Bez nadpisu

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ANTIBIOTICS Prof. MUDr Jirina Martínková, CSc
2006/2007
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Tab.1.Classification of antibacterial
agents bactericidal
bacteriostatic ß-lactam agents
Erythromycin Aminoglycosides
Tetracyclines Co-trimoxazole
Chloramphenicol Vancomycin
Sulfonamides
Trimethoprim
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Tab.2. Mechanism of action

• Inhibition of cell wall synthesis
  Penicillins
• 
  Cephalosporins
• 
  Monobactams
• 
  Vancomycin
• Inhibition of DNA gyrase
  Quinolones
• RNA polymerase
  Rifampicin
• Inhibition of protein synthesis
  Aminoglycosides
• 
  Tetracyclines
• 
  Erythromycin
• 
  Chloramphenicol
• Inhibition of folic acid
  Trimethoprim
• metabolism
  Sulfonamides
• 
  

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• The choice of appropriate antibacterial drugs
  depends on
• Diagnosis of infection
• Broad-spectrum antibiotics for empirical therapy,
  short-spectrum antibiotics for
• selective treatment
• - Patients factors
• Age, sex (pregnant, lactating women), weight,
  allergies, genetic factors, renal and hepatic
  function, concurrent medication
• - Drug factors
• antibacterial spectrum (short-spectrum,
  broad-spectrum activity, Gram-positives
  Gram-negatives),
• pharmacokinetics, adverse effects, drug
  interactions, convenience, cost
• The dose and route of administrations
• depends on infection and patient factors. The
  dose may be guided by plasma concentration
  measurements
• (aminoglycosides, fluorochinolones)
• The duration of therapy
• depends on the nature of the infection and
  response to treatment

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Better communication with the local microbiology
laboratory provides the physician with
information on local prevalence of organisms and
sensitivities MIC is often
quoted by laboratories ---- the minimal
inhibitory concentration of a particular agent
below which bacterial growth is not prevented.
It is an in vitro test in a homogenous culture
system, while in vivo - plasma
concentration should reach a value several-times
higher (8x) - concentration at the site of
infection may be considerably lower than
the plasma
concentration. Therefore, it is necessary to
take into consideration pharmacokinetic
properties of antibiotics (penetration into site
of infection, its metabolism..).
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ß- LACTAM ANTIBIOTICS
CHLORAMPHENICOL MACROLIDES
TETRACYCLINES AMINOGLYCOSIDES
LINCOSAMIDES GLYCOPEPTIDE ANTIBIOTICS
POLYMIXIN ANTIBIOTICS
FLUOROQUINOLONES METRONIDAZOLE
NITROFURANTOIN ANTIMYCOBACTERIAL DRUGS
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ß - LACTAM ANTIBIOTICS
penicillins cephalosporins
monobactams carbapenems
bacteriostatic, bactericidal

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• ß-lactams share general mechanisms of
  antibacterial
• action that involve damage to the cell wall of
  bacteria.
• The steps are
• attachment to specific penicillin-binding
  proteins
• (PBPs) that serve as drug receptors of
  bacteria
• inhibition of cell wall synthesis by blocking
• transpeptidation of peptidoglycan,
• activation of autolytic enzymes in the cell
  wall, which
• result in lesions that cause bacterial death

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Resistance falls into several categories 1.
Certain bacteria (Staphylococcus aureus) produce
ß-lactamases that inactivate some PNC by
breaking the beta-lactam ring 2. Others
(oxacillin) are ß-lactamase resistant because
their beta-lactam ring is protected by part
of the R side chain. 3. Other bacteria lack
specific receptors or lack permeability of
outer layer (drug cannot reach receptors) 4.
Autolytic enzymes in the wall are not
activated 5. Some microorganisms lack the cell
walls or are metabolically inactive 6.
Resistance is due to deficiency or
inaccessibility of PBPs
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• P e n i c i l l i n s
• penicillin G
• penicillin V
• penicillins resistant to
• beta-lactamases
  
• broad spectrum penicillins

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Penicillin G

• highest activity against G-positive organisms,
• little activity against G-neg. rods
• susceptibility to hydrolysis by ß -lactamases
  

Spectrum infections caused by pneumococci,strepto
cocci, meningococci. Non-beta-lactamase-producing
staphylococci, and gonococci, Treponema pallidum
and many other spirochetes, Bacillus anthracis,
clostridia, actinomyces, Listeria, and
Bacteroides (except Bacteroides fragilis).

