BETA LACTAM &

OTHER CELL WALL- &

MEMBRANE ACTIVE ANTIBIOTICS
DR. REINO C. PALACPAC,
OLFU COLLEGE OF MEDICINE
DEPARTMENT OF PHARMACOLOGY
OBJECTIVES
Discuss basic target of the beta lactam antibiotics
CELL WALL
Discuss the beta lactam antibiotics, its
classifications, mechanism of action,
pharmacokinetics, pharmacodynamics, drug
interactions, adverse effects & resistance
Discuss the clinical applications of these drugs as to
their empiric and specific indications
 BETA LACTAM &
OTHER CELL WALL- &
MEMBRANE ACTIVE
ANTIBIOTICS
BACTERIAL CELL WALL

Rigid outer layer that surrounds the cytoplasmic

membrane
Maintains cell shape and integrity
Prevents cell lysis from high osmotic pressure
In gram-positive microorganisms,
the cell wall is 50 to 100 molecules thick,
but it is only 1 or 2 molecules thick in
gram-negative bacteria
 Composed of complex cross-linked polymer of polysaccharides
and polypeptides, peptidoglycan (murein, mucopeptide)

Polysaccharide contains alternating amino sugars,

N-acetylglucosamine and N-acetylmuramic acid
(NAG-NAM)

5 amino-acid peptide is linked to the N-acetylmuramic acid sugar

that terminates in
the D-alanyl-D-alanine
PBP ( transpeptidase ) removes the terminal alanine in the process
of forming a cross link with a nearby peptide
Cross-links give the cell wall its structural rigidity
PEPTIDOGLYCAN
The cell walls of bacteria are essential
for their normal growth and development

Peptidoglycan is a heteropolymeric
component of the cell wall that provides
rigid mechanical stability by virtue of its
highly cross-linked latticework structure
The peptidoglycan is composed of glycan
chains, which are linear strands of two
alternating amino sugars
(N-acetylglucosamine and
N-acetylmuramic acid)
that are cross-linked by peptide chains
(NAG-NAM)
 Biosynthesis of the peptidoglycan involves about
30 bacterial enzymes and may be considered in
three stages:

First stage: precursor formation, takes place in

the cytoplasm
The product, uridine diphosphate (UDP)-
acetylmuramyl-pentapeptide, called a "Park
nucleotide" accumulates in cells when subsequent
synthetic stages are inhibited
The last reaction in the synthesis of this
compound is the addition of a dipeptide, D-
alanyl-D-alanine.
Synthesis of the dipeptide involves prior
racemization of L-alanine and condensation
catalyzed by D-alanyl-D-alanine synthetase
 Second stage: UDP-acetylmuramyl-
pentapeptide and UDP-
acetylglucosamine are linked
(with the release of the uridine
nucleotides) to form a long polymer
 Third and final stage: involves the
completion of the cross-link
This is accomplished by a transpeptidation
reaction that occurs outside the cell
membrane
Transpeptidase - membrane bound
Last step in peptidoglycan synthesis
(inhibited by the beta-lactam antibiotics)

Penicillin binds at the active site of the transpeptidase enzyme that cross-links
the peptidoglycan strands
It mimicks D-alanyl-D-alanine residues that would normally bind to this site
Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a
serine residue in the transpeptidase
Reaction is irreversible and so the growth of the bacterial cell wall is inhibited
Inhibition of transpeptidase:
Spheroblasts are formed
Structural irregularities: binding to PBPs may result in abnormal
elongation, abnormal shape, cell wall defects
Beta Lactam Antibiotics &
Other Cell Wall Synthesis
Inhibitors
PENICILLINS
CEPHALOSPORINS
BETA LACTAMASE INHIBITORS
CARBAPENEMS
MONOBACTAMS
PENICILLINS
 History
The penicillins were the first antibiotics discovered as natural
products from the mold Penicillium.

1928 - Sir Alexander Fleming, professor of bacteriology at

St. Mary's Hospital in London, was culturing Staphylococcus
aureus. He noticed zones of inhibition where mold spores
were growing. He named the mold Penicillium rubrum. It was
determined that a secretion of the mold was effective against
Gram-positive bacteria
1928 - Alexander Fleming
Bread mold (Penicillin notatum) growing on
petri dish
1939 - Florey, Chain, and Associates
Began work on isolating and synthizing large
amounts of Penicillin.
1944 - Used in WWII to treat infections
Late 1940s - available for general use in
US
Structure
Penicillins as well as cephalosporins are called
beta-lactam antibiotics and are characterized by
three fundamental structural requirements:
fused beta-lactam structure
free carboxyl acid group
one or more substituted amino acid side chains

The lactam structure can also be viewed as the covalent bonding of

pieces of two amino acids - cysteine and valine
thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side chain
(R).
Chemical Properties of
Penicillins
The compound consists of 2 basic structures:
1. Thiazolidine Ring
2. Beta-Lactam Ring
- site of action of Beta- lactamase
- site of action of Amidase
- carries secondary amino group (RNH)
- site of attachment of side chain, R, which determines many
of the antibacterial and pharmacologic characteristics of a
derivative (Spectrum and penicillin-resistance)
The penicillin nucleus itself is the
chief structural requirement for
biological activity
metabolic transformation or
chemical alteration of this portion of
the molecule causes loss of all
significant antibacterial activity
MECHANISM OF
ACTION
Last step in peptidoglycan synthesis
(inhibited by the beta-lactam antibiotics)

Penicillin binds at the active site of the transpeptidase enzyme that cross-links
the peptidoglycan strands
It mimicks D-alanyl-D-alanine residues that would normally bind to this site
Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a
serine residue in the transpeptidase
Reaction is irreversible and so the growth of the bacterial cell wall is inhibited
Inhibition of transpeptidase:
Spheroblasts are formed
Structural irregularities: binding to PBPs may result in abnormal
elongation, abnormal shape, cell wall defects
Inhibit the last step in the peptidoglycan
synthesis of the cell wall
Underlying:
inhibition of transpeptidase enzymes
inactivation of penicillin binding proteins (PBPs)
activation of autolysins (murein hydrolases)
Mechanisms of Drug
Actions by Enzyme
Inhibition:
All penicillin derivatives produce their
bacteriocidal effects by inhibition of
bacterial cell wall synthesis
cross linking of peptides on the
mucosaccharide chains is prevented
If cell walls are improperly made cell
walls allow water to flow into the cell
causing it to burst
Mechanisms of
Resistance:
- inactivation of antibiotic by -
lactamases
- modification of PBPs (low affinity for
binding)
- impaired penetration of drug to target
PBPs (gram () bacteria - impermeable)
- presence of an efflux pump (transport
back across the outer membrane)
Gram (-) Cocci
Moraxella catarrhalis
Neisseria gonorrheae
Neisseria meningitidis
Gram (+) Cocci
Streptococcus pneumoniae
Streptococcus, hemolytis (A,B,C,D)
Streptococcus viridans
Staphylococcus aureus
Enteroccocus faecalis
Enteroccocus faecium
Gram (-) Rods
Acinetobacter Pseudomonas aeruginosa
Prevotella Burkholderia pseudomallei
Bacteroides Burkholderia mallei
Brucella Salmonella
Campylobacter jejuni Shigella
Enterobacter Vibrio
Escherichia coli Yersinia pestis
Klebsiella Hemophilus
Helicobacter pylori
Legionella
Proteus mirabilis, vulgaris
Gram (+) RODS
Actinomycoses
Bacillus
Clostridium
Corynebacterium diphtheriae/jeikeium
Listeria
Others:
Acid-fast rods (Mycobacterium)
Spirochetes (Borrelia
bugdorferi/recurrentis, Leptospira,
Treponema pallidium/pertenue)
Mycoplasma
Chlamydiae (psittaci, trachomatis,
pneumoniae)
Resistance to -Lactams Gram pos.
Resistance to -Lactams Gram pos.
CLASSIFICATION
Penicillinase
Susceptible
retain the antibacterial spectrum of penicillin
improved activity against gram (-) organisms

greatest activity against gram-positive

organisms, gram negative cocci, non-beta
lactamase producing anaerobes
little activity against gram-negative rods

