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ANTIMICROBIAL THERAPY V. Ger l According to: - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed. - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower ... – PowerPoint PPT presentation

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Title: Bez nadpisu


1
  • ANTIMICROBIAL THERAPY
  • V. Geršl
  • According to
  • - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore
    Pharmacology, 5th ed.
  • - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower
    Pharmacology, 6th ed.
  • R.A.Howland, M.J.Mycek Lippincotts Illustrated
    Reviews Pharmacology,3rd ed.
  • R.A.Harvey, P.C.Champe Lippincotts Illustrated
    Reviews Pharmacology,4th ed.
  • - B.G.Katzung, S.B.Masters, A.J.Trevor Basic and
    Clinical Pharmacology, 11th ed.

2
PRINCIPLES OF ANTIMICROBIAL THERAPY ATB -
effective in the treatment of infections because
of their selective toxicity-the ability to kill
an invading microorganism without harming the
cells of the host. However, the selective
toxicity is relative (not absolute) ?
concentration of the drug must be controlled (to
attack the microorganism while being tolerated by
the host). Selective antimicrobial therapy
advantage of the biochemical differences between
microorganisms and human beings. SELECTION OF
ANTIMICROBIAL AGENTS depends on 1) the
organisms identity, 2) its susceptibility to an
agent, 3) the site of the infection, 4) patient
factors, 5) the safety of the agent, 6) the cost
of therapy.
3
Classification of some antibacterial agents by
their sites of action. THFA tetrahydrofolic
acid PABA p-aminobenzoic acid
CELL WALL
CELL MEMBRANE
DNA
Inhibitors of cell membrane function
THFA
Ribosomes
Isoniazid Amphotericin B
mRNA
PABA
Inhibitors of nucleic acid function or synthesis
Inhibitors of protein synthesis
Inhibitors of cell wall synthesis
Inhibitors of metabolism
Tetracyclines Aminoglycosides Macrolides Clindamyc
in Chloramphenicol
Fluoroquinolones Rifampin
b-Lactams Vancomycin
Sulfonamides Trimethoprim
(according to Lippincotts Pharmacology, 2006)
4
  • A) Identification and sensitivity of the organism
    main for the selection of the proper drug.
  • Essential - to obtain a sample culture prior the
    treatment (if possible).
  • Empiric therapy prior to organism identification
  • Ideally - to treat when the organism was
    identified and its drug
  • susceptibility established.
  • However, acutely ill patients usually require
    immediate treatment
  • (initiated before results of the culture are
    available).
  • The choice of drug in the absence of sensitivity
    data is influenced by
  • patient (e.g., age),
  • location of the infection,
  • - results of the Gram stain.
  • Possible - initiate empiric therapy with ATB or
    a combination of ATB
  • covering infections by both G and G-
    microorganisms.

5
B) Selecting a drug In the absence of
susceptibility - influenced by the site of
infection, patient's history (hospital - or
community-acquired, immunocompromised patiens,
patient's travel record and age).
Broad-spectrum - initially for serious
infections (identity of the organism is unknown
or the site makes a polymicrobial infection
likely. Also by known association of particular
organisms with infection in given clinical
setting (e.g., G coccus in the spinal fluid of a
newborns - unlikely S. pneumoniae - most likely
Streptococcus agalactiae -sensitive to PNC G).
But, G coccus in older (cca 40 years) v.s.
S. pneumoniae (frequently resistant to PNC G ?
3rd-generation cephalosporin (cefotaxime or
ceftriaxone) or vancomycin.
6
C. Determination of antimicrobial susceptibility
of infective organisms Susceptibility to ATB - a
guide in choosing antimicrobial therapy. Some
pathogens (S. pyogenes, N. meningitidis) -
usually predictable susceptibility to certain
ATBs. In contrast, most G- bacilli, enterococci,
and staphylococcal species - often unpredictable
susceptibility to various ATB (i.e., require
susceptibility testing). The minimum inhibitory
and bactericidal concentrations of a drug can be
experimentally determined.
7
1. Bacteriostatic vs. bactericidal drugs
Bacteriostatic - arrest the growth and
replication of bacteria at serum levels
achievable in the patient - they limit the spread
of infection while the body's immune system
attacks, immobilizes, and eliminates the
pathogens. If the drug is removed before the
immune system has scavenged the organisms, enough
viable organisms may remain to begin a 2nd cycle
of infection. Bactericidal - kill bacteria at
drug serum levels achievable in the patient -
often drugs of choice in seriously ill patients.
However, it is possible for ATB to be
bacteriostatic for one organism and bactericidal
for another. E.g. chloramphenicol (static
against G- rods and -cidal against other
organisms, e.g. S. pneumoniae).
8
2. Minimum inhibitory concentration (MIC) the
lowest concentration of ATB that inhibits
bacterial growth. For effective therapy, ATB
concentration in body fluids should be greater
than the MIC. 3. Minimum bactericidal
concentration (MBC) the lowest concentration of
ATB that results in a 99.9 percent decline in
colony count after overnight broth dilution
incubations.
9
D. Effect of the site of infection on therapy
The blood-brain barrier Capillaries with
varying degrees of permeability carry drugs to
the body tissues. The endothelial cells of the
walls of capillaries of many tissues they have
fenestrations ? allow most drugs not bound by
plasma proteins to penetrate. However, natural
barriers to drug delivery created by structures
of the capillaries in the prostate, the vitreous
body of the eye, and the CNS. HEB - single
layer of tile-like endothelial cells fused by
tight junctions ? impede entry from the blood to
the brain of molecules (except those small and
lipophilic).
10
1. Lipid solubility Agents without a specific
transporter ? pass from the blood to the CSF.
Lipid solubility major determinant of ability
to penetrate into CNS. Lipid-soluble
(quinolones, metronidazole) - penetration to the
CNS. X b-lactam ATB (PNC) - ionized ? low
solubility in lipids ? limited penetration
through the intact BBB. Infections (meningitis)
- BBB does not function effectively ? local
permeability ?. Some b-lactam ATB can enter CSF
in therapeutic amounts. 2. M.w. Low M.w. - ?
ability to cross BBB High M.w. (vancomycin) -
penetrate poorly, even in the presence of
meningeal inflammation. 3. Protein binding
High degree of protein binding ? limited entry
into CSF ? the amount of free (unbound) drug in
serum, rather than the total amount of drug, is
important for CSF penetration.
11
E. Patient factors Important in selecting an
ATB. 1. Immune system Elimination of organisms
from the body depends on an intact immune system.
The host defense system must eliminate invading
organisms. Alcoholism, diabetes,
immunodeficiency virus, malnutrition, advanced
age ? affect a patient's immunocompetency. Higher
than usual doses of bactericidal ATB or longer
courses of treatment required.
12
2. Renal dysfunction Poor kidney function (10
or less of normal) - accumulation of ATB
(eliminated by kidney) - serious adverse effects
? adjust the dose of ATB. TDM of serum levels of
some ATB (e.g., aminoglycosides). The number of
functioning nephrons decreases with age ? elderly
patients particularly vulnerable to accumulation
of drugs eliminated by the kidneys. ? ATB that
undergo extensive metabolism or are excreted via
the bile may be favored. 3. Hepatic
dysfunction ATB concentrated or eliminated by
the liver (e.g., erythromycin and tetracycline) -
contraindicated in liver disease.
13
4. Poor perfusion ? circulation to an area
(e.g., lower limbs of a diabetic) ? ? amount of
ATB that reaches that area ? infections difficult
to treat. 5. Age Renal or hepatic elimination
- often poorly developed in newborns neonates -
particularly vulnerable to chloramphenicol and
sulfonamides. Young children - not to be treated
with tetracyclines (bone growth). 6.
Pregnancy All ATB cross the placenta. Adverse
effects to the fetus are rare (excepting tooth
dysplasia and inhibition of bone growth by TTC).
Some anthelmintics are embryotoxic and
teratogenic. Aminoglycosides - avoid in
pregnancy - ototoxic effect on the fetus. 7.
Lactation Drugs may enter the nursing infant via
the breast milk. Concentration of ATB usually
low, however, the total dose to the infant may be
enough to cause problems.
14
  • F. Safety of the agent
  • Inherent toxicity of the drug
  • Many ATB (e.g. PNCs) - among to least toxic of
    all drugs (they interfere with a site unique to
    the growth of microorganisms).
  • Other ATBs (e.g. chloramphenicol) - less specific
    ? reserved for life - threatening infections
    (serious toxicity).
  • - Safety also related to patient factors that can
    predispose to toxicity.
  • G. Cost of therapy
  • Several drugs - similar efficacy in treating -
    vary widely in cost.