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Pharmacokinetics no absorption from the gut,
low distribution to the CNS (importance of
inflammation) excretion (kidney, milk,
sputum) FORMULATIONS Penicillin G crystalline
salt (Na, K) Crystalline sodium PNC G contains
approxim. 1600 U/mg, 1 million U of PNC G 0.6
g IV, s.c., i.m. at 4-h intervals Procaine
penicillin G (suspension) i.m. delayed absorption
yielding useful levels for 12-24 h after a single
inj. (600 000 U) Penicillin G Benzathine
(suspension) a salt of very low water solubility
for i.m.inj. That yields low but prolonged drug
level. A single inj. of 1.2 million units once
every 3-4 weeks provides satisfactory prophylaxis
against reinfection by beta-hemolytic
streptococci.
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• P e n i c i l l i n s
• penicillin G
• penicillin V
• penicillins resistant to
• beta-lactamases
  
• broad spectrum penicillins

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Penicillin V

• similar antibacterial spectrum to penicillin G
• well absorbed from the gut
• indicated in mild infections of the respiratory
  tract or its associated structures, mainly in
  children (pharyngitis, otitis, sinusitis)
• in a daily dose of 1-4 g (divided to 6 doses)
• drug of first choice in nasopharyngitis due to
  beta-hemolyt. streptococci for 10 days

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• P e n i c i l l i n s
• penicillin G
• penicillin V
• penicillins resistant to
• beta-lactamases
  
• broad spectrum penicillins

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Penicillins resistant to ß-lactamases
The sole indication for their use is infection
by ß-lactamase-producing staphylococci

oxacillin, cloxacillin, dicloxacillin,
nafcillin acid- stable and reasonably well
absorbed from the gut are suitable for
treatment of mild localized staphylococcal
infections
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• P e n i c i l l i n s
• penicillin G
• penicillin V
• penicillins resistant to
• beta-lactamases
  
• broad spectrum penicillins

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Broad spectrum penicillins

• differ from PNC - G in having greater activity
  against G- neg.
  bacteria
• inactivated by ß-lactamases
• include ampicillin
• amoxicillin - complete absorption
  from the GIT
• Especially effective against G-neg. aerobic rods,
  incl. Pseudomonas
• carbenicillin
• ticarcillin
• mezlocillin - azlocillin- piperacillin

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Broad spectrum PNC can be protected from
destruction by ß -lactamases
inhibitors such as clavulanic acid, sulbactam,
or tazobactam co-amoxicillin (clav. acid
amoxicillin) sultamicillin (sulbactam
ampicilin) co-piperacillin (tazobactam
piperacillin) such mixtures are protected
against ß -lactamase producing H. influenzae or
coliform. organisms
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• A d v e r s e r e a c t i o n of PNCs
• allergic reactions type I-IV
• All PNCs and cross-reactants are
  cross-sensitizing.
• Any preparation containing PNC (foods or
  cosmetics) may
• induce sensitization.
• Anaphylactic shock (0.05 of recipients), fever,
  joint swelling,
• intense itching, variety of skin rashes, oral
  lesions,
• interstitial nephritis, hemolytic anemia
• irritation of the CNS increased excitability of
  neurons
• ---convulsions due to a direct influence
• (testing antiepileptic activity)
• gastrointestinal upset (more pronounced with
  oral
• broad spectrum PNC - amoxicillin)-nausea,vomiting,
  diarrhea
• superinfection with staphylococci, yeasts causes
  
• enteritis, vaginitis

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ß - LACTAM ANTIBIOTICS
penicillins cephalosporins
monobactams carbapenems
bacteriostatic, bactericidal

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C e p h a l o s p o r i n s (derivatives of
7-aminocephalosporanic acid)
First generation

• Spectrum
• G-positive cocci (pneumococci, viridans
• streptococci, gr. A hemolytic streptococci,
  and S. aureus.
• G-neg bacteria Escherichia coli, Klebiella
  pneumonie.