Susceptible to destruction/hydrolysis by beta-

lactamases
Penicillinase
Susceptible
I. Narrow Spectrum
Benzylpenicillin Penicillin G
High activity against gram (+)
Low activity against gram ()
Acid labile, destroyed by beta lactamases
60% protein bound
Phenoxymethyl penicillin- Penicillin V
Oral penicillin
 Penicillinase
II.Susceptible
Extended Spectrum
A. Aminopenicillins
a.1 Ampicillin
B. Carboxypenicillins
a.2 Esters b.1. Carbenicillin
a.2.1. Bacampicillin b.1.1 Indanyl Carbenicillin
a.2.2. Pivampicillin
a.2.3. Talampicillin b 1.2 Disodium Carbenicillin
a.3. Amoxicillin
C. Ureido-penicillin b.2 Ticarcillin
c.1. Mezlocillin b.3 Temocillin
c.2. Azlocillin
c.3. Piperacillin
c.4. Apalcillin
Extended Spectrum Penicillins
CARBOXYPENICILLINS and
UREIDOPENICILLINS
Gram (-) aerobes
- Pseudomonas aeruginosa
- Bacteroides fragilis; but in higher amount/
dose
Carboxypenicillins certain indole (-) Proteus
Ureidopenicillins - Klebsiella
Extended spectrum
penicillins:
Carboxypenicillin
CARBENICILLIN
First antipseudomonal carboxypenicillin
Obsolete: CHF, hypoK+, abnormal platelet aggregation
Carbenicillin indanyl Na derivative use in UTI
CARBOXYPENICILLIN (TICARCILLIN)
Less active than ampicillin against enterococci
Ticarcillin Pseudomonas but inferior to piperacillin and
mezlocillin
Extended spectrum
penicillin:
UREIDOPENICILLINS
Piperacillin, mezlocillin, azlocillin
Gram (-) bacilli klebsiella
pneumonia
Mezlocillin more active in Klebsiella;
Pseudomonas; Enterococcus faecalis
Piperacillin Pseudomonas;
Enterobacteriaceae; many
Bacteroides
 Extended-spectrum
penicillins
Ampicillin and Antipseudomonal
(penicillinase susceptible)
Penicillins
retain antibacterial spectrum of penicillin
improved activity against gram (-) organisms
destroyed by beta-lactamases
Methicillin (Staphcillin)
III. Antistaphylococcal
Nafcillin ( Unipen, Nafcil, Nallpen)
Isoxazolylpenicillins
penicillins (Penicillinase resistant)
a. Oxacillin b. Dicloxacillin
c. Cloxacillin d. Flucloxacillin
resistant to staphylococcal beta-lactamases
active against staphylococci and streptococci
inactive against enterococci & anaerobic bacteria, and gram-
negative cocci & rods
Nafcillin

Less strongly protein bound (90%)

resistant to staphylococcal beta-lactamases
active to staphylococci and streptococci
Not active against enterococci, anaerobic bacteria and
gram cocci and rods
 Unitage of
Penicillin
1600 UNITS/MG (crystalline Na)
1 UNIT = 0.6 MCG or ug
1 MU = 0.6 G
dosage and the antibacterial potency of the semisynthetic
penicillins are expressed in terms of weight
minimum inhibitory concentration(MIC) of any penicillin is
usually given in ug/ml
 sodium or potassium salt of the free acid
Procaine salts and benzathine salts
REPOSITORY FORM- IM
Dry crystalline forms of penicillin salts are stable
for years at 4 C
Solutions lose their activity rapidly
PHARMACOKINETICS

ABSORPTION:
vary with the preparation
Impaired by food and drugs (except amoxicillin)
Must be administered 1-2 hours before or after meals
parenteral complete and rapid
Nafcillin not suitable for oral administration
Dicloxacillin, Amoxicillin, Ampicillin acid stable
Gastric juice at pH 2 rapidly destroys the antibiotic
(acid labile)

The decrease in gastric acid production with aging accounts for

better absorption of penicillin G from the gastrointestinal tract of
older individuals.

Absorption is rapid, and maximal concentrations in blood are

attained in 30 to 60 minutes. The peak value is approximately
0.5 unit/ml (0.3 mg/ml) after an oral dose of 400,000 units (about
250 mg) in an adult.
 DISTRIBUTION:
cannot penetrate the blood brain barrier
Probenecid and certain organic acids can inhibit transfer from
CSF to blood stream
Bacterial meningitis: 1-5 mcg/ml = 18-24 M units/day

METABOLISM:
liver
penicillanic/penicillenic acid; penicillamine,
penicilloid acid & other penicilloyl derivatives
( allergenic metabolites )
EXCRETION:
kidneys
- renal excretion inhibited by
probenecid
Nafcillin biliary excretion
Oxacillin, dicloxacillin, cloxacillin-
- kidney & biliary excretion
clinical uses
Penicillin G
Antimicrobial spectrum:
Streptococci, meningococci, enterococci,
penicillin-susceptible pneumococci, non-beta-
lactamase producing staphylococci, treponema
pallidum & many other spirochetes, Bacillus
anthracis, Clostridium species, actinomyces &
other gram (+) rods & non-beta-lactamase-
producing gram (-) anaerobic organisms
Antimicrobial spectrum:
effective doses : 4 - 24 million units/
day IV in 4 -6 div doses depending
upon the organisms, the site and
severity of infections
inhibitory for enterococci at 18
-24 M units with an aminoglycoside
Benzathine Penicillin
G
mean duration of antimicrobial activity 26
days
a single IM 1.2 mil units - Beta-hemolytic
streptococcal pharyngitis (duration?)
IM once q 3-4 weeks prophylaxis against
reinfection with beta-hemolytic streptococci

2.4 Mil units IM once a week for 1-3 weeks-

syphilis (do serological test every month for
at least 4 mos,)
 Parenteral Administration
of Penicillin G
After intramuscular injection, peak concentrations in
plasma are reached within 15 to 30 minutes.
value declines rapidly, since the half-life of penicillin G is
30 minutes
Repository preparations of penicillin G:
penicillin G procaine (4 to 5 days)
penicillin G benzathine (26 days)
 Such agents release penicillin G slowly from the area in
which they are injected and produce relatively low but
persistent concentrations of antibiotic in the blood.
Intrathecal administration is inadvisable
particularly with benzylpenicillin as it can
cause convulsions
IV preferred than IM irritation and local
pain
 Penicillin V
oral form in minor infections
relative poor bioavailability; dosing 4x a day
Narrow antibacterial spectrum
Gram (+) aerobic activities similar to Penicillin
G
5-10x less active against gram (-) microbes,
esp. Neisseria and certain anaerobes

better absorbed from the GIT

Extended Spectrum Penicillins)
AMINOPENICILLINS
same spectrum of activity
(Ampicillin and
UTI, sinusitis, otitis and lower resp infection
Amoxicillin)
Amoxicillin has better absorption
most active of the oral beta lactams vs pen resistant
pneumococci strains
Ampicillin but not amoxicillin is effective for shigellosis
No inherent antimicrobial activity as esters, but pharmacologically active following
hydrolysis to ampicillin
50% higher blood concentration than Ampicillin and Amoxicillin
Ampicillin and
Amoxicillin
not used to treat uncomplicated salmonella
gastroenteritis
somewhat less active than Pen G vs gram (+) cocci
enterococcal grp. D and viridans grp of streptococci
Listeria monocytogenes
H. influenza. And E. coli
Ampicillin doses:
Mild infections: Adults: 1 - 4 gm/day
Severe infections : Adult - 6 - 12 gm/day
PENICILLINASE RESISTANT
ISOXAZOLYL PENICILLINS
(OXACILLIN, CLOXACILLIN,
DICLOXACILLIN)
relatively acid stable and well absorbed, food interferes with absorption
Administered 1 hour before meals
Mild-moderate localized staphylococcal infections
indication is infection by beta lactamase producing staphylococci,
streptococci and pneumococci
Isoxazolyl penicillins .25 - 0.5 g orally every 4-6 hrs
15 - 25mg/kg/d for children mild localized staphylococcal infections
NAFCILLIN/METHICILLIN
Oxacillin or Nafcillin, 8-12 g/d given
by intermittent IV infusion of 1-2 g
every 4-6 hours
Serious systemic staphylococcal
infections
Methicillin no longer used bec. of its
nephrotoxicity
ADVERSE EFFECTS:
1. Hypersensitivity reactions
most common major antigenic determinant penicilloyl
polylysine (PPL), penicilloic acid & products of alkaline
hydrolysis
Anaphylactic rxn, serum sickness, skin rashes
angioedema marked swelling of lips, tongue, face and
periorbital tissues + DOB, giant hives
desensitization
2. Gastrointestinal disturbances after oral administration
3. Convulsions following rapid IV injection
ADVERSE EFFECTS:
4. Accidental injection into the sciatic nerve-severe
pain and nerve dysfunction - persisting for weeks
5. Chronic use may cause:
- hepatitis
- overgrowth of minor/atypical organisms following
use of broad spectrum preparations
 Specific toxicities

