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Beta-Lactam Antibiotics Pharmacology Deo L. Panganiban, md
Antibiotics, particularly, beta-lactams,
targets the cell walls of the organism Some antimicrobial drugs
selectively
interfere the synthesis of the bacterial cell wall
The cell wall is composed of polymer (peptidoglycan) which are
joined to each other by peptide crosslinks
Beta lactamases in Gram-negative bacteria are found in the
periplasmic space
Note: To be maximally effective, inhibitors of cell wall
synthesis requires actively proliferating microorganisms Beta
lactams have little or no effect on inactive or
not growing bacteria
BETA-LACTAM ANTIBIOTICS
Their structure contains a beta-lactam ring The major
subdivisions are:
Penicillins whose official names usually include or end in
cillin
Cephalosporins which are recognized by the inclusion of cef or
ceph in their official names
Carbapenems (e.g. meropenem, imipenem)
Monobactams (e.g. aztreonam) Beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam)
Note: Beta lactams are named after the beta lactam ring that is
essential to the activity of these antibiotics
PENICILLINS
Most widely effective antibiotic Least toxic drug Nucleus
(thiazolidine ring): chief
requirement for biological activity Metabolic transformation
& chemical
alteration = LOSS of ALL significant antibacterial activity if
destroyed
Side chains: determines antibacterial & pharmacological
characteristics of a particular type of penicillin
Note: The nature of the side chain will affect the antimicrobial
spectrum and the stability to stomach acid and also susceptibility
to bacterial degradation enzymes (beta lactamases)
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Mechanism of Action
Bactericidal Inhibits cell wall synthesis by:
1. Binding to specific receptors (Penicillin-binding proteins or
PBPs) located in the bacterial cytoplasmic membrane
Interferes with the last step of bacterial cell wall synthesis
known as transpeptidation or cross linkage
Exposure of the osmotically less stable membranes
Lysis can occur thru osmotic pressure or activation of
autolysins
The success of a penicillin antibiotic in causing cell death is
related to the size of the antibiotic, charge and
hydrophobicity
2. Inhibition of transpeptidase enzymes which act to cross-link
the linear peptidoglycan chains that form part of the cell wall
3. Activation of autolytic enzymes lesions in the cell wall
The exact autolytic mechanism is not known
May be due to the inhibition of the autolysins
Note: Read on page 792 & 794 of Katzung for the mechanism of
action of beta lactams
Semisynthetic Penicillins
Discovery of 6-aminopenicillanic acid Development of
semi-synthetic
penicillins Serves as the nucleus of semi-synthetic
penicillins Side chains:
Added to the nucleus of the beta lactams
Alters the susceptibility of resultant
compounds to -lactamases changes antibacterial activity &
pharmacological properties
Unitage
Penicillins are drugs which are measured
and administered in units International Unit:
Specific PCN activity in 0.6 g of Crystalline Sodium salt of
Penicillin G: 1 mg (pure Penicillin G sodium) =
1667 U 1 mg (pure Penicillin G potassium)
= 1595 U
1 unit = 0.6 g 1 million units = 0.6 g
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3 jcc Spidey Transcriptions
Semisynthetic penicillins (dosage & potency) Expressed by
weight
Classification
1. Narrow spectrum: Penicillin G & Penicillin V
Highly active = Gram-positive cocci, Gram-negative cocci, and
non--lactamase-producing anaerobes (readily hydrolyzed by
penicillinase)
Ineffective for most Staphylococcus aureus strains
Note: Gram negative bacteria have porins in their cell wall.
