Therapeutics

against infections
By
Dr. Omerel-Adil Abdalla
Two ways to spread the light; be
The candle
or
The mirror
that reflect it
Introduction
 Inhistory many scientists to them goes our
gratitude; Fleming , Ehrlich and others
 Antibiotics
and
Antimicrobials
 Classification
 It is classified according to :
A- Origin of production into:-
1. Antibiotic: Chemical produced by a
microorganism.

2. Antimicrobial agent: Synthetic

Chemical
 Classification
B- Fate of action into:-
1. Bacteriostatic:- inhibits growth and
reproduction of bacteria without killing
them .

2. Bactericidal:- kills bacteria.

 Classification
C- Site of action:-
1. Inhibitors of cell wall synthesis and
Membrane active agents.
2. Inhibitors of protein synthesis.
3. Inhibitors of folate metabolism.
4. Inhibitors of DNA synthesis.
5. Inhibitors of RNA synthesis.
 Principles and Definitions
 Generally, don’t combine bacteriostatic and
bactericidals.
 Which categories to chose?
Bacteriostatic: Duration of treatment
sufficient for host defenses
Bactericidal :Usually antibiotic of choice
 No antibiotic is effective against all
microbes.
 Principles and Definitions
 Therapeutic Index: Toxic dose/ Effective
dose.
 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
 Inhibitors
of
Cell Wall Synthesis
β Lactam Group
 1- Penicillin
 General Activity: Bactericidal G +ve , G-ve cocci
non- b-lactamase.
 Special Usages: in meningitis and endocarditis.
 Serious side effects: Rare ; Anaphylaxis, interstitial
nephritis, pseudomembranous colitis, encephalopathy.
 Contraindications: Hypersensitivity, intrathecal
injection, but save in pregnancy.
 Excretions: Renal.
 Examples:
 Penicillinase ß-lactamase -sensitive penicillins
 Benzylpenicillin (penicillin G, parenteral(
 Penicillin V (phenoxymethyl penicillin, oral(
 Penicillinase-resistant penicillins
 Flucloxacillin.
 clavulanic acid.
 Broad-spectrum penicillins
 Amoxicillin.
 Combination: Co-amoxiclav (amoxicillin + clavulanic
acid(, Ampiclox (amoxicillin + cloxacillin (
 Antipseudomonal penicillins
 Piperacillin (with tazobactam; Tazocin)
 Ticarcillin (plus clavulanic acid)
 Cephalosporins -2

 General Activity: Bactericidal, similar to penicillins,

broader spectrum , more stable to b-lactamases , not
active against enterococci and L. monocytogenes.
 Special Usages:
First-generation : active against G +ve cocci ,G-ve
PEcK = (Proteus , Escherichia and Klebsiella) ,
Poor activity against Pseudomonas.
Second-generation: like the first-generation drugs,
in addition H.inf & Neisseria
(HeNPEcK)
Third-generation :
More G -ve, and able to cross BBB, some are
antipseudomonal , decreased activity against
G +ve especially S. aureus.

Fourth-generation :
G +ve and G -ve ,with good activity against
P.aeruginosa, S. aureus, good activity against
most
penicillin-resistant strains of streptococci .
 Fifth generation On the horizon
It was only issued an approvable letter in March
2008. The FDA is requesting additional
information
 Indication :
 Complicated skin infections including diabetic
foot infections
 MRSA
 Hospital-acquired pneumonia, including
ventilator associated pneumonia.
 Serious side effect:
Cross-allergenicity with penicillin 10%.
interstitial nephritis.
 Contraindications:
 Excretions:Renal
 Examples:
 First-generation: Cephalexin.
 Second-generation: Cefuroxime.
 Third-generation: Cefotaxime, ceftazidime,
ceftriaxone, cefixime, cefpodoxime .
 Fourth-generation: Cefepime.
 Fifth generation: Ceftobiprole
 3- Monobactams
(Aztreonam)
Active against G -ve ; cocci and bacilli , no
activity against G +ve bacteria or anaerobes,
resistant to ß-lactamase.