Procaine Penicillin G after accidental IV injection:

- pulmonary embolism
- acute psychotic reactions
Oxacillin and Nafcillin:
- hepatitis
- granulocytopenia, bone marrow depression
Disodium Carbenicillin and high dose Penicillin G Na
- hypernatremia
Specific toxicities
Penicillin G Potassium
- hyperkalemia with high doses
Penicillin G Sodium
- Jarisch-Herxheimer reaction
Carbenicillin and Ticarcillin
- bleeding diathesis
Methicillin - interstitial nephritis
Ampicillin
- pseudomembranous colitis
 Drug-drug Interactions
Penicillins bind to and inactivate aminoglycosides
chemical antagonism
MUST NOT administered simultaneously through
the same I.V. line or through the same syringe -
crystallize and precipitate in the line or in the
vessels
infusions should be staggered by about 1 to 2 hour
Classification of the Penicillins
and Summary of Their
Pharmacological Properties
1. Penicillin G and its close congener penicillin V are highly active
against sensitive strains of gram-positive cocci, but they are
readily hydrolyzed by penicillinase
ineffective against most strains of Staphylococcus aureus
2. The penicillinase-resistant penicillins (methicillin,
nafcillin, oxacillin, cloxacillin, and dicloxacillin) have
less potent antimicrobial activity against
microorganisms that are sensitive to penicillin G
effective against penicillinase-producing Staph. aureus.
 3. Ampicillin, amoxicillin, bacampicillin, and
others comprise a group of penicillins whose
antimicrobial activity is extended to include such
gram-negative microorganisms as Haemophilus
influenzae, E. coli, and Proteus mirabilis
hydrolyzed readily by broad-spectrum beta-
lactamases that are found with increasing
frequency in clinical isolates of these gram-
negative bacteria.
Clinical indications
of penicillins
(general)
Penicillin G (benzylpenicillin) DOC for meningitis;
pneumococcal pneumonia and pneumococcal
meningitis: 20M 24M U/day 7-10 days (most
penicillin-resistant pneumococci are resistant to
3rd generation cephalosporin)
Pen G and Penicillin V (phenoxymethyl penicillin)
(gm (+) and gm (-) cocci, Neiseria species;
meningococci; anaerobes-Clostridium species;
Borrelia burgdorferi (Lyme disease); T. pallidum;
Leptospia
Penicillin G - resistant to S. aureus, S.
epidermidis, Strep. viridans,
Corynebacterium diphtheria
Procaine Pen G vs. Benzathine Pen G
4-5 days 26 days
Pen G vs Pen V (stable in acidic
medium)
Strep. pharyngitis: (group A-hemolytic strep
or Strep pyogenes)
Procaine Pen G 600,000 U OD X 10 days
Benzathine penicillin 1.2 M U single dose
Endocarditis ( Strep. viridans)
Procaine Pen G 1.2 M U 4x/day X 4 weeks
Pen G 12M -20M U IV X 2 weeks
+ Streptomycin 500 IM every 12 hrs.
or Gentamicin 1mg/kg every 8hrs.
Enterococci endocarditis
Pen G 20M U + Aminoglycoside X 4 weeks
Syphilis < 1yr duration
Pen G procaine 2.4 U/day IM + Probenecid
1gm/day PO X 10days
or Pen G benzathine 1-3 weekly IM of 2.4 M U
(in pts. with HIV)
Congenital syphilis Pen G 50,000 U/kg daily in 2
divided doses X 10 days
Actinomycosis (DOC) Pen G 12M 24M U IV/day
X 6weeks + oral Pen V 500mg QID X
2-3 mos
Diphtheria (eliminate carrier)
Pen G 2-3M U/day X 10-12 days or Pen G
procaine injection (single)
Antrax (DOC) Pen G 12M -20M U IV/ day X
10-12days
Clostridial (DOC) Pen G 12M 20M U /
day IV X 10-12days
Gingivostomatitis (leptotrichia buccalis +
spirochetes) or Trench mouth
Pen V 500mg IV every 6hrs. X 10-12
days
Ratbite fever (Spirillium minor and
Streptobacillus moniliformis) Pen G 12M
15M U IV X 3-4weeks
Listeria infections: (DOC) Pen G 15M 20M U
IV/ day or ampicillin +/- gentamicin X 2
weeks
Lyme disease - tetracycline
- amoxicillin 500mg TID X 21days
- severe cases: Pen G 20M U IV/ day X
14days + 3rd generation sephalosporin
Erysipelas Pen G 1.2M U single dose
With endocarditis Pen G 12m 20M U IV/ day
X 4 weeks
CEPHALOSPORIN
S
BASIS FOR CLASSIFICATION:
Antimicrobial Spectrum
Pharmacokinetic Properties
 Cephalosporins

1st Generation 2nd Generation 3rd Generation 4th Generation

Cefadroxil * Cefaclor * Cefdinir * Cefepime

Cefazolin Cefamandole Cefoperaxone Cefpirome

Cefalexin * Cefonicid Cefotaxime

Cephalothin Ceforanide Ceftazidime

Cephaprin Cefotetan Ceftibuten *

Cephradine * Cefoxitin Ceftizoxime

Ceftriaxone

Moxalactam
Cefuroxime *
Cefixime *

Ceftaroline
* Oral Agent Cefpodoxime *
CEPHALOSPORINS -
examples
A. First Generation
5. Cephradine Anspor,
1. Cephaloridine Loridine, Velosef
Ceporan
6. Cephapirin Cefadyl
2. Cephalothin Keflin
7. Cephadroxil Duricef
3. Cephalexin Keflex,
Ceporex
4. Cefazolin Kefzol, Ancef
 CEPHALOSPORINS
B. Second Generation
1. Cefaclor Ceclor
2. Cefoxitin Mefoxin
3. Cefuroxime Zinacef, Zinnat
4. Cefonicid Monocid
5. Cefotetan Cefotan
6. Cefamandole Mandol
7. Cefprozil Cefzil
8. Loracarbef Lorabid
9. Cefmetazole Zefazone
10. Ceforanide
Cephalosporins
C. Third Generation
7. Cefotiam Ceradolan
1. Cefotaxime Claforan
8. Cefixime Suprax
2. Cefoperazone Cefobid
9. Cefetamet Globocef
3. Moxolactam Moxam
10. Cefpodoxime Vantin
4. Ceftizoxime Cefizox
11. Ceftibuten Cedax
5. Ceftriaxone Rocephin
12. Cefdinir Omnicef
6. Ceftazidime Fortum
CEPHALOSPORINS
Fourth Generation
1. Cefepime Cepimax
2. Cefpirome Cefrom
 GENERAL PROPERTIES OF
CEPHALOSPORINS
7 amino-cephalosporanic acid parent compound
Substitutions at R1 & R2 produce named compounds
- contains an R2 that makes the compound stable in
dilute acid and highly penicillinase resistant
- MW 400-450
- soluble to water and relatively stable to ph and
temperature changes
- mechanisms of Action and Resistance similar to
penicillins
GENERAL PROPERTIES
OF CEPHALOSPORINS
Antimicrobial Spectrum:

- generally broader spectrum than Penicillins

-generally more effective than Penicillins against

B-lactamase-producing microbes
(except enterococci, Methicillin-resistant Staph.
Aureus and Staph epidermidis)
CEPHALOSPORINS
FIRST GENERATION:

Good activity vs gm (+) & modest vs gm (-) microbes ( ex:

strep, staph, E. coli, K. pneumoniae, Proteus mirabilis) and
anaerobes ( ex: peptococci, peptostreptococci)
Penetration to the CSF is inadequate
Oral drugs used for the treatment of UTI, for minor
staphylococcal lesions, or for minor polymicrobial infections
such as cellulitis or soft tissue abscess.
CEPHALOSPORINS
FIRST GENERATION
not used in serious systemic infections
Urine concentrations are high
Excretion by glomerular filtration and tubular secretion
(reduce dosage in renal failure)
Cefazolin - penetrates well into most tissues- the drug of
choice for surgical prophylaxis
only first generation parenteral cephalosphorin
(IM/IV)
Alternative to an antistaphylococcal penicillin
CEPHALOSPORINS
SECOND GENERATION

Better activity vs anaerobes

first gen drugs activity but with extended gm (-) coverage (

beta-lactamase-producing )

IM is painful

renal adjustment
CEPHALOSPORINS
SECOND GENERATION
Oral dosage for adults is 10-15 mg/kg/d in two to four
divided doses;
Children 20-40 mg/kg/day up to a maximum of 1 g /day.
Clinical uses: sinusitis, otitis
Cefoxitin, cefmetazole and cefotetan B. fragilis and some
serratia strains (mixed anaerobic infections like peritonitis,
diverticulitis, PID) ; colorectal surgery
Cefamandole, cefuroxime, cefonicid, ceforanide
& cefaclor H. influenzae, M. catarrhalis
Cefuroxime pneumococcus
crosses the BBB & for community-acquired pneumonia
 THIRD GENERATION
less active than the first generation vs gm (+) cocci but most active
against gram (-) including B-lactamase- producing strains
Cefoperazone, Ceftazidime (DOC P. meningitis) more active against
Pseudomonas
Cefoperazone, Cefotaxime active against anaerobes
Ceftizoxime and monolactam active against B. fragilis
Ceftriaxone & cefotaxime + vancomycin and ampicillin
meningitis caused by pneumococci, meningocci,
H. influenzae & susceptible gram (-) enteric rods
Penicillin resistant strains of pneumococci
THIRD GENERATION

Ceftizoxime, Moxolactam B. fragilis

Cross BBB except Cefoperazone, Cefixime,
Ceftibuten and Cefpodoxime proxetil
Cefixime, cefdinir, ceftibuten & cefpodoxime - ORAL
Excretion renal
Cefoperazone and Ceftriaxone: bile
- Probenecid does not affect renal excretion
 THIRD GENERATION
Ceftriaxone (DOC) 125 mg inj. IM;
and Cefixime, single 400 mg - N. gonorrhea
Ceftriaxone DOC severe Lyme disease
Cefoperazone 25- 100 mg/kg/d injected q 8-12 hrs.
Cefixime 200 mg orally twice a day or 400 mg OD
Cefpodoxime proxetil & Ceftibuten 200 mg 2x/day

3rd gen cephalosporin: +/- aminoglycosides:

DOC for Klebsiella, Enterobacteriaceae, Proteus, Providencia,
Serratia, Haemophilus
THIRD GENERATION
Meningitis caused by pneumococci, meningococci, H. influenza &
susceptible
enteric gm (-) rods but not by L. monocytogenes; used in combination
with aminoglycosides for Rx of meningitis caused by P. aeruginosa
with vancomycin for meningitis due to non-penicillin susceptible
pneumococci
With febrile neutropenia - ceftazidime + other antibiotics
Cefotaxime - has failed pneumococcal meningitis
CEPHALOSPORINS
FOURTH GENERATION
More resistant to hydrolysis by chromosomal B- lactamases (eg.
those produced by Enterobacter) but can be hydrolyzed by extended
spectrum B-lactamases
Highly active against Haemophilus and Neisseria
Good activity against P. aeruginosa, enterobacteriaceae, Staph
aureus, S. pneumoniae
Penetrates CSF
Cleared by kidneys
Tx for nosocomial infections (Enterobacter, Citrobacter, Serratia)
CEPHALOSPORINS
- MRSA
Currently under development

Ceftaroline fosamil prodrug of ceftaroline and

ceftobiprole medocaril

Increased binding to PBP 2a that mediates methicillin

resistance in staph
ADVERSE EFFECTS of
Cephalosporins
1. Allergy- 5-20% cross allergenicity with penicillin
2. Toxicity:
> Renal toxicity interstitial nephritis and even tubular
necrosis
> Cephalosporin that contains a methyl thiotetrazole group
(Cefamandole, Moxolactam, Cefmetazole, Cefoteta,
Cefoperazone) cause disulfiram like reactions,
hypoprothrombinemia and bleeding disorders
Antidote: Vit. K 10 mg 2x/ week
ADVERSE EFFECTS
of Cephalosporins
Toxicity: (Cont)
> Moxolactam interferes with platelet function,
severe bleeding
3. Superinfection
Clinical uses (general)
Gonorrhea Ceftriaxone 250mg SD IM
Gonococcal urethritis, disseminated gonococcal
infection Ceftriaxone 1gm daily IM or IV X 7-10days
Opthalmia neonatorum Ceftriaxone 50-100mg/kg/day
IV X 7-10days
Pneumococcal pneumonia 3rd generation or
vancomycin
Pneumococcal meningitis 3rd generation + Vancomycin
Salmonella Ceftriaxone or Fluoroquinolone
OTHER BETA LACTAM
DRUGS
MONOBACTAMS
Monocyclic beta lactam ring
For aerobic gm (-) rods (P. aeruginosa)
For penicillin allergy: pneumonia, meningitis and sepsis
Resistant to beta-lactamases and active against gram negative rods
including Pseudomonas and Serratia
No activity against gram positive bacteria or anaerobes
For Enterobacteriaceae, P. aeruginosa, H. influenzae, gonococci : 2 g
every 6-8hrs.
Monobactam:
Aztreonam
MOA: interacts with penicillin binding proteins and
induces the formation of long filamentous bacteria
- resembles ceftazidime in structure

Given 1-2 g IV every 8 hrs. T1/2 1-2 hrs.

AE: occ. skin rash, elevations of serum aminotransferases

BETA LACTAMASE
INHIBITORS
Resemble B-lactam molecules but themselves have very weak
antibacterial action
Bind to Beta-lactamase, inactivate them and prevent the destruction
Synergistic with other beta-lactams
Active against Ambler class a B-lactamases staph, H. influenzae, N.
gonorrhea, salmonella, shigella, E. coli and K. pneumoniae
Not active against class C B-lactamases Enterobacter sp., Citrobacter
sp., S. marcescens, P. aeruginosa; B-lactamase B. fragilis, M.
catarrhalis
BETA LACTAMASE
INHIBITORS
Available only in fixed combinations with specific penicillins
A. Clavulanic Acid + Amoxicillin (Augmentin)
B. Clavulanate K + Ticarcillin (Timentin)
C. Sulbactam Pivoxil + Ampicillin (Unasyn)
D. Tazobactam + Piperacillin (Tazocin)
Indicated as empirical therapy immunocompetent patients;
mixed aerobic and anaerobic infections- abdominal infections
CARBAPENEMS
new class of drugs which are structurally similar to the
penicillins

developed to deal with betalactamase producing Gram-

negative organisms, which were resistant to broad spectrum
and extended spectrum penicillins

not resistant to carbapenemases or metallo-B-lactamases

Enterococcus faecium, MRSA, Clostridium difficile,
Burkholderia cepacia and Stenotrophomonas maltophilia

derived from Streptomyces species

Carbapenems
Indications:
P. aeruginosa except: ertapenem
Mixed aerobic and anaerobic infections
Penicillin-susceptible pneumococci
Enterobacter infections
Febrile neutropenic patients: imipenem, meropenem,
doripenem +/- aminoglycoside
CARBAPENEM:
IMIPENEM
gram (-) rods, gram- positive organisms and anaerobes
inactivated by dehydropeptidases in renal tubules resulting in low
urinary concentrations
combined with Cilastatin (dehydropeptidase inhibitor) to reduce
inactivation
penetrates body tissues and fluids well including the CSF
binds to penicillin binding proteins.
disrupts cell wall synthesis and is bactericidal
0.25 0.5 g IV q 6-8 hrs
 Side effects:
Individuals who are allergic to the penicillin may
demonstrate cross-reactivity with imipenem
nausea and vomiting
Seizures have been reported with high doses, particularly in
patients with renal failure
Skin rashes

Indications: Urinary tract infection, lower respiratory tract

infection, intraabdominal and gynecologic; skin, soft tissue,
bone and joint infections
CARBAPENEM:
Meropenem
similar to imipenem
not degraded by dehydropeptidase, thus no cilastatin is
needed.
Excessive levels in kidney failure can cause seizures with
imipenem but not with meropenem

0.5 1 g. IV every 8 hrs.