These porins permit transmembrane entry of antibiotics Pseudomonas
aeruginosa lacks porins which make them intrinsically resistant to
many antimicrobial
agents
Penicillin G (prototype)
Absorption:
Gastric acid pH 2 destroys drug Rapid absorption; food
ingestion
interferes with enteric absorption = at least 30 minutes before
meals to 1 hour after meals
Penicillin V Better absorbed in GIT Excreted through the kidneys
More acid stable Effective against anaerobic
organisms I.V. Penicillin G rapid peak plasma
conc. & excretion Clinical uses:
Treat infections: Streptococci, Pneumococci, Meningococci,
Gram-positive bacilli, spirochetes
Resistant via -lactamase (penicillinase) production Most strains
of S. aureus &
Gonococcus Aminoglycosides enhance activity
against enterococci if added to the treatment dosage
Penicillin V: oral drug for infections of oropharynx
2. Very Narrow Spectrum, Penicillinase-resistant or
Anti-staphylococcal penicillins: Methicillin, Nafcillin, Oxacillin,
Cloxacillin, Dicloxacillin
Methicillin (prototype)
Less potent antimicrobial activity against
microorganisms that are sensitive to penicillin G
Effective against penicillinase-producing S. aureus & S.
epidermidis primary use
3. Extended-spectrum penicillins: Ampicillin,
Amoxicillin, Piperacillin, Ticarcillin Ampicillin &
Amoxicillin wider spectrum
than penicillin G but still readily hydrolyzed
by broad-spectrum -lactamases Indications same as those of
penicillin
G Effective against Gram-negative
bacteria: Haemophilus influenzae, E. coli, Proteus mirabilis and
Listeria monocytogenes
Enhanced antimicrobial activity if combined with -lactamase
inhibitors
Ampicillin synergistic with Aminoglycosides in Listeria &
enterococcal infections
Amoxicillin is used as prophylaxis to patients undergoing dental
procedures with problematic heart valves
Piperacillin & Ticarcillin Most are synergistic with
Aminoglycosides Also known as anti-pseudomonal
antibiotics Piperacillin is the most potent as
compared to ticarcillin but is not effective against Klebsiella
sp.
Gram-negative rods: Pseudomonas, Enterobacter
Susceptible to penicillinases Combined with penicillinase
inhibitors
4. Anti-pseudomonal penicillins: Carbenicillin, Carbenicillin
indanyl, Ticarcillin Extended antimicrobial spectrum to include
(in combination with clavulanic acid and tazobactam):
Pseudomonas, Enterobacter, & Proteus
species Inferior to ampicillin against Gram-
positive cocci and Listeria monocytogenes
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GJJDRDI NA METH ni CLOX (OX) si PEN
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GJJDRTICAR (teka), pinaEXTEND ako ng PIPE kong AMO, AMP!
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4 jcc Spidey Transcriptions
Resistance
1. Enzymatic hydrolysis of beta-lactam ring
(by -lactamase) loss of bacterial activity More than 300
beta-lactamases:
Penicillinases & cephalosporinases Hydrolyzes cyclic amide
bond of
beta lactams Major cause of resistance to
penicillin
-lactamase formation major mechanism of resistance
To prevent inactivation - combine penicillin with bacterial
enzyme inhibitors: Ex. Clavulanic acid, Sulbactam,
Tazobactam Natural resistance to penicillin are
those organisms that do not have a peptidoglycan wall or have
cell wall which are not permeable to drugs
Acquired resistance to penicillin via plasmid transfer
Gram-positive organisms secrete beta lactamases extacellularly
while Gram-negative organisms confine beta lactamases in the
periplasmic space
2. Structural change of target penicillin-binding proteins
(PBPs): Modified PBP have lower affinity to
beta lactam antibiotics Methicillin-resistance in staphylococci
Resistance to penicillin G in
pneumococci & enterococci Produce PBPs which have low
affinity for binding -lactam antibiotics Inhibited at high
drug
concentrations (unattainable to certain drugs)
3. Changes in PORIN structures in the outer membrane Synonymous
to decreased permeability
of the drug Only in Gram-negative rods Impedes or reduces access
of the drugs
to penicillin-binding proteins: Absence of proper porin channels
Down-regulation of its production
4. Presence of an EFFLUX pump Only in Gram-negative rods
Cytoplasmic & periplasmic protein
compounds that efficiently transport
some -lactam antibiotics from periplasm back to outer
membrane
Pharmacokinetics
Vary in gastric acid resistance Determines oral bioavailability
Polar compounds not fully
metabolized
Note: The route of administration is determined by the stability
of the drug to gastric acid and by the severity of the infection If
the infection is severe, the drug should be
administered directly into the bloodstream.