15
ROUTE OF ADMINISTRATION Oral route mild
infections, outpatient basis, economic pressures.
If i.v. therapy initially - the switch to oral
agents as soon as possible. Some ATB (e.g.,
vancomycin, aminoglycosides, amphotericin) -
poorly absorbed from GIT - adequate serum levels
cannot be obtained by oral administration.
Parenteral administration - if poorly absorbed
from GIT serious infections.
16
  • RATIONAL DOSING
  • Based on ATB pharmacodynamics (relationship of
    drug concentrations to antimicrobial effects) and
    pharmacokinetic properties (the absorption,
    distribution, and elimination).
  • 3 important pharmacodynamic properties have a
    significant influence on the frequency of dosing
  • concentration-dependent killing
  • time dependent killing
  • post-antibiotic effect

17
Concentration-dependent killing Some ATB
(aminoglycosides, fiuoroquinolones, carbapenems)
- a significant increase in bacterial killing as
the concentration of ATB increases from 4- to
64-fold the MIC of the drug ? administration by a
once-a-day bolus infusion achieves high peak
levels ? rapid killing of the infecting pathogen.
Concentration-independent or time-dependent
killing Other ATB (b-Iactams, glycopeptides,
macrolides, clindamycin, linezolid) - increasing
the concentration of ATB to higher multiples of
the MIC does not significantly increase the rate
of kill ? efficacy of ATB without dose-dependent
killing effect is best predicted by the
percentage of time that blood concentrations of
drug remain above the MIC. E.g., PNC and
cephalosporins, dosing schedules ensuring blood
levels greater than MIC for 60 70 of the time
- clinically effective ? severe infections -
better treatment by infusion than by intermittent
dosing.
18
Post-antibiotic effect (PAE) A persistent
suppression of microbial growth that occurs after
levels of antibiotic have fallen below the MIC.
PAE the length of time it takes (after the
transfer) for the culture to achieve log phase
growth. (To measure the PAE, a test culture is
first incubated in ATB-containing medium and then
transferred to ATB-free medium). PAE T C T
time required for the viable count in the test
(in vitro) culture to increase tenfold above the
count observed immediately before drug removal C
time required for the count in an untreated
culture to increase tenfold above the count
observed immediately after completion of the same
procedure used on the test culture
19
  • Antimicrobial drugs with a long PAE (several
    hours) ? often only one dose per day (e.g.,
    aminoglycosides and fluoroquinolones - long PAE,
    particularly against G- bacteria).
  • Proposed mechanisms of PAE
  • Slow recovery after reversible nonlethal damage
    to cell structures
  • Persistence of the drug at a binding site or
    within the periplasmic space
  • The need to synthesize new enzymes before growth
    can resume
  • In vivo PAEs usually much longer than in vitro
    PAEs due to postantibiotic leukocyte
    enhancement (PALE) and exposure of bacteria to
    subinhibitory ATB concentrations.

20
  • CHEMOTHERAPEUTIC SPECTRA
  • the species of microorganisms affected by that
    drug
  • - Narrow spectrum (acting only on a single or a
    limited group of microorganisms- e.g. isoniazid
    only against mycobacteria).
  • - Extended spectrum (ATB effective against G and
    also against a significant number of G- bacteria
    - e.g., ampicillin - acts against G and G-
    bacteria).
  • Broad spectrum (e.g. TTC and chloramphenicol) -
    affect a wide variety of microbial species.
  • Their administration can drastically alter the
    nature of the normal bacterial flora and
    precipitate a superinfection of an organism,
    e.g., candida.

21
  • COMBINATIONS OF ATB
  • Treatment with the single agent that is most
    specific for the organism ? it
  • ? the possibility of superinfection,
  • ? emergence of resistant organisms,
  • minimizes toxicity.
  • However, situations where combination of ATB is
    necessary (TBC).
  • A. Advantages of drug combinations
  • Certain combinations (e.g., b-Iactams and
    aminoglycosides) synergism rare example ?
    multiple drugs used in combination indicated only
    in special situations (e.g., infection is of
    unknown origin).
  • B. Disadvantages of drug combinations
  • A number ATB act only when organisms are
    multiplying ? co-use of bacteriostatic ATB 2nd
    bactericidal ATB ? the 1st drug interfere with
    the action of the 2nd drug (e.g. TTC X PNC or
    cephalosporins)

22
SYNERGISM ANTAGONISM When the inhibitory or
killing effects of two or more ATBs used together
are significantly greater than expected from
their effects when used individually - synergism.
Synergism - marked by a fourfold or greater
reduction in the MIC or MBC of each drug when
used in combination versus when used alone.
Antagonism - when the combined inhibitory or
killing effects of two or more ATBs are
significantly less than expected when the drugs
are used individually.
23
Three major mechanisms of antimicrobial
synergism
  • Blockade of sequential steps in a metabolic
    sequence Trimethoprim-sulfamethoxazole -
    blockade of 2 sequential steps in the folic acid
    pathway ? much more complete inhibition of
    growth.
  • Inhibition of enzymatic inactivation
    Enzymatic
    inactivation of b-lactam ATBs major mechanism
    of resistance. Inhibition of b-lactamase by
    b-lactamase inhibitors (e.g, sulbactam) ?
    synergism.
  • Enhancement of antimicrobial agent uptake
  • PNCs and other cell wall-active agents can
    ? uptake of aminoglycosides by a number of
    bacteria (incl. staphylococcí, enterococci,
    streptococci, P. aeruginosa /Enterococci
    resistant to aminoglycosides because of
    permeability barriers/).
  • Amphotericin B - enhances the uptake of
    flucytosine by fungi.