Carbapenem:
ERTAPENEM
longest half life, once a day dosing ( 1 gram IV)
Irritating IM so may give 1% lidocaine
Less active than the other carbapenems against
pseudomonas and acinetobacter
Not degraded by dyhydropepetidases
Insufficiently active against P. aeruginosa
Carbapenem:
DORIPENEM
Similar to imipenem
Sligthly greater activity against gram negative
aerobes and slightly less activity against gram
positive
Not degraded by dihydropeptidases
0.5g in 1-hr infusion every 8 hrs.
GLYCOPEPTIDES
VANCOMYCIN
- gram (+) bacteria only
Produced by S. orientalis & Amycolaptosis orientalis
Molecular weight: 1500
Water soluble, stable
MOA inhibits cell wall synthesis
- binds firmly to D-Ala-D-Ala terminus of nascent peptidoglycan
pentapeptide
- inhibits transglycosylate, preventing further elongation of
peptidoglycan and x-linking
RESISTANCE:
Enterococci and vancomycin-resistant S. aureus
modification of the D-Ala-D-Ala binding site of the
peptidoglycan building block in which the terminal D-
Ala is replaced by D-lactate resulting to loss of a
critical H bond that facilitates high affinity binding of
vancomycin to its target and loss of activity
VANCOMYCIN
Poorly absorbed from the intestinal tract
oral for the Rx of antibiotic associated enterocolitis caused by C.
difficile 0.125-0.25 g every 6hrs;
alternative drug: metronidazole
99% excreted by glomerular filtration
t: 6-10 days - not removed by dialysis
Dose: 30-60mg/kg/day in 2-3 divided doses or
1 g every 12hrs. ; children: 40mg/kg/day in
3-4 divided doses
Rx for parenteral vancomycin: sepsis or endocarditis
caused by MRSA
Plus gentamicin of enterococcal endocarditis
(Enterococcus faecium and E. faecalis) with penicillin
allergy
Plus Cefotaxime, Ceftriaxone or Rifampicin for Rx of
meningitis of pen resistant strain of pneumococcus
Causes phlebitis, chills and fever, red man or red neck
syndrome; rare: ototoxicity, nephrotoxicity,
Monitor serum concentrations <60mcg/ml
TEICOPLANIN
Very similar to vancomycin
Can be given IM & IV
OD
T = 45-70 hours
Available in Europe
DALBAVANCIN
Semisynthetic lipoglycopeptide derived from teicoplanin
Same MOA with vancomycin
Improved activity against gram (+) bacteria, MRSA and
vancomycin-intermediate S. aureus
Not active against vancomycin resistant enterococci
long t1/2 : 6-11 days
Development is on hold
TELAVANCIN
Semisynthetic lipoglycopeptide derived from vancomycin
Gram (+) bacteria
Complicated skin and soft tissue infection: 10mg/kg IV OD
Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of
peptidoglycan in the growing cell wall
Targets the bacterial cell membrane & causes disruption of membrane
potential & increases permeability
T1/2: 8 hours
teratogenic
 OTHER CELL WALL
/MEMBRANE ACTIVE
AGENTS
 FOSFOMYCIN
inhibits cytoplasmic enzyme enol pyruvate transferase by
covalently binding to the cysteine residue of the active site
Blocks the addition phosphoenolpyruvate to UDP-N-
acetylglucosamine 1st step in the formation of UDP-N-
acetylmuramic acid, the precursor of acetylmuramic acid
(bacterial cell wall)
- Transported into the cell by glycerophosphate or glucose 6
phosphate transport systems (resistance)
FOSFOMYCIN
Active against both Gram (+) and Gram (-)
In vitro synergism with beta-lactams, animoglycosides or
fluoroquinolones
Excreted through the kidneys
Available orally ( 3 g. single dose in uncomplicated UTI) and
parenterally
Safe in pregnancy
BACITRACIN
From Bacillus subtilis
active against Gram (+) organisms
inhibits cell wall formation by interfering with dephosphorylation in
cycling of the lipid carrier that transfers peptidoglycan subunits to
the growing cell wall
Nephrotoxic ; topical use
500 units/g ointment + polymyxin B or Neomycin for skin, wounds
and mucous membranes
solutions of 100-200 units/ml for irrigation of joints, wounds and
pleural cavity
CYCLOSERINE
From Streptomyces orchidaceous
widely distributed into tissues
excreted through the urine
Analog of D-alanine, inhibiting its incorporation into the peptidoglycan
pentapeptide by inhibiting alanine racemase, which converts L-alanine to D-alanine
and D-alanyl-D-alanine ligase
0.5 1 g / d in 2-3 divided doses
Gram (+) and gram (-) organisms but exclusively for M. tuberculosis (0.5-1 g/d)
resistant to 1st line agents
causes dose related CNS toxicity, headaches, tremors, acute psychosis,
convulsions (<0.75g/day)
DAPTOMYCIN
Novel cyclic lipopeptide fermentation product of
Streptomyces roseosporus
Similar activity with vancomycin except that it is more rapidly
bactericidal in vitro and it is active against vancomycin-
resistant strains of enterococci and staph aureus
Known to bind to the cell membrane via calcium-dependent
insertion of its lipid tail resulting to depolarization of the cell
membrane with K+ efflux and rapid cell death
Cleared in the kidney
Causes myopathy & creatinine phosphokinase levels
increase (weekly monitoring)
Antagonized by pulmonary surfactant (do not use in
pneumonia)
If given > 2wks, can cause allergic pneumonitis
Clinical uses:
- alternative to vancomycin
- active against vancomycin-resistant Enterococci and S.
aureus (skin and soft tissue infections: 4mg/kg/day)
- bacteremia and endocarditis: 6mg/kg/day OD
Selection of an
antimicrobial agent
Clinical judgement to give or not to give
Knowledge of the most likely infecting
organism
Identification of bacteria (gm stain)
Testing for microbial sensitivity
Pharmacokinetic factors
Host factors
 Tetracyclines,
Macrolides,
Clindamycin,
Chloramphenico,
Streptogramins and
Oxazolidones
Tetracyclines
Crystalline amphoteric substances solubility
Available as hydrochlorides soluble
TIGECYCLINE Tetracycline analog
Glycylcycline and a semisynthetic derivative
of minocycline
Mechanism of Action
Bactreriostatic Broad Spectrum
Inhibits Protein Synthesis
Enters the microorganism thru:
a. Passive diffusion
b. Active transport
Binds reversibly to the 305 sub unit of the
bacterial ribosome blocks the binding of
amino acyl t RNA on the MRNA ribosomes
complex
Active against q(+) and q(-) bacteria,
angerobes, rickettsiae, chlamydige,
mycoplasma
Resistance
Due:
1.Impaired influx or increase efflux- active
transport protein pump
2.Ribosomes protection due to protein
production interferes tetracycline binding
most important
3.Enzymatic inactivation
TET (AE) efflux pump q(-) species resistant to older tetracycline,
doxycycline, minocycline susceptible to tigecycline
TET (K) efflux pump staphylococci resistant to tetracycline only
TET (M) q(+) species resistant to tetracycline, doxycycline,
minocycline (not to tigecycline)
Pharmacokinetics
Differs in their absorption Oral Administration
30% - chlortetracycline
60-70% - tetracycline, ox tetracycline, demeclocycline,
methacycline
95-100% - doxycycline, minocycline
Tigecycline poor oral absorption given IV
Absorption Upper small intestine
- impaired by food except doxycycline and minocycline
- impaired bi divalent cat ions Ca, Mg, Fe, AI
- affected by dairy products, antacids and alkaine ph
Dose: 500mg of 6hrs tetracycline HCL or Ox
tetracycline
- peak plasma level: 4-6mcg/ml
: 200mg of 12hrs Doxycycline or
minocycline
- peak plasma level: 2-4mcg/ml
Widely distributed to tissues and body fluids
(except CSF)
Minocycline tears and saliva useful for the
eradication of meningococcal state
- dose: 200mg x 5days (oral)
Rifampicin more preferred (minocycline
resistance)
Crosses the placenta, excreted in milk
Bound to growing bones and teeth chelation of
calcium
Drug Interaction: Carbamazepine, phenytoin,
barbiturates, alcohol ingestion shortens half life
of Doxycycline
Excretion BILE and urine (10-50%) glomerular
filtration
- Enterohepatic circulation
- Feces 10-40%
- non-renal mechanism doxycycline, tigelcycline
Classification of Tetracycline
Based on half-lives:
1.Short Acting 6-8rs
a. Chlortetracycline
b. Tetracycline
c. Oxytetracycline