IV/IMDrugs Picarcillin
Carbenicillin Piperacillin
Ampicillin + SUlbactam Ticarcillin + Clavulanic acid
Piperacillin + Tazobactam Oral Preparation Drugs
Penicillin V Amoxicillin (highest absorption)
Amoxicillin + Clavulanic acid Carbenicillin indanyl (UTI)
Note: Most penicillins are incompletely absorbed after oral
administration and reach the intestines in sufficient amounts to
affect the composition of the intestinal flora Absorption of
penicillinase-resistant penicillins are decreased by the presence
of food in the stomach All penicillins can cross the placental
barrier but is not known to cause teratogenicity
Excreted unchanged in kidneys via:
Glomerular filtration Tubular secretion inhibited by
probenecid Partial excretion in bile:
Methicillin Nafcillin
Plasma half-lives Variable: 30 minutes 1 hour
Benzathine & Procaine Penicillin G: IM administration
Long plasma half-lives slow release into the bloodstream (forms
a depot)
Blood-brain Barrier Most penicillins cross the barrier when
there is meningeal inflammation
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Toxicity
1. Allergies (most important adverse reaction) Most common:
severe pruritus,
urticaria, fever, joint swelling, hemolytic anemia, nephritis,
anaphylaxis
Methicillin nephritis Nafcillin neutropenia Ampicillin
maculopapular rash which
may not be an allergic reaction 510 %: have allergic reaction
upon re-
exposure Cross-allergenicity must be assumed Antigenic
determinants:
Include penicillin degradation products such as penicilloic
acid
2. Disturbances of the GIT Nausea & vomiting (second
most
common adverse effect): Ampicillin & other penicillins
GIT upsets: Direct irritation Yeast or Gram-positive overgrowth
Pseudomembranous colitis =
ampicillin (chronic intake) 3. Na+ & K+ toxicities when
overly high
doses are used in patients with renal or cardiovascular
disease
CEPHALOSPORINS
7-Aminocephalosporanic acid nucleus
The nucleus of the Cephalosporins, 7-
aminocephalo-sporanic acid, bears a close resemblance to
6-amino-penicillanic acid
The intrinsic antimicrobial activity of natural cephalosporins
is low, but the attachment of various R1 and R2 groups has yielded
hundreds of potent compounds of low toxicity
Cephalosporins can be classified into four major groups or
generations, depending mainly on the spectrum of their
antimicrobial activity
Cephalosporins are similar to penicillins, but more stable to
many bacterial betalactamases and therefore have a broader spectrum
of activity
However, strains of E. coli and Klebsiella species expressing
extended-spectrum beta-lactamases that can hydrolyze most
cephalosporins are becoming a problem
Cephalosporins are not active against enterococci and L.
monocytogenes
Antibiotics related to Penicillins structurally &
chemically
More resistant to -lactamase than penicillins
Synthetic (majority) Classification:
Antimicrobial activity Resistance to -lactamases Designation:
1st 4th Generations
Mechanism of Action
Inhibit cell wall synthesis similar to
penicillin
Mechanism of Resistance
Similar to penicillin Not effective against
Methicillin-resistant
Staphylococcus aureus, Listeria monocytogenes & Clostridium
dificile
1st Generation Cephalosporin
Excellent choice for surgical prophylaxis; penetrates many
tissues except the CNS Should not be used for meningitis Not active
against enterococci and P. aeruginosa
Drugs Cephalotin, Cefadroxil, Cephapirin, Cefazolin,
Cephalexin
Spectrum of activity
Gram-positive: Excellent (except Enterococci,
Methicillin-resistant S. aureus, & S. epidermidis)
Gram-negative: Poor to relatively modest activity Anaerobic:
Poor coverage
Clinical uses
Surgical prophylaxis (drug of choice) Endocarditis (due to S.