Cephalexin, cephazolin


Second generation
Active against organisms affected by
first-generation drugs, but they have an
extended G-neg coverage (Enterobacter, Klebsiella
and indol-positive Proteus are usually
sensitive).
Cefaclor( in patients who are allergic to PNC),
cefamandole, cefuroxime (crosses the blood-brain
barrier)



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Third generation

• expanded G-neg coverage (active against
  Enterobacter, Citrobacter, beta-lactamase
  producing strains of H. influenzae).
• some of them are ineffective against G-pos.
  organisms, mainly staphylococci and enterococci
  (resistant organisms, as well as fungi often
  proliferate and may induce superinfection)

• ability to reach the CNS, levels in
  cerebrospinal fluid are sufficient
• to inhibit most pathogens
• cefotaxime, ceftriaxone, ceftazidime
• are indicated in
• meningitis, sepsis (of unknown cause in the
  immunocompetent patient), in neutropenic febrile
  immunocompromised patients (in combination with
  aminoglycosides)

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ß - LACTAM ANTIBIOTICS
penicillins cephalosporins
monobactams carbapenems
bacteriostatic, bactericidal

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M o n o b a c t a m s

• active against G-neg. rods (incl. Pseudomonas
  and Serratia, H. influenzae, Neisseria
  meningitidis)
• resistant to ß-lactamases
• no activity against G-pos. bacteria or anaerobes

aztreonam, IV


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ß - LACTAM ANTIBIOTICS
penicillins cephalosporins
monobactams carbapenems
bacteriostatic, bactericidal

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C a r b a p e n e m s

• wide spectrum with good activity against many
  G-neg. rods,
• G-pos. organisms, and anaerobes.
• resistant to ß -lactamases

• imipenem IV
• is inactivated by dihydropeptidases in renal
  tubules resulting in
• low urinary concentrations. Consequently, it
  is administered
• together with an inhibitor of renal
  dihydropeptidase, cilastatin,
• for clinical use
• penetrates body tissue and fluids well,
  including the cerebrospinal
• fluid
• indicated for infections caused by susceptible
  organisms that are resistant to other available
  drugs. Since Pseudomonas may rapidly develop
  resistance to imipenem, the simultaneous use of
• an aminoglycoside is required. Febrile
  neutropenic patients.

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• Adverse effects
• nauzea, vomiting, diarrhea, skin rashes, and
  reactions at
• the infusion sites.
• excessive levels in patients with renal failure
  may lead
• to seizures

meropenem
is a safer carbapenem. Its usage is similar
to that of imipenem.

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MACROLIDES
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MACROLIDES
bacteriostatic and bactericidal

• Spectrum similar to PNC
• against G-pos. bacteria and spirochetes, but not
  against
• most G-neg. organisms
• distinctively, they are effective against
  several unusual organisms including Mycoplasma
  pneumoniae, Legionella and Chlamydia

• erythromycin
• Pharmacokinetics
• well absorbed, distributed adequately to most
  sites except brain and CSF
• inactivated by hepatic N-demethylation
• E. is remarkably safe antibiotic, may be used
  in pregnancy and children

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Tab. 3. Comparison of macrolides
erythromycin clarithromycin azithromycin
oral dose frequency usually qds
bd od GIT
adverse effects common less
common less common tissue penetration
reasonable high
extremely high
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• Indications
• respiratory infections (including Mycoplasma
• pneumoniae, psittacosis, Campylobacter enteritis)
• useful alternative to penicillin in
  penicillin-allergic patients
• useful for skin infections
• Interactions erythromycin inhibits CYP450 and
  causes
• accumulation of theophylline, and warfarine.