2.Intermediated Acting 12hrs

a. Demeclocycline
b. Methacycline

3.Long Acting 16-18hrs

a. Doxycycline
b. minocycline
Clinical Conditions
Doc: Rickettsial infections
Indicated for: mycoplasma pneumonia, chlamydige, STD,
some spirochetes, a(+) and a(-) organisms, vibro
infections
Tetracycline in combination regimens gastic and
duodenal uclers H.pylori
Cholera tetracycline stops shedding of vibros
Gonococcal infection not recommended, resistance
Other indications: acne, bronchitis, CAP, lyme dse,
relapsing fever, leptospirosis, non-TB mycobacteria
Demeclocycline inhibits action of ADH, treatment for
SIADH
Tigecycline 1st glycylcycline in clinical practice
broad spectrum
CLINICAL CONDITIONS: coagulase (-) straph, staph
aureus, streptococci, vancomycin and methicillin
resistant strains, penicillin resistant and susceptible
strains, acinetobacler sp., rickettsial inf, chlamydiasp,
mycobacteria, legionella, q(+) and q(-) anaerobes,
skin inf, intraabdomial inf, CAP
Dose (tigelcycline): IV-100mg LD
Excretion BILE
Adverse Effects: NIV
Tetracycline
A.Oral Dosage: Tetracycline HCL 0.25-0.50g q6 (adult)
- 20-40mg/kgld q6 (children)
:Demeclocycline and methacycline 600mg daily
:Doxycycline and minocycline 100mg BID not
affected by food
Drug interaction: not to be given with milk, antacids, FeSO4
Avoided: Pregnancy, children <8yrs old deposition in bones
and teeth

B.Parental Dosage
Tetracycline IV 0.1-0.59 q 6-12hrs
Doxycycline IV 100mg q 12-24hrs
Im not recommended
 Adverse Effect
1. GIT N/V, diarrhea
- direct local irritation of the intestinal tract
- result in intestinal functional disturbances, anal
pruritus, vaginal and oral candidiasis
Clost. Defficite associated colitis
2. Bony structures and teeth
- calcium deposition
- deposited in fetal teeth fluorescence,
deiscoloration and enamel dysplasia
- bones deformity or growth inhibitions
3. Other Toxicities
- hepatic necrosis 4gms IV daily
- renal tubular acidosis nitrogen retention
- impaired kidney function
- venoms thrombosis IV
- dizziness, vertigo doxycycline > 100mg
Macrolides
Macrocyclic lactone ring (14-16 atoms) deoxy sugars
are attached
Erythromycin prototype drug 2 sugars attached to
14 atom lactone ring
- from Streptomyces erytheus
- clarithromycin and azithromycin
semisynthetic derivatives of
erythromycin
Erythromycin
Macrolide ring and 2 sugars (desosamine and
cladinose)
Poorly water soluble, readily soluble in organic
solvents
Loses activity at acid ph and 20c temp
Stable at 4 degree Celsius temperature
Mechanism of Action
Bactericidal
Inhibitions of protein synthesis binds to 50s
ribosomal RNA Peptidyl transferees center
Transpeptidation is prevented by blocking of Polypeptide
exit channel Peptidyl T RNA is dissociated from
ribosomes
Inhibits formation of 50s ribosomial sub unit
Active against: q(+) org: pneumococci, sheptococci,
staphylococci, corynebacterium
q(-) org: Neisseria, Bordetella, Bartonella, Rickettsial
sp. Trponema, campylobaterial
Resistance Plasmid-encoded
Due:
1.Reduced permeability of call membrane (active
efflux)
2.Production of esterases hydrolyzes macrolides
3.Ribosomal protection ribosomial binding site
macrolide inducible or constituitive methylase
Pharmacokinetics
Food interferes with absortion
Stearates and esters better absorption
Erythromycin estolate lauryl salt of propionyl ester
best absorbed oral preparation
Serum half life 1.5hrs normal pxs, 5hrs anuric pxs
Excretion BILE (majority) feces, urine (5%)
Widely distributed in all tissues except brain and CSF
Crossed the placenta
Clinical Indications: Doc: Corynebacterial
Infections
Indicated for: respiratory, genital, chlamydial
infections
: CAP pneumococcus, m. pneumonia,
legionella pneumophila
: penicillin substitute penicillin allergic pxs
: resistance to group A strep and penicillin
susceptible pneumococci less attractive as 1st line
agents for pharyngitis, skin, soft tissue infections
pneumonia
: prophylaxis endocarditis dental
procedure
- valvular heart diseases
Dose: Erythromycin base, stearate, estolate 0.25-
0.50ms q 6
: erythromycin thylsuccinate 0.4-0.6q q6
IV erythromycin gluceptate or lactobionate 0.5 q6
Adverse Effects: anorexia, NIV, diarrhea
: acute cholestatic hepatitis
: hypersensitivity
Drug Interaction: Theophylline, warfarin, cyclosporine,
methyl prednisolone inhibit cytochrome p450
Clarithromycin
Derived from erythromycin by addition of methyl group
Better oral absorption
Active against: Myco leprae, Toxoplasma gondii. H.influenza
Dose: 250-500g q12,100mg
Half-life: 6hrs
Widely distributed in all tissues
Metabolized in the liver 4 hydroxyclarith
romycin major metabolite antibacterial property
Excretion - Urine
Azithromycin
15 atom lactone macrolide ring
From erythromycin by addition of methylated nitrogen
Active against: myco avium complex, T. gondii
: chlamydial infections (highly active)
: H. influenza (sl. More active)
Widely distributed in all tissues except CSF
Slowly released for tissues (2-4days)
Once daily dosing (5days)
Given 1hr before 2hrs after meals
Ketolides
14 membered ring macrolide
Differs from erythromycin: substitution of a Keto group
for the neutral sugar i-cladinose
TELITHROMYCIN active against: strep pyogenes, strep.
Pneumoniae, staph ureus, H. influenza, Moraxella,
mycoplasma, legionella, chlamydia sp, H. pylori, Neisseria,
B.fragills, T.gondii, non TB mycobacterium., CAP-USA
Metabolized BILE- urine
Dose: 800mg
Reversible inhibitor of CYP3A4 enzyme
Adverse Effects: liver failure, hepatitis
Clindamycin
Chlorine substituted derivative of lincomycin
Obtained for Streptomyces lincolnensis

Mechanism of Action:
Inibition of protein synthesis interferes with amino acyl
translocaion rxns
Binds with 50s sub unit of the bacterial ribosome