aureus)
Cephalotin : impervious to -lactamase penetration UTI : E. coli,
Proteus, Klebsiella Pneumonia: Klebsiella
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Note: Bacteroides fragilis is NOT sensitive
Routes of administration
Given per OREM: Cephalexin, Cefadroxil, Cephradine should not be
relied on systemic infections
Given INTRAVENOUSLY: Cephalotin, Cephapirin, Cefazolin (drug of
choice for surgical prophylaxis)
Side effects
Hypersensitivity reactions : most common, identical to those of
penicillins Cross-reactive allergic reaction Nephrotoxicity:
Cephalotin (high doses acute tubular necrosis)
2nd Generation Cephalosporin
Active against organisms inhibited by 1st generation drugs
Extended Gram-negative coverage Cefamandole, cefuroxime, cefaclor -
active against H. influenzae, but not against Serratia or
Bacteroides fragilis Cefoxitin and Cefotetan active against
Bacteroides fragilis and some Serratia strains but are less
active against H. influenzae Not active against enterococci and
P. aeruginosa Cefuroxime sodium prototype drug
Drugs Cefamandole, Cefaclor, Cefotetan, Cefonizid, Cefuroxime,
Cefprozil, Cefoxitin
Route of administration Given per OREM: Cefaclor, Cefpodoxime,
Cefprozil & Cefuroxime Given INTRAVENOUSLY: All others except
Cefuroxime
Spectrum of activity (Cefuroxime, Cefaclor)
E. coli, Klebsiella, Proteus, H. influenzae, Moraxella
catarrhalis Increased activity against Gram-negative organisms Not
as active against Gram-positive organisms as the 1st generation
drugs
Spectrum of activity (Cefoxitin, Cefotetan, Cefmetazole)
Inferior activity against S. aureus compared to Cefuroxime BUT
with added activity against Bacteroides fragilis & other
Bactroides spp.
Mechanism of Action
Cell wall synthesis inhibitors Limited CNS penetration: some may
cross BBB when meninges are
inflamed Cefuroxime - does not require meningeal inflammation to
enter CNS
Clinical Uses
Cefotetan and Cefoxitin Bacteroides fragilis sepsis Serratia
nosocomial infections
Meningitis: Cefuroxime UTI Sinusitis; otitis media Soft tissue
& bone infections
Side Effects
Hypersensitivity reactions (most common) Disulfiram-like
reaction: Cefamandole, Cefotetan In elderly: Severe bleeding 2nd to
hypoprothrombinemia: Cefotetan,
Cefamandole (treatment = Vitamin K) Gram-positive & fungal
super infections
3rd Generation Cephalosporin
Ceftriaxone, Ceftazidime prototype drugs Ceftriaxone and
Cefotaxime drug of choice for the treatment of meningitis
Ceftazidime activity against P. aeruginosa Cefotaxime known for
good CNS penetration
Drugs Ceftriaxone, Ceftazidime, Cefotaxime, Ceftizoxime,
Cefixime, Cefoperazone, Cefpodoxime proxetil, Ceftibuten, Cefdinir,
Moxalactam
Route of Administration
Given per OREM: Cefixime Given INTRAVENOUSLY: All others
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7 jcc Spidey Transcriptions
Ceftriaxone: longest half-life (6 8 hours) Cefpodoxime proxetil
= H2-blockers & antacids decreases absorption
Spectrum of Activity
Gram-negative - Broad coverage Gram-positive - Decreased
Anaerobic - moderate activity Aerobic - some activity Effective
against: H. influenzae, N. gonorrhea & Enterobacter
Clinical Uses
Meningitis: H. influenzae, N. meningitidis, S. pneumoniae
Ceftriaxone (drug of choice)
Pneumonia/sinusitis Gonorrhea 2nd to N. gonorrheae Ceftriaxone
& Cefixime: drugs of choice in penicillinase-producing
Neisseria
Chancroid secondary to H. ducreyi Stage 2 Lyme disease :
Ceftriaxone UTI seconadary to Pseudomonas, Proteus & Klebsiella
Infections due to: Bacteroides fragilis, Salmonella, Serratia
nosocomial infections