4- Carbapenems
(Meropenem)
Good activity against G +ve and G –ve
cocci , rods, and anaerobes.
Resistant to most ß-lactamase but not
MRSA or Clostridium
Inhibitors of cell wall synthesis
Non β Lactam Group
1- Vancomycin
 General Activity: Bactericidal , active only against
gram-positive bacteria, particularly staphylococci
organisms.
 Special Usages: in MRSA, CDID.
 Serious side effect: Phlebitis at the site of injection,
Ototoxicity, nephrotoxicity ,"red man" syndrome.
 Contraindications: Sensitivity.
 Excretions: Renal
 Cycloserine -2
It is used almost exclusively to treat
tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to
.first-line agents

Side effect: CNS toxicity, acute psychosis,

.and convulsions
 Inhibitors
of
Protein Synthesis
 Tetracyclines -1
 General Activity: Bacteriostatic; G +ve , G-ve
including anaerobes . Absorption decreased by milk and
minerals.
 Special Usages: Rickettsia, Chlamydia, Mycoplasma
and some Spirochetes .
 Serious side effects: Photosensitivity, teeth
hypoplasia and discoloration in less than 8 years old.
 Contraindications: Renal fail., pregnancy, lactation
 Excretions: Renal
 Examples: Tetracycllin, Doxycycllin, Demeclocycline
 Macrolides -2
 General Activity: Bacteriostatic.
 Special Usages: Inclusive of Mycoplasma,
Chlamydia , Rickettsia, Helicobacter,
Pneumococci and Legionella.
Clarythromycin is second line antituberculous.
 Serious side effects: Chol. hepatitis (erythro) ,
transient h. loss, th.phlebitis. CYP inhibitor
(except Azithromycin)
 Contraindications: Sensitivity.
 Excretions: Mainly Hepatic
 Examples: Erythro, Clarithro, Azithro
 Aminglycosides -3
 General Activity: Bactericidal G-ve aerobic bacilli
 Special Usages: Empirical coverage ,especially in
bacteremia and sepsis .
 Serious side effects: Ototoxicity. Nephrotoxicity
 Contraindications: Hypersensitivity.
 Excretions: Renal
 Examples: Gentamycin , Amikacin , Neomycin ,
Streptomycin
 4- Clindamycin
 Bacteriostatic
 For anaerobic infection caused by bacteroides
and other anaerobes.
 Common adverse effects are Clostridium
difficile induced diarrhea and colitis .
 5- Chloramphenicol
 It is a bacteriostatic broad-spectrum antibiotic
against both aero and anaero , G+ve and G-ve.
 Active against Rickettsiae but not Chlamydiae,
H influenzae and N meningitidis. Used
topically in eye infections.
 Side effects: Potential idiosyncratic Bone
marrow toxicity, gray baby syndrome, CYP
inh
 Inhibitors
of
Folate metabolism
 Sulphonamides
 General Activity: Bacteriostatic, broad both G+ve and G
-ve aerobic, Nocardia , Chlamydia trachomatis, and some
protozoa.
Rickettsiae are not inhibited but are stimulated.
 Special Usages: UTI , Typhoid fever,
Pneumocystis jiroveci , toxoplasma , plasmodia.
 Serious side effects: bone marrow toxicity, hemolytic
reactions in patients with G-6-PDD,
SJ syndrome , CYP inh.
displace warfarin from the plasma.
 Contraindications: Hypersensitivity.
 Excretions: Renal
 Examples: Septrin (trimethoprim-sulfamethoxazole
mixtures)
 Inhibitors
of
DNA synthesis
 Fluoroquinolones
 General Activity: Bactericidal Broad but better
against G-ve aerobic bacilli
 Special Usages: UTI ,Typhoid fever, SBP and
2nd line AntiTB .Absorption delayed by antacids
and H2 block.
 Serious side effects: CNS toxicity, QTc
prolongation , Tendinitis ,Photosensitivity, CYP
inh.
 Contraindications: Hypersensitivity, preg,
childern.
 Excretions: Renal and hepatic
 Examples: Cipro, Norfloxacin, levofloxacin,
Nalidixic acid.
 Metronidazole
 General Activity: Bactericidal, against
anaerobic bacteria and sensitive protozoans
 Special Usages: Anaerobic infections
(empirical), amibaisis.
 Serious side effects: GIT Symptoms, metallic
taste, increase alcohol toxicity, peripheral
neuropathy.
 Contraindications: Hypersensitivity, preg.
 Excretions: Renal and hepatic
 Examples:
 Nitrofurantoin
 General Activity: Bacteriostatic.
 Special Usages: UTI
 Serious side effects: GIT Symptoms,
pneumonitis, CNS demyelination, haemolysis
in G6PDD
 Contraindications: Hypersensitivity, preg.
 Excretions: Renal .
 Examples:
 Inhibitors
of
RNA synthesis
 Rifampin
 General Activity: Bactericidal against G+ve and
G-ve cocci, some enteric bacteria,
mycobacteria, and chlamydia.
 Special Usages: Tuberculosis, leprosy,
brucelosis, osteomyelitis, meningococcal
carriage
 Serious side effects: orange discoloration,
cholestatic jaundice and hepatitis, CYP inducer
 Contraindications: Hypersensitivity.
 Excretions: hepatic
 Examples: Rifampicin,rifabutin
 !Drug Interactions
 Cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and
3A4).
 Levels increased by (Metabolism inhibited by)
Macrolides (Erythromycin) , Azoles (Fluconazole,
Itraconazole), Protease inhibitors, Ciprofloxacin
 Levels decreased by (Metabolism induced by)
Rifampin.
 Oral Contraceptives
Decreased with rifampin & nafcillin +/- others .
 Drugs affected by CYP 450
Many like; Statins, Cyclosporine, Benzodiazepines,
Theophylline, Anticonvulsants, oral hypoglycemics
 ?What Anti Microbial to choose
1. Pharmacokinetic factors:
 Sufficient antibiotic must penetrate to the site of the
infection. (Difficult sites include the brain, eye and
prostate and abscesses).
 Knowledge of the standard pharmacokinetic
considerations of absorption, distribution,
metabolism and excretion.
 Interacting medications.
 Resistance trends.
 Allergies, organ dysfunction.
 Formularies and cost
2. Disease –related:
 Local epidemiology of the organisms.
 Exposure history, risk factors for
specific microbes.
 weight, height.
 Three ways antibiotics used
Prophylaxis-1
 Medical.
 Procedural (surgery).