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CHLORAMPENICOL
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• CHLORAMPHENICOL
• is a potent inhibitor of microbial protein
  synthesis,
• binds reversibly to a receptor site on the 50S
  subunit of
• the bacterial ribosome. There, it interferes
  with the
• incorporation of amino acids into newly formed
  peptides
• by blocking the action of peptidyl transferase.

Ch. has a broad spectrum, is bacteriostatic for
many G-neg. bacteria and for rickettsiae. Some
salmonellae are susceptible, but plasmid-mediated
resistance to chloramphenicol has appeared
(results from the production of chloramphenicol
acetyl- transferase). Effective against
streptococci and staphylococci.

• Pharmacokinetics
• after oral administration - well absorbed and
  penetrates tissues
• exceptionally well including the CNS- a unique
  property for the
• treatment of central nervous system infections
• inactivated by conjugation with glucuronic acid
  

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• Indications (limited to)
• Salmonella infections - typhoid fever (many
  strains are
• now resistant, and cotrimoxazole is often
  used)
• serious infections with H. influenzae
  meningitis,
• pneumonia
• anaerobic or mixed infections in the CNS (brain
  abscess)
• as an alternative to tetracyclines in several
  rickettsial inf.

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• Adverse effects
• nausea, vomiting, diarrhea
• hematologic dose-related erythroid suppression
  is
• common and predictable
• aplastic anemia occurs
  unpredictably with
• an incidence of approxim. 140 000. This is
  irreversible in
• 50 of cases.
• Gray baby syndrome
• the gray color of the skin is due to shock
  (hypotension and
• tissue hypo-perfusion). Chl. accumulates in
  neonates
• (mainly in premature) due to reduced
  glucuronidation
• in the immature liver.

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TETRACYCLINES
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TETRACYCLINES
inhibit microbial protein synthesis

• are broad spectrum antibiotics,
• bacteriostatic for many G-pos. and neg.
  bacteria,
• including some anaerobes,
• for rickettsiae, chlamydiae, mycoplasmas, and
  for some
• protozoa

• Pharmacokinetics
• well absorbed orally, their absorption is
  impaired by
• food due to chelation with divalent ions
  (milk and its
• products - Ca 2), and antacids (Mg 2, Fe
  2)
• undergo elimination by both the liver
  (enterohepatic
• circulation-high concentrations in bile) and
  the kidney
• (high concentrations in the urine)
• t1/2 varies from 6 to 12 hr (the shorter acting
  drugs are
• given four times daily, the longer ones once
  daily)

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• cross the placenta to reach the fetus and are
  also
• excreted in milk
• tetracycline, oxytetracycline
• doxycycline, minocycline newer agents
  (absorption is 90-100, slow elimination)
• indication
• drugs of choice in infections with Mycoplasma
  pneumoniae, chlamydiae, rickettsiae, and some
  spirochetes
• useful in G pos. and neg. bacterial infections,
  related to
• the respiratory and urinary tract, sinusitis
• Lyme disease, brucelosis, tularemia,
  leptospirosis

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• Adverse effects
• due to alteration of normal flora in the gut
• vitamin B complex and vit K deficiency
• nausea, vomiting, diarrhea
• superinfection due to resistant organisms
  candida, pseudomonas, clostridia, resistant
  coliforms---anal
• itching, vaginal or oral candidiasis,
  enterocolitis, shock
• in children TTC are readily bound to calcium
  deposited in newly formed bone or teeth
  in young children
• (pregnancy, children under 8 years of age !).
  Discoloration
• of teeth and enamel dysplasia, deformity of
  bones, growth inhibition
• impaired hepatic function in patients with
  preexisting hepatic insufficiency or when high
  doses are given IV
• IVinj. can lead to venous thrombosis
• phototoxicity (sensitisation to sunlight)

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AMINOGLYCOSIDES
42
AMINOGLYCOSIDES

