14-
34 weeks
*IV in labour
*syrup to neonate from
birth to 6 weeks age
Amantadine &
ranitidine
Prevent& treat
influenza A virus in
classic strain.
Neuraminidase
inhibitors;
Zanamivir
&Oseltamivir:
influenza A& B
inhibit neuraminidase
enzyme needed for
viral replication.
HBV
Goals:
1- ↓ Progression → cirrhosis → HCC.
2- prevent vertical transmission
3-prevent reactivation in immune-
compromised patients
4- prevent acute liver failure in acute
hepatitis B
Drugs:
1-Nuecleoside reverse transcriptase
inhibitors. Long term as tenofovir
2- Standard or pegylated interferon-alfa:
in mild and moderate chronic hepatitis B
combination are not recommended :
***check the table P 45
HCV
Goals: 1-Elimination of virus & improve
symptoms. PCR after 6 months .
2-decrease the incidence of cirrhosis & cancer.
3- Prolong survival.
factors to choose :
1- viral genotype
2- previous treatment experience
3- presence of de/ compensated cirrhosis
4- adverse effects & drug interactions
5- renal impairment
6-HIV or HBV coinfection
treatment :
1- old and limited :
pegylated interferon alpha :
alone or with ribavirin
-injections
-long treatment duration
-many side effects
-SVR 30-40%
-many contraindications
-used in :
pediatrics less than 12 y. DAA not approved
coinfection with HBV
Ribavirin :
not alone
with interferon and DAA
↓ viral load ..↑ SVR
adverse effects : hemolytic anemia &
teratogenicity
2- new : DAA
Uses Acyclovir:
Topical: a) herpetic -conjunctivitis.
b) Localize genital herpes simplex.
Oral: prophylaxis: a) CMV in organ transplant.
b) Reactivation of latent virus
in immune-compromised.
Therapy: a) Herpetic gingiva-stomatitis.
b) Recurrent genital herpes simplex.
c) Chicken box in immune –
compromised.
d) Herpes simplex in immune-
competent.
IV: a) Disseminated herpes simplex.
b) Varicella zoster in immune-compromised.
Gancyclovir :treatment, preemptive treatment &
prophylaxis in immune-compromised of CNMV.
Foscarnet: in case of resistance against Acyclovir&
Gancyclovir.
Valacyclovir : prodrug , like acyclovir with better
oral bioavailabilty .
ADR 1- Acyclovir:
Neurotoxicity: seizure.
Nephrotoxicity: reversible crystalline
nephropathy.
IV: phlebitis.
Oral: nausea &vomiting.
2- Gancyclovir:
Bone marrow depression.
3- Foscanet :
reversible renal dysfunction prevented by
hyperhydration
hypo ( calcemia-kalemia-Magnesemia)
1- GIT.
2- Bronchospasm.
& ↓ Lung function &
asthma with zanamivir
10. ANTI-MICROBIAL AGENTS 9
Directly Acting Antivirals (DAAs):
advantages adverse effects fixed combinations
- specific
- convenient as given orally
- short duration
- target different viral
genotypes
- high SVR 100%
- few tolerable side effects
- givin with de/compensated
cirrhosis
عكسالحاجاتالليخلتالnterferoni
وحشة
1- most common:
headache,
fatigue, diarrhea
& nausea
2- may result in
HBV
reactivation in
coinfected
patients
that’s way all
patients should
be screened for
HBV
1- Harvoni: sofosbuvir and ledipasvir
2- Epclusa: sofosbuvir and velpatasvir
3- Vosevi: sofosbuvir, velpatasvir and
voxilaprevir
sofobuvir (sovaldi)
- once daily / orally
- approved in combinations
- well tolerated safety profile
contraindications:
renal elimination so not used with severe
renal impairment
• other combinations are safe since they
are metabolized by the liver
11. ANTI-MICROBIAL AGENTS 10
Anti-fungal Chemotherapy
systemic drug for systemic infection systemic (oral) drug for
superficial infection
tropical drug
for superficial
infection
Amphotericin B flucytosine Azoles Echino-
candins
azoles Griseo-
fulvin
terbinafi
n
Nyastatin
mechanism disrupt cell membrane
Function
pores
block nucleic acid
synthesis
Inhibit ergosterole synthesis
by inhibiting
cyt P450 dependent enzymes
inhibit cell
wall glycan
synthesis
disrupt
micro-
tubular
function
inhibit
ergosterol
synthesis
cell membrane
spectrum broadest .. intial
induction regimen
Narrow broad ------- candidiasis
dermato-
phytes
Dermato-
phyte
Dermato-
phyte
candida
kinetics -poorly absorbed
IV .. systemic ..aerosol
pulmonary
- No cross BBB No CSF
-no dose adjustment in
renal impaired
-AMB lipid complex is
highly protein bound
nephrotoxicity
↓ infusion associated
side effects
***a New lipid
formulation of AMP :
highly protein bound
and ↓ side effects and
nephrotoxicity.
-oral in
combination with
amphotericin B
-√ CSF
-converted to 5
fluorouracil by
cystosine
deamination
Imidazoles
well absorbed
clotrimazole :
-topical
-No CSF
-affect P450
enzymes
-metabolized
-superficial
inf . only
ketoconazole
clotrimazole
Triazoles
-oral / IV
-√ CSF
-↓effect on
human
steroid
synthesis
-↑safety
-in liver
-superficial
invasion inf.
1st:
fluconazole
itraconazole
2nd:
vanconazole
-poorly
absorbed oral
-IV only
-not liver
metabolized
no cyt.
. NO
Interaction
imidazole
↓
Keto-
conazole
triazole
oral
conc. in skin
oral not absorbed oral
IV systemic toxicity
topical only
topical
amphotericin:
candida
topical Azoles
Imidazoles
( ketoconazole
/isoconazole ) /
Triazole
( voriconazole )
candida /
dermatophytes
tropical terbinafin:
dermatophytes
Adverse
Effects
1- infusion related
chills,fever,muscle
spasm,vomiting,hypertio
n
slow infusion
premedicate antipyretic
antihistamine
2- cumulative toxicity
nephrotoxicity
anaemia (decrease renal
erthropoeitin)
hypokalemia
Kidney
1- Hepato-toxicity
raised liver
enzymes
2- Bone marrow
toxicity
3- Alopecia
spot baldness
1- hepatotoxicity
elevation in transaminase
..hepatitis..liver failure
2-Imidazole endocrinal
disturbances due to inhibition
of synthesis of gonadal &
adrenal steroids due to
inhibition of human cyt p 450
3-inhibit cyt P450
↑plasma level of liver
metabolized drugs
itraconazole / vanconazole
fluconazole
liver
1-
hepatotoxicity
cyclosporine
raised liver
transaminase
2- Histamine
release
irritation /
headache
3- fever
1-
hepatoxicit
y
2- bone
marrow
depression
3- allergic
reaction
4- cyt P 450
inducer
↓efficacy of
other drugs
rare GIT
disturbanc
e
tropical
amphotericin :
local irritation
hypersensitivity
cell membrane only