Resistance
1.Mutation of ribosomial receptor site
2.Methylase modification
Pharmacokinetics
Dose: oral 0.15-0.39gms q8, 10-20mg/kg (children)
Protein bound
Penetrates well into most tissues except CSF
Penetrates well into abscesses
Metabolized: liver
Excretion BILE, urine
Half-life: 2.5hrs (normal) 6hrs (anuric)
Clinical Indications: skin soft tissue infections staph and
strep
active against: methicillin resistant staph, anaerobes
(bacteriodes sp)
: clinda and aminoglycosides/cephalosporin
penetrating wounds of abdomen
: septic abortion, pelvic absecess, PID, lung abscess
: Dental prophylaxis endocariditis
: CLINDA and PRIMAQUINE alternative to TMX
Pneumocystis jiroveci in AIDS
- AIDS related toxoplasmosis of the brain
Adverse Effects: nausea, diarrhea, rashes
: impaired liver function
: clostridium defficile colitis risk factor
Streptogramins
Mechansism of Action
Quinupristin DALFOPRISTIN combination of 2
Share the same ribosomial binding site
Inhibits protein synthesis
Bactericidal except Enterococcus faecuim
Resistance:
due: 1. modification of quinuspristin binding site
2. enzymatic inactivation of dalfopristin
3. efflux
Pharmacokinetics
IV dose: 7.5mg/lg q 8-12hrs
Rapidly metabolized liver half-life Quinupristin 0.85hrs
Excretion FECES
Hepatic insufficient dose reduction to 7.5mg/kg 12 or
5mg/q8
Inhibits cytochrome P3A4 metabolized warfarin, diazepain,
aztemizole, terfenadine, cisapride, cyclosporine
Clinical Indications: infections cause by staph, vancomycin
resistant strains of E. faecuim
Adverse Effects: pain at infusion site, arthralgia myalgia
syndrome
Chloramphenicol
Neutral stable compound
Alcohol soluble, poorly water soluble
Chloramphenicol succinate highly water soluble
Mechanism of Action
Inhibits protein synthesis
Binds reversibly to 50s sub unit
Inhibits peptide bond formation
Bacteriostatic q(+) and q(-) org. broad spectrum
Bactericidal H. influenza, Meningitis, bacteriodes
Pharmacokinetics
Dose: 50-100mg/kld-orally absorbed
Chloramphenicol palmitate prodrug free cmc oral
Chloramphenicol succinate IV prodrug
Widely distributed in all tissues and body fluids, CNS, CSF
Inactivated by: conjugation of glucuronic acid
: reduction to inactive aryl amines
Excretion urine majority , FECES, BILE small
Hepatic insufficient reduce the dose
Dose: 25mg/kg/d - NB
Clinical Indications serions rickettsial infections
- alternative drug: bact. Meningitis
- ophthalmic sol ocular tissues
- not effective: chlamydia
Adverse Effects
oral or vaginal candidiasis
Suppression of RBC production aplasctic anemia
prolonged use
Gray Baby Syndrome > 50mg/kg/d vomiting, flaccidity,
hypothermia, gray color, shock, vascular collapse
Drug interactions: antagonizes bacterial drugs penicillin
Inhibits hepatic microsomal enzymes
Oxazolidones
Mechanism of Action
Linezolid new class
- inhibits protein synthesis prevents formation of
ribosomes complex
- binding site: 23s ribosomal RNA of the 50s sub unot
no cross resistance
Bacteriostatic, some bacteriocidal
Resistance irritation of the LINEZOID binding site
Pharmacokinetics
Well absorbed orally 100% bioavailability
Half-life: 4-6hrs
Oxidative metabolism
Dose: 600mg oral/IV
Clinical Indications effective for vancomycin
resistant E. faecuim inf, mosocomial pneumonia, CAP.
Soft tissue and skin inf, multidrug resistant TB, nocardia
Adverse Effects: hematologic toxicities thrombocy
topenia, anemia, neutropenia, peripheral neuro
Aminoglycosides and
Spectinomycin
b. Mechanism of Action
Irreversible inhibitors of PROTEIN SYNTHESIS
Passive Diffusion cytoplasm (oxygen dependant process)
enhancement by cell wall drugs
Binds to 30s sub unit
Protein synthesis inhilated by:
a. Interference with initiation complex peptide formation
b. Misreading by MRNA
c. Break up of polysomes non-functional monosomes

c. Resistance
Mechanism:
a. Production of transferase enzyme inactivation adenylation,
acetylation, phosphorylation encountered clinically
b. Impaired entry of aminoglycoside into cell
c. Deletion of alternation on the 30s sub unit
d. Pharmacokinetics:
Poor oral absorption
Given IM o , IV serum half-life 2-3hrs
Given IV 30-60mm infusion
Removed by dialysis (40-60%)
Highly polar compounds
Preferred: single injection post antibiotic effect
antibacterial activity persist beyond measurable drug is
present
Synergistic killing B lactam or vancomycin
Excretion kidneys
- creatinine clearance excretion
Dose: 5-7 mg/kg (gentamycin)
Adverse Effects:
Ototoxic and nephrotoxic > 5days at high dose
Avoid loop diuretics (furosemide, ethacrynic acid) and
nephrotoxic agents (vancomycin or amphotheracin)
potentiates nephrotoxicity
Neomycin, kanamycin, amikacin most ototoxic
Neomycin, tobramycin, gentamycin most nephrotoxic
Gentamycin, streptomycin most vestibulotoxic
High dose curable like resp. paralysis
antidote: calcium gluconate
Clinical indications:
Mostly used against: q(-) enteric bacteria sepsis
: q(+) org combined with B lactam
synergism
: penicillin and aminoglycoside
(bactericidal), enterococcal endocarditis,
vridans strep, staphylococcal
endocarditis
Streptomycin
Isolated from stracin of Streptomyces friseus
Clinical Indications
1. Mycobacteria infections
- second line anti Tb
- dose: 0.5-1g/d (adult), 7.5-15mg 1kg/d (children)
- 1m or IV
2. Non TB infections
- plaque, tubaremia, brucellosis
dose: 1g/d (adults), 15mg/kg/d (children)
- 1m combined with oral tetracycline
- penicillin and streptomycin enterococcal endocartisis
viridans strep endocarditis
Adverse Effects: hypersensitivity rxns
: pain at injection site
:vertigo and loss of balance (vestibular
function) most serious toxic effect
irreversible
: streptomycin avoided PREGNANCY
deafness in the New born
Gentamycin
Isolated from micromonospora purpurea
Gentamycin sulfate prodrug active only q(-), coliforms
Gentamycin and Blactam synergism against E.coli,
proteus, klebsiella pneumonia, Enterobacter serratia
Resitance: streptococci and enterococci resistant to
gentamycin failure of the drug to penetrate the cell
: straphylococcal resistance monotherapy selection of
permeability mutants
: q(-) bacteria plasma encoded enzymes difucntional
enzymes inactivates netilmycin, tobramycin, amikacin
not streptomycin
Clinical Indications:
A.IM and IV administration
- used in severe infections (sepsis and pneumonia) q(-)
bacteria
- combined with other drugs avoid resistance
- dose: 5-6mg/kg/d single dose
- Dentamycin and cell wall active agents endocarditis by
q(+) bacteria
- Synergistic Killing bactericidal activity
- shorter duration of tx
B.Topical and ocular administration (0.1-0.3% gentamycin
SO4)
C.Intrathecal administration meningitis q(-) bacteria,
obsolete
Adverse Effects:
Nephrotoxicity reversible
Ototoxicity irreversible vestibular
slysfunction
Tobramycin
Gentamycin and tobramycin cross resistance
Dose: 5-6mg/k 1m and IV
Gentamycin slightly more active serratia
marcoscens
Tobramycin slightly more active pseudomonas
Enterococcus faecalis susceptible to both genta and
tobramycin
Enterococcus faecium resistant tobramycin
Adverse Effects:
Ototoxicity
Nephrotoxicity
- inhalational tobramycin (300mg) P.geryginose
cystic fibrosis
Amikacin
Semi-synthetic derivative of kanamycin, less toxic
Dose: 500mg q 12hrs (adult), 15mg/kg/d (children)
1m or IV
Clinical Indications: multidrug resistant myco TB,
streptomycin resistant drug
: active: Pseudomonas, proteins,
Enterobacter, serratia
: dose: (TB) 7.5-15mg/kg/d
Adverse Effects:
Ototoxicity, nephrotoxicity
Netilmicin
Additional of an ethyl group to the 1-amino
position of 2 deoxystreptamine ring
Dose: 5-7 mg.kg/d IM or IV
Neomycin and
Kanamycin
Paromomycin member of this group