24
Synergistic Action E.g., in the treatment of
enterococcal endocarditis - bactericidal activity
is essential for the optimal management of
bacterial endocarditis. PNC or ampicillin in
combination with gentamicin or streptomycin is
superior to monotherapy with PNC or vancomycin.
When alone - PNCs and vancomycin are only
bacteriostatic against susceptible enterococci.
When combined with aminoglycoside - bactericidal
activity results. The addition of gentamicin or
STM to PNC - reduction in the duration of therapy
in viridans streptococcal endocarditis.
Combinations of ATBs - may be of benefit in G-
infections in febrile neutropenic cancer patients
and in systemic infections caused by Pseudomonas
aeruginosa. Other synergistic combinations more
effective than monotherapy Trimethoprim-sulfamet
hoxazole - treatment of bacterial infections and
Pneumocystis jiroveci (carinii) pneumonia.
b-Lactamase inhibitors and hydrolyzable
b-lactams against S. aureus and Bacteroides
fragilis.
25
Two major mechanisms of antimicrobial antagonism
  • Inhibition of -cidal activity by static agents
    Bacteriostatic agents
    (e.g., TTC and chloramphenicol) can antagonize
    action of bactericidal cell wall-active agents
    (because cell wall-active agents require that the
    bacteria be actively growing and dividing).
  • Induction of enzymatic inactivation
    Some G-
    bacilli (incl. enterobacter species, P.
    aeruginosa, Serratia marcescens, Citrobacter
    freundii) possess inducible b-lactamases.
    b-Lactam ATBs (e.g., imipenem, cefoxitin,
    ampicillin) are potent inducers of b-lactamase
    production. If an inducing agent is combined with
    an intrinsically active but hydrolyzable b-lactam
    (e.g., piperacillin) antagonism may result.

26
Antagonistic Action Few clinically relevant
examples. A study of patients with pneumococcal
meningitis - patients who were treated with the
combination of PNC and chlortetracycline had a
mortality rate of 79 compared with a mortality
rate of 21 in patients who received penicillin
monotherapy (see the 1st mechanism above). The
use of an antagonistic antimicrobial combination
does not preclude other potential beneficial
interactions. E.g., rifampin may antagonize
action of anti-staphylococcal PNCs or vancomycin
against staphylococci. However, the
aforementioned antimicrobials may prevent the
emergence of resistance to rifampin.
27
DRUG RESISTANCE Bacteria are said to be
resistant to ATB if their growth is not halted by
the maximal level of ATB that can be tolerated by
the host. Some organisms - inherently resistant
to ATB (e.g., G- resistant to vancomycin).
However, microbial species (normally responsive
to ATB) may develop more virulent, resistant
strains through spontaneous mutation or acquired
resistance and selection.
28
A. Genetic alterations leading to drug resistance
Resistance develops due to the ability of DNA to
undergo spontaneous mutation or to move from one
organism to another. 1. Spontaneous mutations of
DNA Chromosomal alteration (insertion,
deletion, substitution of nucleotides) in the
genome ? mutation may - persist, - be corrected,
- be lethal to the cell If cell survives - it
can replicate and transmit its mutated properties
to progeny cells. Mutations producing resistant
strains ? organisms that may proliferate under
certain selective pressures (e.g.,
rifampin-resistant Mycobact. tuberculosis when
rifampin used as a single ATB). 2. DNA transfer
of drug resistance Of particular clinical
concern - due to DNA transfer from one bacterium
to another. Resistance usually encoded in
extrachromosomal R factors (resistance plasmids).
Plasmids may enter cells by transduction (phage
mediated), transformation, or bacterial
conjugation.
29
  • B. Altered expression of proteins in
    drug-resistant organisms
  • Variety of mechanisms
  • lack of or an alteration in an ATB target site,

    - lowered penetrability of ATB due to decreased
    permeability, - increased
    efflux of ATB,

    - presence of ATB-inactivating enzymes.
  • 1. Modification of target sites through mutation
    - resistance to one or more related ATB (e.g., S.
    Pneumoniae resistance to b-lactam ATB involves
    alterations in one or more of the major bacterial
    PNC-binding proteins ? decreased binding of ATB
    to its target).

30
2. Decreased accumulation Decreased uptake or
increased efflux of ATB - it is unable to access
to the site of action in sufficient
concentrations. - G- organisms can limit
penetration of certain ATB (b-Iactams, TTC,
chloramphenicol) because of an alteration in the
number and structure of porins (channels) in the
outer membrane.
- Presence of an efflux pump can limit
levels of ATB in organism. 3. Enzymic
inactivation The ability to destroy or
inactivate ATB. 1) b-lactamases
("penicillinases") hydrolytically inactivate
b-Iactam ring of penicillins, cephalosporins, and
related ATB
2) acetyltransferases - transfer an
acetyl group to the ATB (inactivation of
chloramphenicol, aminoglycosides)

3) esterases that hydrolyze the lactone ring of
macrolides. Multiple drug resistance by this
mechanism - clinically significant problem (e.g.,
methicillin-resistant S. aureus (MRSA) - also
resistant to all ATB except vancomycin and
possibly ciprofloxacin, rifampin and
imipenem/cilastatin).
31
PROPHYLACTIC ANTIBIOTICS Certain clinical
situations require the use of ATB for the
prevention rather than the treatment of
infections. But, the indiscriminate use of ATB ?
bacterial resistance and superinfection,
prophylactic use is restricted to clinical
situations where benefits outweigh the potential
risks. The duration of prophylaxis - by the
duration of the risk of infection.
32
Some clinical situations in which prophylactic
ATB are indicated
  • Prevention of streptoccocal infections in
    patients with history of rheumatic heart disease.
    Patients may require years of treatment.