Side Effects
Hypersensitivity reactions Diarrhea: Cefoperazone
Disulfiram-like reaction :Cefoperazone In elderly: Severe Bleeding
secondary to hypoprothrombinemia: Cefoperazone (contains
methylthiotetrazole group) Moxalactam (interferes with platelet
function)
Gram-positive & fungal super infections
4th Generation Cephalosporin
Drugs Cefepime, Cefpirome
Spectrum of Activity
Comparable to 3rd Generation but more resistant to chromosomal
-lactamases
Highly active against: Haemophilus & Neisseriae Good
activity against: P. aeruginosa,
Enterobacteriaceae, S. aureus & S. pneumoniae Animal
meningitis models: penetrates well into the
CSF
Pharmacokinetics Clearance: Kidneys Half-life: 2 hours
CARBAPANEMS
-lactams: fused -lactam ring & a 5-membered ring system that
differs from penicillin in being saturated and containing a carbon
atom instead of a sulfur atom
Imipenem/Cilastatin, Meropenem, Ertapenem
Broader spectrum of activity Effective against P. aeruginosa,
and
treatment for mix aerobic and anaerobic infections
Drug of choice for enterobacter infections Resistant to beta
lactamase
IMIPENEM/CILASTATIN
Imipenem: Binds to PBPs, disrupts bacterial cell
wall synthesis death of microorganisms
Cilastatin: Inhibits the enzyme dehydrogenase in
renal proximal convoluted tubules
inhibits cleavage of Imipenem (has nephrotoxic metabolite)
Good tissue and CNS penetration Resistant to -lactamases Given
IM or IV; Not absorbed orally Clearance:
Kidneys = 70% unmetabolized Adjust dose in renal
insufficiency
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8 jcc Spidey Transcriptions
Spectrum: Broadest spectrum -lactam
antimicrobial Excellent activity against:
Aerobic & anaerobic Gram-positive & Gram-negative
organisms
Good activity against: P.aeruginosa & B. fragilis
Poor activity: Methicillin-resistant S. aureus
Side effects: Nausea & vomiting most common Seizures (1.5%)
In high doses (patients with CNS
lesions) and those with renal insufficiency
Cross-sensitivity allergic reactions Contraindicated in
epilepsy:
Decreased seizure threshold
Note: Imipinem is susceptible to destruction by
metallo-betalacamases
MONOBACTAMS
AZTREONAM
Monobactam: Interacts with PBPs = induces formation
of long, filamentous bacterial structures
Extremely resistant to -lactamases Given IM or IV Spectrum:
Gram-negative Aerobic rods P. aeruginosa & Serratia
Side effects: No Cross-reactivity with Penicillin &
Cephalosporin Streptococcus & Enterococci
superinfections Elevation of transaminases Can cause abnormal
liver function test
BETA-LACTAMASE INHIBITORS
Clavulanic acid Sulbactam Tazobactam Resemble B-lactam
molecules; weak
antibacterial May inhibit bacterial B-lactamases =
protect penicillin from inactivation Most active against Ambler
class A beta
lactamases Fixed-combinations with specific penicillins
Extends spectrum of a penicillin provided that inactivity of
that penicllin is due to beta lactamase destruction and the
inhibitor is active against that B-lactamase produced
Antibacterial spectrum = determined by penicillin
Combinations indicated for: Empirical therapy of infections
with
wide range of potential causative agents
Mixed aerobic and anaerobic infections Doses = single agents
(except piperacillin-
tazobactam: 3 g every 6 hours) Adjust in renal insufficiency
(based on
penicillin)
OTHER CELL WALL SYNTHESIS INHIBITORS
VANCOMYCIN
Streptococcus orientalis Active only against Gram-positive
bacteria:
staphylococci MOA: binds firmly to D-Ala-D-Ala terminus
of nascent peptidoglycan pentapeptide = inhibits transglyosylase
= prevents elongation of peptidoglycan and cross-linking