Pharmacokinetics:
Poorly absorbed from the gut
Excretion FECES, urine glomerular filtration

Clinical Indications:
a.Topical ointments Neomycin polymycin
bacitracin infected skin tesims
b.Oral 0 elective bowel sx
Adverse Effects:
Ototoxicity vestibular function
Deafness
Nephrotoxicity
Curare like respiratory paralysis kanamycin
instilled in peritoneal cavity antidotes:
calcium gluconate, neostigmine
Allergic rxns
Spectinomycin
Aminocyclitol antibiotic
Lacks amino sugar and glycosidic bonds
Alternative tx drug resistant gonorrhea or penicillin
allergic gonorrhea pxs
Dose: 40mg/kg Im

Adverse Effects:
Pain at injection site
 Sulfonamides,
Trimethoprim and
Quinolones
Anti-Polate Drugs:
Sulfonamides
- similar to p-aminobenzoic acid (PABA)
- attached to amido or amino group of SULFANAMIDE
nucleus
- soluble at alkaline ph
Mechanism of Action:
Structural analogs of PABA inhibits digydropteroate
synthesis and folate production
PABA purine and nucleio acid synthesis
Sulfonamide and dihydrofolate reductase inhibitor
Resistance to sulfonamides:
dose: a. overproduction of PABA
b. production of folic acid enzyme
c. impair permeability to sulfonamide
Pharmacokinetics
3 major groups:
1.Oral, absorbable (short, intermediate, short acting)
2.Oral non-absorbable
3.Topical
- widely distributed to tissues, body fluid, CSF
Clinical Indications:
Doctrimeyhroprim sulfamethroxazote
pneumocystis, jireveci pneumonia, toxoplasmosis,
nocardiosis
a.Oral absorbable agents:
Sulfisoxazote and sulfamethoxazote short to medium acting
agents UTI
Sulfadiazine and pyrimethamine synergism 1 st line in Acute
Toxoplasmosis
Sulfadoxime and pyrimethamine (fansidar) 2md line for MALARIA
Sulfadoxime only long acting sulfonamide
Folinic Acid 0 10mg oral minimize BM suppression

b.Oral non-absorbable agents

Sulfazalazine (salicyazosulfapyradine) ulcerative colitis, IBD,
enteritis

c.Topical agents
Sodium sulfacetamide opthtalmic solution bacterial conjunctivitis,
trachoma
Adverse Effects:
Fever, skin rashes, exfoliative dermatitis,
photosensitivity, urticarial, N/V, diarrhea, steven-Johnson
syndrome, stomatitis, arthritis, conjunetivitis, hepatitis,
PAN, psychosis
A.Urinary Disturbances
- Sulfonamides precipitate in urine crystalluria,
hematuria, obstruction, nephrosis, allergic
nephrisis
B.Hematologic Disturbances
Hemolytic or aplastic anemia, granulo cytopenia,
thrombocytopenia, leukomoid rxn
GGPD dificency
Kernicterus in the New Born avoided in pregnancy
 Trimethoprim
Sulfamethoxazole
Mixtures
Mechanism of Action
Trimethoprim trimethoxybenzylpyrimidine selective
inhibits dihydrofolic acid reductase, dyhydrofolic acid
tetrahydrofolic acid synthesis of Purines and DNA
Pyrimethamine selective inhibits dihydrofolic acid
reductase of protozoans as to mammals (trimethoprim)
Resistance to trimethoprim reduced cell permeability
due to plasmid encoded dihydrofolate reductase
Pharmacokinetics
Orally alone or combined with sulfamethoxazole
IV- trimethoprim and sulfamethoxazole (1.5)
Widely distributed in body tissues, fluids and CSF more
lipid soluble
Excretion urine 24hrs
Trimethoprim prostatic fluid and vaginal fluid more
antibacterial activity due to acidity
Clinical Indications:
a.Oral Trimethoprim
- given alone 100mg BID acute UTI
b.Oral trimethoprim sulfamethoxazole (TMP-SMZ)
P.jroveci pneumonia, shigellosis, salmonella, UTI,
prostatitis, non-TB mycobacteria, suspectible and
resistant methicillin staph aureus, pneumococcus,
H.influenza, Moraxella, klebsrella (not mycoplasma)
c.IV tmx-smx
- trimethoprim 80mg and sulfamethoxazole 400mg per 5ml
in 125ml of DSW infusion over 60-90mins
- Doc: moderately severe pneumocystis pneumonia
dose: 10-20mg/kg of trimethoprim component
d.Oral pyrimethamine and sulfonamide
Adverse Effects:
Trimethoprim megaloblastic anemia, leukopenia,
granulocytopenia, trimethoprim and sulfamethoxazole, CNS
disturbances

DNA GYRASE INHIBITORS:

Fluor quinolones synthetic fluorinated analogs of nalidixic acid
Mechanism of Action:
Quinolones block bacterial DNA synthesis by inhibiting
topoisomerase II (DNA gyrase) and topoisomerase IV
- inhibition of DNA gyrase prevents relaxation of
supercoiled DNA normal transcription and
replication
- inhibition of toposcpmerase IV interferes with
separation of replicated chromosomial DNA
Fluoro quinolones
Active againts q(-) gerobic bacteria
Limited activity q(+) org
NORFLOXACIN least active against q(+) and (-) org
CIPROFLOXACIN, ENOXACIN, LOMEFLOXACIN, LEVOFLOXACIN,
OFLOXACIN, PEFLOXACIN 2nd group excellent against q(-),
mod to good activity against q(+) org
Methicillin susceptible staph aureus susceptible to fluoro
quinolones
CIPROFLOXACIN most active against q(-) org P. aeruginosa
LEVOFLOXACIN q(+) org strep pneumonia
GATIFLOXACIN, GEMIFLOXACIN, MOXIFLOXACIN 3rd
group improved activity q(+) org. strep and staph
FLOORO QUINOLONES active against a typical
pneumonia (mycoplasma, chlamydia), legionella,,
myco TB, myco avium resistancedue to a) point
muntations low level resistance - plasma
Pharmacokinetics
Absorbed orally (80-95% bioavailability)
Widely distributed in body tissue
Long half lives: LEVOFLOXACIN, GEMIFLOXACIN,
GATIFLOXACIN< MOXIFLOXACIN once/day
EXCRETION Kidneys Tubular Secretion
- GLOMEBULAR FILTRATION
Given orally or IV
Contraindicates : hepatic failure
Clinical Indications:
Effective in UTI P.aeruginosa
Bacterial diarrhea: shigella, salmonella. ETEC,
campylobacter
Soft tissue, bone, joints, intra abdominal and
respiratory tract infections (EXCEPT NON FLOXACILIN)
CHROFLOXACILIN OC prophylaxis and treatment
anthrax , CIPROFLOXACILIN, LEVOFLOXACILIN
chlamydial urethritis, cervicitis
CIPROFLOXACILIN, LEVOFLOXACILIN, MOXIFLOXACILIN
used in TB an a typical mycobacteria, eradication of
meningococci from carries
LECIFLOXACIN, GATIFLOXACIN, GEMIFLOXACIN,
MOXIFLOXACIN respiratory fluoroguinolones
ADVERSE EFFECTS:
NIV, diarrhea, headache, dizziness, insomnia, skin
rashes, abnormal liver function
Phososensitivity lomefloxacin and pefloxacin
Prolonged QT interval qatilfloxacin, lexofloxacin,
gemifloxacin, moxifloxacin
Hyperglycemia and hypoglycemia (oral hypoglycemia)
gatilfloxacin
Damage growing cartilage arthropathy avoided in
<18yrs old (except cystic fibrosis)
Avoided: pregnancy
Avoided: hypokalemia, anti-arrhythmic drugs (sotalor,
amiodarone), quinidine or procainamide