2. Pretreatment of patients undergoing dental
extractions who have implated prosthetic devices
(e.g., artificial heart valves) to prevent
seeding of the prosthesis.
3. Prevention of tuberculosis or meningitis
among individuals who are in close contact with
infected patients.
4. Treatment prior to certain surgical
procedures (e.g., bowel surgery, joint
replacement, some gynecologic) to prevent
infection.
5. Treatment of the mother with zidovudine to
protect the fetus in the case of an HIV-infected,
pregnant woman.
33
COMPLICATIONS OF ATB THERAPY A. Hypersensitivity
Hypersensitivity to ATB or their metabolic
products - frequent. (e.g., PNC -
serious hypersensitivity). B. Direct toxicity
High serum levels of some ATB - toxicity by
directly affecting cellular processes in the host
(e.g., aminoglycosides - ototoxicity by
interfering with membrane function in the hair
cells of the organ of Corti). C. Superinfections
Particularly with broad-spectrum ATB or
combinations of ATB - alterations of the normal
microbial flora of the upper respiratory,
intestinal, and genitourinary tracts (?
overgrowth of opportunistic organisms - fungi or
resistant bacteria).
34
SITES OF ANTIMICROBIAL ACTIONS Classification of
ATB in a number of ways, by 1) chemical
structure (e.g., b-Iactams or aminoglycosides),
2) mechanism of action (e.g., cell wall
synthesis inhibitors), 3) activity against types
of organisms (e.g., bacteria, fungi, or viruses).
35
INHIBITORS OF CELL WALL SYNTHESIS Interfere
with synthesis of the bacterial cell wall - a
structure that mammalian cells do not possess.
The cell wall polymer called peptidoglycan
(consists of glycan units joined to each other by
peptide cross-links). To be maximally effective,
these agents require actively proliferating
microorganisms. Little or no effect on bacteria
that are not growing !! The most important
beta-lactam ATB (contain beta-Iactam ring that is
essential to their activity) and vancomycin
36
Summary of antimicrobial agents affecting cell
wall synthesis. Cilastatin is not ATB but a
peptidase inhibitor that protects imipenem from
degradation.
Agents affecting the cell wall
b-lactamase inhibitors
Clavulanic acid Sulbactam Tazobactam
Other antibiotics
b-lactam antibiotics
Bacitracin Vancomycin Daptomycin
Penicillins
Carbapenems
Monobactams
Cephalosporins
Ertapenem Imipenem/cilastatin Meropenem
Amoxicillin Ampicillin Dicloxacillin Indanyl
carbenicillin Methicillin Nafcillin Oxacillin Peni
cillin G Penicillin V Piperacillin Ticarcillin
Aztreonam
2nd generation
1st generation
4th generation
3rd generation
Cefadroxil Cefazolin Cephalexin
Cefaclor Cefprozil Cefuroxime Cefoxitin
Cefepime
Cefdinir Cefixime Cefotaxime Ceftazidime Ceftibute
n Ceftizoxime Ceftriaxone
(according to Lippincotts Pharmacology, 2009)
37
PENICILLINS pen i SILL ins 1928, A.
Fleming The most widely effective ATBs and also
the least toxic drugs known - increased
resistance limited their use. They differ in the
substituent attached to the 6-aminopenicillanic
acid residue. The nature of side chain affects
the antimicrobial spectrum, stability to stomach
acid, and susceptibility to bacterial degradative
enzymes (b-Iactamases). A. Mechanism of action
Bactericidal - interfere with the last step of
bacterial cell wall synthesis (transpeptidation
or cross-linkage) ? osmotically less stable
membrane ? cell lysis can occur (through osmotic
pressure or through the activation of
autolysins). PNCs are only effective against
rapidly growing organisms that synthesize a
peptidoglycan cell wall ? i.e., inactive against
organisms devoid of this structure (e.g.,
mycobacteria, protozoa, fungi, and viruses).
38
1. Penicillin-binding proteins PNCs inactivate
proteins on the bacterial cell membrane. These
PNC-binding proteins (PBPs) bacterial enzymes
involved in the synthesis of the cell wall.
Exposure to PNC - not only prevent cell wall
synthesis, but also lead to morphologic changes
or lysis of susceptible bacteria. Alterations in
some of these target molecules - resistance to
PNCs. Methicillin-resistant S. aureus (MRSA)
apparently arose because of such an alteration.
2. Inhibition of transpeptidase Some PBPs
catalyze formation of cross-linkages between
peptidoglycan chains. PNCs inhibit this
transpeptidase - hindering the formation of
cross-links essential for cell wall integrity ?
the "Park nucleotide" ( Park peptide -
UDP-acetylmuramyl-L-Ala-D-Gln-L-Lys-D-Ala-D-Ala,
accumulates).
39
3. Production of autolysins Particularly G
cocci produce degradative enzymes (autolysins -
that participate in the remodeling of the
bacterial cell wall). In the presence of PNC,
the degradative action of the autolysins ?
absence of cell wall synthesis. The exact
autolytic mechanism is unknown it may be due to
a disinhibition of the autolysins.
Antibacterial effect of a PNC the result of
both inhibition of cell wall synthesis and
destruction of cell wall by autolysins.
40
Antibacterial spectrum Determined partly by the
ability of PNC to cross the bacterial
peptidoglycan cell wall and to reach PNC-binding
proteins. Other factors size, charge,
hydrophobicity G - cell wall that are easily
traversed by PNC ? susceptible. G- - outer lipid
membrane surrounding the cell wall a barrier to
the water-soluble PNCs (they cannot reach the
site of action). However, G- bacteria have
proteins inserted in the lipopolysaccharide layer
acting as water-filled channels (porins) - permit
transmembrane entry. P. aeruginosa lacks porins
? these organisms are resistant to many
antimicrobial agents. ? PNCs mostly little
use in the treatment of intracellular pathogens.
41
1. (NATURAL) PENICILLINS a.
PENICILLIN G (benzylpenicillin) - therapy for
infections caused by a number of G and G- cocci,
G bacilli, and spirochetes. Susceptible to
inactivation by beta-lactamases. b. PENICILLIN V
(phenoxymethylPNC)- a spectrum similar to PNC G,
but it is not used for treatment of septicemia
(because of its higher minimum bactericidal
concentration - MLC). Treatment of oral
infections, where it is effective against some
anaerobic organisms. Penicillin V is more
acid-stable than penicillin G. c. PROCAINE
PENICILLIN G prolonged action, i.m. d. BENZATHINE
PENICILLIN Very long action depo form, i.m.
42
2. ANTISTAPHYLOCOCCAL
PENICILLINS METHICILLIN NAFCILLIN OXACILLIN
CLOXACILLIN DICLOXACILLIN penicillinase-resis
tant PNCs Use infections caused by
penicillinase-producing staphylococci.
Methicillin-resistant strains (MRS) are usually
susceptible to vancomycin, rarely to
ciprofloxacin, rifampin.
43
3. EXTENDED SPECTRUM PNC AMPICILLIN
and AMOXICILLIN Destroyed by ?-lactamases
!!! Spectrum similar to PNC G, but more
effective against G- bacilli - extended-spectrum
PNCs. Ampicillin - drug of choice for the G
bacillus Listeria monocytogenes. Widely used in
the treatment of respiratory infections. Amoxicill
in - employed prophylactically by dentists for
patients with abnormal heart valves who are to
undergo extensive oral surgery. Resistance is
now a problem (inactivation by plasmid-mediated
penicillinase - E. coli and H. influenzae -
frequently resistant). Formulation with a
beta-lactamase inhibitor (e.g. clavulanic acid,
sulbactam) can protect the PNC from enzymatic
action.
44
4. ANTIPSEUDOMONAL PENICILLINS
CARBENICILLIN TICARCILLIN Antipseudomonal
penicillins. S. aureus is resistant. Broad
spectrum susceptible to breakdown by
beta-lactamase. Effective against many G-
bacilli, ineffective against Klebsiella (it
constitutes penicillinase). Formulation of
ticarcillin with clavulanic acid or sulbactam ?
extension of antimicrobial spectrum (i.e. it
includes penicillinase-producing organism).
45
5. ACYLUREIDO PENICILLINS PIPERACILLIN - the
most potent. Broad spectrum susceptible to
breakdown by beta-lactamase also effective
against P. aeruginosa and large number of G-
organisms. Formulation with tazobactam ?
extension of spectrum (i.e. it includes
penicillinase-producing organism). MEZLOCILLIN al
so effective against P. aeruginosa and large
number of G- organisms. It is susceptible to
beta-lactamase. AZLOCILLIN 6. REVERSED SPECTRUM
PNCs MECILLINAM More potent against G- enteric
bacteria, hydrolyzed by ?-lactamases.
Pivmecillinam is a pro-drug, hydrolyzed to
mecillinam.
46
Penicillins and aminoglycosides Antibacterial
effects of all b-Iactam ATB synergistic with
aminoglycosides. Cell wall synthesis inhibitors
alter the permeability of bacterial cells ? they
can facilitate the entry of other ATBs (e.g.,
aminoglycosides). ? enhanced antimicrobial
activity. These drug types should never be
placed in the same infusion fluid (on prolonged
contact, the positively charged aminoglycosides
form an inactive complex with the negatively
charged PNCs).
47
  • C. Resistance
  • Natural resistance - organisms
  • - lack the peptidoglycan cell wall (e.g.
    mycoplasma)
  • - cell wall impermeable to the drug
  • Acquired resistance to PNCs by plasmid transfer
    clinical problem
  • (multiplication of these organisms ? ?
    dissemination of resistance
  • genes).
  • ?-lactamase activity hydrolysis the cyclic
    amide bond of the beta-lactam
  • ring - loss of bactericidal activity. Enzymes
    are constitutive or
  • (more commonly) acquired by the transfer of
    plasmids.
  • Some ?-lactam ATBs are poor substrates for
    ?-lactamases ?
  • resist cleavage ? activity against ?-lactamase
    producing organisms.