Resistance to Vancomycin
Modification of D-Ala-D-Ala binding site of
the peptidoglycan building block = terminal D-Ala is replaced by
D-lactate
Results in loss of a critical hydrogen bond that facilitates
high-affinity binding of
Vancomycin to its target loss of activity
Antibacterial Activity
Bactericidal for Gram-positive pathogens Most Staphylococci
(including nafcillin &
methicillin-resistant strains) are killed by 4ug/ml or less
Kills slowly & only if cells are actively dividing
Pharmacokinetics
Poorly absorbed in GIT (if given p.o.=>
treatment of antibiotic induced enterocolitis due to Clostridium
dificile
Must be administered IV Widely distributed = CNS penetration is
7 -
30 % if with meningeal inflammation 90 % - glomerular
filtration
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9 jcc Spidey Transcriptions
Clearance proportionate to creatinine clearance
Clinical Uses
Sepsis Endocarditis due to Methecillin-resistant
staphylococci Combined with gentamicin - for
enterococcal endocarditis in penicillin-allergic patients
Combined with cefotaxime, ceftriaxone, rifampin - for meningitis
caused by highly penicillin-resistant pneumococci
Adverse Reactions
10% - Minor Phlebitis at injection site chills & fever
Ototoxicity & nephrotoxicity rare, BUT if
combined with drugs having these toxicities
Increased risk Red man or Red neck syndrome
infusion-related flushing (histamine-induced): prolong infusion
or increase dose-intervals
FOSFOMYCIN TROMETAMOL
Stable salt of Fosfomycin Inhibits the cytoplasmic enzyme
enolpyruvate transferase covalently binds to cysteine residue of
the active site = blocks the addition of phosphoenolpyruvate to UDP
N-acetylglucosamine = blocks formation of N-acetylmuramic acid
(found only in bacterial cell walls)
Against both Gram-positive & Gram-negative organisms at
concentrations 125 g/ml
In vitro synergism with -lactams, aminoglycosides,
fluoroquinolones
Oral or parenteral Oral bioavailability = 40 % Half-life 4 hours
Excretion kidneys
BACITRACIN
Cyclic peptide mixture from Tracy strain of Bacillus
subtilis
Active against G (+) pathogens MOA : interferes with
dephosphorylation in
cycling of the lipid carrier that transfers peptidoglycan
subunits to the growing cell wall
Markedly nephrotoxic (if given systemically): proteinuria,
hematuria, nitrogen retention
Allergies rare Limited to topical use = local antibacterial
activity Excretion glomerular filtration 500 units/g in ointment
form (mixed with
polymyxin or neomycin) Treatment of mixed bacterial flora
infections in surface wounds, skin or mucous membranes
Solutions (100-200 units/ml) : in saline for irrigation of
joints , wounds or pleural cavity
Clinical use
Uncomplicated lower urinary tract
infections in women Single dose : 3 grams Safe for pregnant
women
CYCLOSERINE
Streptomyces orchidaceus Water-soluble Unstable in acid pH
Inhibits G(+) and G(-) Exclusively for treating Tuberculosis
secondary to M. tuberculosis Structural analog of D-alanine MOA:
Inhibits incorporation of D-alanine
into peptidoglycan pentapeptide by inhibiting alanine racemase,
which converts L-alanine to D-alanine and D-alanyl-D-alanine
ligase
0.25 g = 20-30 ug/ml (blood levels) Widely distributed in
tisuues Excretion = kidneys
Adverse reactions
Dose-related CNS symptoms: headaches, acute psychosis,
seizures
Avoid effects: < 0.75 g/d
END
Moving on doesnt mean you forget about things. It just means you
have to accept whats happened
and continue living. - Erza Scarlet
Good luck and God bless 2016!
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