2-Empiric (usually up to 72 hours)

Diagnosis of infection made based on S/S,
Likely pathogens suspected but specific
pathogen not yet known.
3- Definitive
Microbiologic or serologic diagnosis .
 ?How long to treat
 Not well defined!
 Usually 7 to 14 days!
 Longer for Endocarditis, Osteomyelitis,
Endometritis until afebrile 24-48 hrs
 Progress note & set endpoint!
 Prolonged unnecessary therapy increases
risk of resistance and adverse effects
 Critical Thinking Exercises 1
A nurse asks you why it is important to determine
if the patient is allergic to penicillin before giving
cephalosporin
The most correct answer is that persons
allergic to penicillin .
A. are allergic to most antibiotics.
B. respond poorly to antibiotic therapy.
C. require higher doses of other antibiotics.
D. have a higher cross allergy to the cephalosporin.
E. Interaction between old pencillin doses and new cephalosporin.
 Antibiotic Resistance
 Introduction
 Alexander Fleming recognized the potential
danger of antibiotic resistance.
 In 1945, he warned that misuse of penicillin
could lead to the selection and propagation of
mutant forms of bacteria resistant to the drug.
 The first penicillin-resistant bacteria appeared
several years later. Their mutant gene encoded
for a penicillin-destroying enzyme penicillinase.
Intensive care units seem to have
particularly high incidences of resistant
microbes.
 Mechanisms of resistance
1. Bacteria become resistant through
 Adaptations (product of selection).
 Acquisition and transmission of antibiotic
resistance (horizontal gene transfer).
2. Decreased transport of the antibiotic into the cell
3. Production of enzymes that destroy the inhibitory
capacity of the antibiotic.
4. Modification of the antibiotic binding site so that the
drug no longer binds to the target.
5. Production of alternate molecules that can replace
those disrupted by the antibiotic.
 Preventing the use of antibiotics
 Verify diagnosis & need for antibiotics
 Consider other (non-infectious) causes of
symptoms.
 Remember: antibiotics don’t work against
viruses.
 Vaccinate at risk patients.
 Wash your hands!, also stethoscopes.