48
  • - Decreased permeability of PNCs through the
    outer cell membrane -
  • prevents reaching the penicillin-binding protein.
  • - Efflux pump ? ? amount of intracellular drug.
  • Altered PNC binding proteins Modified PBPs -
    lower affinity for ?-lactam ATB ? greater
    concentrations of ATB necessary.
  • This may explain MRSA (methicillin-resistant
    staphylococci).

49
  • Pharmacokinetics
  • Administration determined by the stability of
    ATB to gastric acid and by the severity of the
    infection.
  • Routes of administration
  • Ticarcillin, carbenicillin, piperacillin,
    combinations of ampicillin with sulbactam,
    ticarcillin with clavulanic acid, and
    piperacillin with tazobactam must be administered
    i.v. or i.m.
  • PNC V, amoxicillin, amoxicillin clavulanic
    acid, indanyl carbenicillin (for treatment of
    UTIs) - only as oral preparations.
  • Others are effective by the oral, i.v., or
    i.m. routes.
  • b. Depot forms Procaine PNC G and benzathine PNC
    G - administered i.m. Slowly absorbed, persist
    at low levels over a long time period.

50
2. Absorption Most PNCs - incompletely absorbed
after oral administration ? reach intestine in
sufficient amounts to affect the intestinal
flora. However, amoxicillin - almost completely
absorbed ? not appropriate therapy
salmonella-derived enteritis (therapeutically
effective levels do not reach the organisms in
the intestinal crypts). Absorption of PNC G and
all penicillinase-resistant PNCs - impeded by
food in the stomach ? to be administered 30-60
min before meals or 2-3 hours postprandially.
Other PNCs are less affected by food.
51
3. Distribution All PNCs cross the placental
barrier - none showed to be teratogenic.
Penetration into certain sites (e.g. bone or
CSF) is insufficient for therapy, unless these
sites are inflamed. During the acute phase
(first day) - inflamed meninges more permeable to
PNC ? ? ratio in the amount of drug in CNS
compared to the amount in the serum. As
inflammation subsides - permeability barriers are
reestablished. Levels in the prostate are
insufficient to be effective against
infections. 4. Metabolism Host metabolism of
?-Iactams - usually insignificant (some
metabolism of PNC G in patients with impaired
renal function).
52
5. Excretion The primary route renal tubular
secretion and glomerular filtration. Patients
with impaired renal function - adjust dosage
! T1/2 of PNC G can ? (normal of 0.5-1.0 h) to
10 hours in renal failure. Probenecid inhibits
the secretion of PNCs !! Nafcillin - eliminated
primarily through the biliary route. Also
preferential route for the acylureido PNC in
renal failure. PNCs - also excreted into
breast milk and into saliva.
53
  • E. Adverse reactions
  • PNC - among the safest drug ? blood levels are
    not monitored, although adverse reactions do
    occur.
  • Hypersensitivity The most important. The major
    cause is metabolite - penicilloic acid (it reacts
    with proteins and serves as a hapten).
  • Cca 5 of patients have some kind of reaction
    (from urticaria to angioedema and anaphylaxis).
  • Cross-allergic reactions can occur among ?-lactam
    ATB !
  • (Rashes can develop with all PNCs, maculopapular
    rash in 100 among patients with mononucleosis
    who are treated with ampicillin).
  • Diarrhea
  • Disruption of the normal balance of GIT
    microorganism - common. Especially in agents that
    are incompletely absorbed or with extended
    spectrum.
  • Also pseudomembranous colitis may occur.

54
  • Nephritis Acute interstitial nephritis in high
    doses of methicillin (no
  • longer available)
  • Neurotoxicity PNCs irritate neuronal tissue ?
    seizures if injected
  • intrathecally or in very high blood levels.
    Epileptics - especially at risk.
  • - Platelet dysfunction decreased coagulation
    (esp. with
  • antipseudomonal PNCs - carbenicillin and
    ticarcillin).
  • Concern when patient is predisposed to hemorrhage
    or receiving
  • anticoagulants.
  • Cation toxicity Generally administered as the
    Na or K salt. Toxicity
  • by large quantities of ions. Na excess ?
    hypokalemic acidosis
  • (use the most potent ATB ? it permits lower doses
    of drug and
  • accompanying cations).
  • - Hoigné syndrom (suspension of PNC is by mistake
    injected
  • i.v. embolisation of pulmonary veins
    tachypnea, anxiety, dyspnea)
  • - Nikolaus syndrom (suspension of PNC by mistake
    i.a.
  • embolisation in arteries even amputation
    necessary)

55
Clinical uses of penicillins
  • Given p.o. - in more severe cases i.v. often in
    combination with other ATB.
  • Uses include
  • ? bacterial meningitis (e.g. by N.
    meningitidis, S. pneumoniae) benzylPNC,
    high doses i.v.
  • ? bone and joint infections (e.g. S.
    aureus) f\ucloxacillin
  • ? skin and soft tissue infections (e.g.
    Streptococcus pyogenes or S.
  • aureus) benzylPNC, flucloxacillin
    animal bites co-amoxiclav
  • ? pharyngitis (from S. pyogenes)
    phenoxylmethylPNC
  • ? otitis media (S. pyogenes, H.
    influenzae) amoxicillin
  • ? bronchitis (mixed infections common)
    amoxicillin
  • ? pneumonia amoxicillin
  • ? urinary tract infections (e.g. with E.
    coIl) amoxicillin
  • ? gonorrhea amoxicillin ( probenecid)
  • ? syphilis procaine benzylPNC
  • ? endocarditis (e.g. with Streptococcus
    viridans or Enterococcus faecalis)
  • ? serious infections with Pseudomonas
    aeruginosa piperacillin.
  • This list is not exhaustive !!!

56
CEPHALOSPORINS b-Iactam ATB closely
structurally and functionally related to PNC.
Mostly produced semisynthetically. The same
mode of action as PNCs, the same resistance
mechanisms. However, they are more resistant
than the PNCs to b-Iactamases. A. Antibacterial
spectrum Classified as first, second, third, or
fourth generation, based on their bacterial
susceptibility patterns and resistance to
b-Iactamases. Ineffective against MRSA, L.
monocytogenes, Clostridium difficile, and
enterococci.
57
1. 1st generation Act as PNC G - resistant to
the Staphylo. penicillinase also activity
against Proteus mirabilis, E. coli, and
Klebsiella Pneumoniae (the acronym PEcK). E.g.,
cephalexin, cephalotin, cefazolin 2. 2nd
generation Greater activity against 3
additional G- organisms H. influenzae,
Enterobacter aerogenes, some Neisseria species
(HENPEcK) E.g., cefuroxime, cefamandol,
cefaclor Activity against G organisms is weaker.
The exceptions - related cephamycin - cefoxitin
sef OX i tin - little activity against H.
influenzae. Effective against Bacteroides
fragilis cefoxitin is the most potent.
58
3. 3rd generation Inferior to 1st-gen. against
G cocci - ? activity against G- bacilli and most
other enteric organisms and Serratia marcescens.
Ceftriaxone or cefotaxime - agents of choice in
the treatment of meningitis. Ceftazidime -
against P. aeruginosa. 4. 4th generation
Cefepime - administered parenterally,
Cefpirome Wide antibacterial spectrum - against
streptococci and staphylococci (but only those
that are methicillin-susceptible). Also
effective against aerobic G- organisms
(enterobacter, E. coli,
K. pneumoniae, P. mirabilis, and P. aeruginosa).
59
  • B. Resistance
  • Mechanisms - the same as in PNCs.
  • Though not susceptible to hydrolysis by the
    staphylococcal penicillinase,
  • they may be susceptible to extended spectrum
    b-Iactamases.
  • C. Pharmacokinetics
  • Administration
  • Some orally.
  • Most of cephalosporins must be admin. IV or IM
    (poor oral absorption).

60
2. Distribution All very well into body fluids.
All cross the placenta. However, adequate
therapeutic levels in the CSF (regardless of
inflammation) - only the 3rd-generation
(ceftriaxone or cefotaxime) - effective in the
treatment of neonatal and childhood meningitis
caused by H. influenzae. Cefazolin - prophylaxis
prior to surgery because of its half-life and
activity against penicillinase-producing S.
aureus. Its ability to penetrate bone is
especially useful in orthopedic surgery. 3.
Fate Biotransformation is not clinically
important. Elimination renal tubular secretion
and/or glomerular filtration ? adjust doses in
severe renal failure !!! Ceftriaxone and
Cefoperazone - excreted in bile into the feces ?
employed in patients with renal insufficiency.
61
D. Adverse effects Number of adverse affects
(frequently associated with particular drug). 1.
Allergy Patients with an anaphylactic response
to PNCs should not receive cephalosporins. To be
avoided or used with caution in individuals
allergic to PNCs (cca 5-15 show
cross-sensitivity). Incidence of allergic
reactions to cephalosporins is 1-2 in patients
without a history of allergy to PNCs. 2. A
disulfiram-like effect If cefamandole,
cefotetan, or cefoperazone is ingested with
alcohol or alcohol-containing medications. They
block the 2nd step in alcohol oxidation ?
accumulation of acetaldehyde. (Toxicity is due to
the presence of the methylthiotetrazole (MTT)
group). 3. Bleeding Associated with agents that
contain the MTT group - because of anti-vitamin K
effects ? the vitamin corrects the problem. 4.
Nephrotoxicity, diarrhea.
62
Clinical uses of the cephalosphorins
  • Septicaemia (e.g. cefuroxime, cefotaxime)
  • Pneumonia caused by susceptible organisms
  • Meningitis (e.g. cefriaxone, cefotaxime)
  • Biliary tract infection
  • Urinary tract infection (especially in pregnancy,
    or in patients unresponsive to other drugs)
  • Sinusitis (e.g. cefadroxil).

63
  • OTHER ?-LACTAM ATB
  • CARBAPENEMS

    IMIPENEM, MEROPENEM,
    ERTAPENEM
  • Synthetic ATB - differ from PNCs in the S atom of
    the thiazolidine ring.
  • Imipenem - compounded with cilastatin to protect
    it from metabolism by
  • renal dehydropeptidase.
  • Antibacterial spectrum
  • The broadest spectrum ?-lactams. Active against
    pencillinase
  • producing G and G- , anaerobes, and P.
    aeruginosa.
  • But, resistant strains of P. aeruginosa reported
    (also to Ertapenem).
  • Imipenem resists hydrolysis by most ?-lactamases,
    but not the metallo
  • beta lactamases.
  • Meropenem - antibacterial activity similar to
    imipenem.
  • A role in empiric therapy.

64
2. Pharmacology Imipenem and meropenem i.v.,
penetrate well into CNS. Ertapenem i.v. or i.m.
Imipenem - excreted by glomerular filtration,
cleavage by dehydropeptidase in the brush border
of the proximal renal tubule to form an inactive
metabolite that is potentially nephrotoxic. Compou
nding the imipenem with cilastatin
(dehydropeptidase inhibitor) protects the parent
drug from cleavage ? prevents the formation of a
toxic metabolite. Note The dose must me
adjusted in patients with renal
insufficiency. MEROPENEM, ERTAPENEM not cleaved
in the kidney !! 3. Adverse effects Nausea,
vomiting, diarrhea. Eosinophilia and neutropenia
(less common). High levels may provoke seizures
(meropenem less likely).
65
MONOBACTAMS AZTREONAM Unique because the
?-lactam rings is not fused to another ring.
Narrow antimicrobial spectrum ? it precludes
its use alone in empiric therapy. Aztreonam is
resistant to the action of ?-lactamases. Antibact
erial spectrum primarily against the
enterobactericeae. Unique among the
beta-lactams because of its effectiveness
against P. aeruginosa and other aerobic G-
bacteria, and because of its lack of activity
against G organisms or anaerobes.
66
Pharmacology IV or IM , excreted in the urine
can accumulate in patients with renal
failure. Adverse effects relatively nontoxic,
but it may cause phlebitis, skin rash, and
occasionally, abnormal liver function tests. Low
immunogenic potential, little cross-reactivity
with antibodies induced by other ?-lactam a
safe alternative for treating patients allergic
to PNC.
67
BETA-LACTAMASE INHIBITORS Hydrolysis of ?-lactam
ring (by enzymatic cleavage with ?-lactamase or
by acid) destroys antimicrobial activity.
Beta-lactamase inhibitors CLAVULANIC ACID,
SULBACTAM, TAZOBACTAM - contain ? lactam ring,
but they do not have significant antibacterial
activity. They bind to and inactive ?-lactamases
protection of the ATBs that are normally
substrates for these enzymes. They are formulated
with PNC derivatives to protect them from
enzymatic inactivation AUGMENTIN (amoxycillin and
clavulanic acid) TIMENTIN (ticarcillin and
clavulanic acid) Piperacillin
tazobactam Ampicillin sulbactam Not all
?-Iactamases are inhibited. E.g., tazobactam
(with piperacillin) does not affect P. aeruginosa
?-Iactamase ? this organism is refractory to
piperacillin.
68
  • OTHER AGENTS AFFECTING THE CELL WALL
  • VANCOMYCIN - glycopeptide
  • TEICOPLANIN (similar, longer acting) -
    glycopeptide
  • DALBAVANCIN (extremely long T0.5) - glycopeptide
  • The emergence of staphylococci resistant to most
    ATBs except
  • vancomycin ? reintroduction of this agent - as
    the 1st line against
  • staphylococci and streptococci resistant to
    ?-lactam ATBs.
  • 1. Action Inhibition of the synthesis of the
    cell wall phospholipids and
  • peptidoglycan polymers ? prevents the
    transglycosylation step in
  • peptidoglycan polymerization ? weakening the cell
    wall, damaging the
  • underlying cell membrane.
  • 2. Spectrum Bactericidal.
  • Use infections caused by MRS (methicillin-resist
    ant Staphylococci), and
  • pseudomembranous colitis caused by Clostridium
    difficile or staphylococci.

69
Vancomycin - effective primarily against G
organisms . Lifesaving in the treatment of MRSA
epidermidis infections and enterococcal
infections. ? in resistant strains - ? in
vancomycin-resistant bacteria (e.g., Enterococcus
faecium, Enterococcus faecalis) ? restric use of
vancomycin for serious infections caused by
b-Iactam-resistant, G microorganisms, or for
patients with G infections with a serious
allergy to the b-Iactams. Oral vancomycin -
limited to treatment for potentially
life-threatening ATB-associated colitis due to C.
difficile or staphylococci. Used in individuals
with prosthetic heart valves and in patients
undergoing implantation with prosthetic devices.
Hospitals a problem with MRSA or MRSE. New
protein synthesis inhibitors - quinopristin/dalfop
ristin and linezolid - are available for the
treatment of vancomycin-resistant organisms.
Vancomycin acts synergistically with
aminoglycosides - combination can be used in
enterococcal endocarditis.
70
3. Resistance due to plasmid-mediated changes in
permeability to the drug (probably also by ?
binding of vancomycin to molecules). 4.
Administration Slow i.v. infusion - for
systemic infections or prophylaxis. Not absorbed
after oral admin. ? used p.o. for the treatment
of ATB-induced colitis due to C. difficile when
metronidazole was ineffective. Inflammation
allows penetration into the meninges - often
necessary to combine with e.g., ceftriaxone.
5. Metabolism minimal (90 - 100 excreted by
glomerular filtration) adjust dosage in renal
failure! Half-life 6-10 hours over 200 hours
in end- stage renal disease. 6. Adverse effects
Serious problem (fever, chills, and/or phlebitis
at the infusion site). Flushing ("red man
syndrome"). Shock as a result of rapid
administration. Rashes. Ototoxicity and
nephrotoxicity - more common when administered
with other drug (e.g., aminoglycoside) that can
also produce these effects.
71
DALBAVANCIN A semisynthetic lipoglycopeptide
derived from teicoplanin. The same mechanism of
action as vancomycin and teicoplanin but improved
activity against many G bacteria incl.
methicillin-resistant and vancomycin-intermediate
S aureus. It is not active against most strains
of vancomycin-resistant enterococci. Extremely
long T0.5 (6-11 days) - it allows once-weekly
i.v. administration. In clinical trials.
72
  • TELAVANCIN - glycopeptide
  • A semisynthetic lipoglycopeptide derived from
    vancomycin.
  • Active versus G bacteria, incl. strains with
    reduced susceptibility to vancomycin.
  • T0.5 approx. 8 hrs ? once-daily i.v. dosing
  • Two mechanisms
  • like vancomycin, it inhibits cell wall synthesis
    by binding to the D-Ala-D-Ala terminus of
    peptidoglycan in the growing cell wall.
  • In addition, it targets the bacterial cell
    membrane and causes disruption of membrane
    potential and increases membrane permeability.
  • The drug is awaiting approval for use in the U.S.

73
B. BACITRACIN mixture of polypeptides that
inhibits bacterial cell wall synthesis. Active
against a wide variety of G organisms. Use
restricted to topical application because of its
nephrotoxicity. C. POMYMYXIN B and
COLISTIN (polymyxin E) Simple basic peptides,
interaction with cell membrane - cationic
detergent properties, bactericidal on G
(pseudomonas, coliform) not absorbed from GIT
resistance rare G, proteus, and neisseria are
resistant. Adverse effect neuro- and
nephrotoxicity Use Topically ! Orally - gut
sterilisation, topical treatment (eye, ear, skin)
- ointments with polymyxin B, in mixtures with
bacitracin or neomycin (or both) for
superficial skin lesions Very rarely used
except topically (colistin for salvage parenteral
therapy of infections caused by strains of
Acinetobacter baumannii and P. aeruginosa that
are resistant to all other agent)
74
D. FOSFOMYCIN Inhibition of wall synthesis
against G and G- Synergism with piperacilin,
aminoglycosieds, 3rd generation of
cephalosporines
75
E. DAPTOMYCIN Cyclic lipopeptide fermentation
product of Streptomyces roseosporus. Activity
similar to vancomycin treatment of resistant G
incl. MRSA and VRE (vancomycin-resistant
enterococci). Bactericidal concentration-dependen
t killing admin. i.v. via infusion Mechanism
probably depolarisation of cell membrane ? K
efflux and death inhibition of DNA, RNA, protein
synthesis. Use Complicated skin infection,
bacteriemia by S. aureus not for pneumonia
(inactivated by pulmonary surfactans). 90-95
bound to plasma protein not metabolized cleared
renally (adjust dosage in renal impairment!).
Adverse effects myopathy (discontinue
statins), constipation, nausea, headache,
insomnia, ? hepatic transmaninases
76
AGENTS WITH OTHER MECHANISMS USED
TOPICALLY MUPIROCIN (pseudornonic acid) -
produced by Pseudomonas fluorescens. Rapidly
inactivated after absorption systemic levels are
undetectable. Active against G cocci, incl.
methicillin-resistant S. aureus. M. inhibits
staphylococcal isoleucyl tRNA synthetase.
Low-Ievel resistance due to point mutation in
the gene of the enzyme observed after prolonged
use. However, local concentrations with topical
application are high and resistance appears not
to result in clinical failure. High-Ievel
resistance - due to the presence of a second
isoleucyl tRNA synthetase gene is plasmid-encoded
? complete loss of activity. Hospital strains
with high-Ievel resistance. More than 95 of
staphylococcal isolates are still susceptible.
I ointment for topical treatment of minor skin
infections (e.g., impetigo). Application over
large infected areas (decubitus ulcers, open
surgical wounds) - factor leading to
mupirocin-resistant strains - not recommended.
77
Protein Synthesis lnhibitors A number of ATBs -
effects by targeting the bacterial ribosome,
which has components that differ structurally
from those of the mammalian cytoplasmic ribosome.
In general, the bacterial ribosome is smaller
(70S) than the mammalian ribosome (80S), and is
composed of 50S and 30S subunits (as compared to
60S and 40S subunits). The mammalian
mitochondrial ribosome, however, more closely
resembles the bacterial ribosome ? high levels of
drugs (e.g., chloramphenicol, tetracyclines) may
cause toxic effects as a result of interaction
with the mitochondrial ribosomes.
78
Summary of protein synthesis inhibitors
PROTEIN SYNTHESIS INHIBITORS
Tetracyclines
Demeclocycline Doxycycline Minocycline Tetracyclin
e
Glycylcyclines
Tigecycline
Aminoglycosides
Amikacin Gentamicin Neomycin Streptomycin Tobramyc
in
Macrolides/Ketolides
Azithromycin Clarithromycin Erythromycin Telithrom
ycin
Chloramphenicol
Clindamycin
Quinupristin/Dalfopristin
(according to Lippincotts Pharmacology, 2009)
Linezolid
79
TETRACYCLINES Closely related compounds (4 fused
rings - substitutions on the rings - responsible
for a variation in the drugs' individual
pharmacokinetics ? small differences in their
clinical efficacy). CHLORTETRACYCLINE,
OXYTETRACYCLINE, TETRACYCLINE, DEMECLOCYCLINE,
METHACYCLINE, DOXYCYCLINE, MINOCYCLINE A.
Mechanism of action Entry into susceptible
organisms - by passive diffusion and by an
energy-dependent transport protein mechanism (in
the bacterial inner cytoplasmic membrane).
Nonresistant strains concentrate the TTCs
intracellularly. TTC bind reversibly to 30S
subunit of the bacterial ribosome ? blocking
access of the amino acyl-tRNA to the
mRNA-ribosome complex at the acceptor site ?
bacterial protein synthesis is inhibited.
80
B. Antibacterial spectrum Broad spectrum ATB
also effective against organisms other than
bacteria. The drugs of choice for rickettsial,
mycoplasma and chlamydial infections (also
Borrelia, cholera). Bacteriostatic. C.
Resistance Widespread resistance limits their
clinical uses. (inability of the organism to
accumulate the drug). Any organism resistant to
one tetracycline is resistant to all. The
majority of penicillinase-producing staphylococci
- now insensitive to TTC
81
D. Pharmacology 1. Absorption adequately but
incompletely after oral ingestion. Dairy foods
in the diet - ? absorption (formation of
nonabsorbable chelates of the TTC with calcium
ions). Nonabsorbable chelates are also formed
with other divalent and trivalent cations (e.g.
in Mg and Al antacids, and in Fe
preparations). Doxycycline and minocycline
completely absorbed. Note It may be a problem
if the patient self-treats the epigastric upsets
caused by TTC ingestion with antacids.
82
2. Distribution Concentration in the liver,
kidney, spleen, and skin and bind to tissues
undergoing calcification (e.g.,teeth, bones), or
to tumors with high Ca content e.g. gastric
carcinoma). Penetration into body fluids is
adequate. Though all enter the CSF, levels are
insufficient for therapeutic efficacy, except for
MINOCYCLINE. It enters the brain in the absence
of inflammation and also appears in tears and
saliva effective in eradicating the
meningococcal carrier state. Not effective for
CNS infections. All TTCs cross the placental
barrier and concentrate in fetal bones and
dentition.
83
3. Fate All concentrate in the liver, partially
metabolized, conjugated to soluble glucuronides.
Drug and/or metabolites - secreted into the
bile, most TTCs reabsorbed in the intestine and
then enter the urine by glomerular filtration.
Doxycycline - can be used for infections in
renally compromised patients - preferentially
excreted via the bile into the feces!!!
Obstruction of the bile duct, hepatic or renal
dysfunction can increase T0,5 of TTC. TTCs also
excreted in breast milk.
84
E. Adverse effect - Gastric discomfort
Epigastric distress - common (from irritation of
the gastric mucosa) - can be controlled if taken
with foods other than dairy products. - Effects
on calcified tissues Deposition in the bone and
primary dentition during calcification in
growing children ? discoloration and hypoplasia
of the teeth and a temporary stunting of
growth. Use in pregnancy and in children younger
than 8 years (or before the second dentition)
should be avoided !!! - Fatal hepatotoxicity
described in pregnant women after high doses of
TTCs (especially if they were experiencing
pyelonephritis).
85
  • - Phototoxicity e.g., severe sunburn after
    exposition to sun or ultraviolet rays. This
    toxicity - most frequently with doxycycline and
    demeclocycline (dem e kloe SYE kleen).
  • - Vestibular problems (e.g., dizziness, nausea,
    vomiting) - minocycline (concentrates in the
    endolymph of the ear and affects function). Also
    doxycycline.
  • - Superinfections E.g., with candida (e.g. in
    the vagina) or with resistant staphylococci in
    the intestine. Pseudomembranous colitis due to an
    overgrowth of Clostridium difficile - also
    reported.
  • - dysmicrobia, hypovitaminosis B and K
  • - anorectal and anogenital syndrome (itching in
    anal and genital area)
  • antianabolic effect hypodynamia
  • - benign, intracranial hypertension (pseudotumor
    cerebri) - headache and blurred vision - rarely
    in adults
  • - decreased activity of pancreatic lipase and
    amylase (indication in
  • pancreatitis)
  • - very good penetration into ischemic tissues
    (abscesses...)

86
F. Contraindications Renally-impaired patients
should not be treated with any of the TTCs
except doxycycline. Children (under 8 years),
pregnant women, nursing mothers.
87
Clinical uses of tetracyclines
  • Antibiotics of first choice for rickettsial,
    mycoplasma and chlamydial infections,
    brucellosis, cholera, plague and Lyme disease.
  • Second choice - infections with several different
    organisms.
  • They are useful in mixed infections of the
    respiratory tract and in acne.
  • A use of democloxyxline distinct from its
    antimicrobial action is for chronic hyponatraemia
    caused by inappropriate secretion of antidiuretic
    hormone (e.g., by some malignant lung tumours)
    the drug inhibits the action of ADH.

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GLYCYLCYCLINES - TIGECYCLINE Derivative of
minocycline structure similar to TTC,
bacteriostatic (inhibition of synthesis of
proteins binding to 30 S ribosomal subunit).
Broad spectrum
effective against multi-drug resistance G (MRS,
Streptococci, VR enterococci, extended-spectrum
beta-lactamase producing G- and anaerobic
organism atypical agents, rickettsiae,
chlamydia, and legionella and rapidly growing
mycobacteria
Not effective against e.g.
Proteus, Pseudomonas Developed to overcome TTC
resistant organisms (based on efflux and
ribosomal protection) Administration i.v.
infusion only (100-mg loading dose then 50 mg
every 12 hours)

Extensively distributed
(excellent tissue and intracellular penetration),
not significantly metabolized in the liver
biliary/fecal excretion (adjust dosage in liver
impairment not necessary in renal impairment)
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Use skin and skin- structure infection and
intra-abdominal infections. Concentrations in
the urine low - not effective for UTIs. Active
against a wide variety of multidrug-resistant
nosocomial
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