• are transported into cells and block bacterial
  protein synthesis by
• binding to the 30S ribosome
• their penetration through the cell membrane of
  the bacterium
• depends partialy on oxygen-dependent active
  transport---they have
• minimal action against anaerobic organisms

• Spectrum powerful bactericidal agents
• against many aerobic G-neg and some G- pos.
  organisms
• used with a penicillin in infections caused by
  streptococci,
• listeria or pseudomonas

Pharmacokinetics poorly absorbed from the gut,
administration IV and i. m. , distribution into
extracellular fluid, excretion by glomerular
filtration without metabolic transformation T1/2
2-3 hr
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AMINOGLYCOSIDES

• CLGE is highly correlated with CLCR

CLCR or creatininemia is used for prediction of
the individual dosage regimen in patients with
renal impairment (renal insufficiency or renal
failure- Fig.4). Another possibility how to
predict the dosage regimen is TDM (therapeutic
drug monitoring - see below) Fig. 4 shows the
simple way of the dosage regimen prediction using
a nomogram. The dose is calculated according to
the body weight (mg/kg), the interval between the
doses is adjusted according to clearance of
creatinine (CLcr) or creatininemia
44

Tab.4. A nomogram for GE dosage
regimens according to creatininemia and /or
creatinine clearance
45

• Indication
• monotherapy in urinary infections
• with simultaneous administration of PNC or
  CEPH in severe infections (sepsis, pneumonia)
  caused by G-neg. bacteria that are likely to be
  resistant to other drugs
• (patients with these infections are aften
  immunocompromised)
• topical eye drops for treating eye infections

• Adverse effects- toxicity dose-related, with the
  potential for
• increasing with duration of treatment
• ototoxicity irreversible destruction of the
  sensory cells in the
• cochlea and vestibular organ of the
  ear---vertigo, ataxia and loss
• of balance (vestibular damage) auditory
  disturbances, including
• deafness (cochlear damage)
• nephrotoxicity consists of damage to the
  kidney tubules, can be
• reversed if the use of the drug is stopped
• paralysis due to neuromuscular blockade (not
  used during general anesthesia!)

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• 1st generation neomycin (local use),
  streptomycin and kanamycin (antiTBC)
• 2nd generation
• gentamicine, tobramycine, amikacin, netilmicin
• main properties
• - both bactericidal effects and toxicity are more
  related to plasma concentrations than to the dose
• the therapeutic window is narrow
• That is why
• TDM-therapeutic drug monitoring -
  detection of plasma concentration is used for the
  individual dosage regimen (and toxicity)
  prediction
• in preterm neonates
• in the elderly (glomerular filtration
  diminishes)
• in patients with renal dysfunction
• What are limits?
• Ctrough (plasma concentration) just before next
  dose
• Cpeak (at 0.5 h after i.v. 30-min inf)
• dosage TDS---OD

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Tab.5.
Recommended Ctrough Cpeak
mg/L mg/L gentamicin
tobramycin 0.5-2 6 -10
netilmicin amikacin 1-8 20
-30
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TDM
NEWBORNS during the first week of the postnatal
age (mainly for immaturity) CHILDREN,
ADULTS impairment of renal function
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Fig. 1 demonstrates postnatal development (in
days and months) of hepatic elimination (the
upper part) and renal elimination (the lower
part). The data show the time when the adult
value of glomerular filtration is reached in
one-month interval approx. In case of immature
neonates, this interval can be even prolonged. It
means that gentamicin elimination in neonates is
slow (if compared to children and/or adults).
Drug accumulation The dosage regimen should be
adjusted according to the individual patient need

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Fig.1. POSTNATAL DEVELOPMENT OF SPECIFIC HEPATIC
AND RENAL FUNCTION (from Gladtke 1979).
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Fig.2 Body weight and the gestational and
postnatal age The total body water (TBW) and
extracellular body water (ECW) gradually
decreases before and after delivery we know,
that gentamicin is distributed to extracellular
water . in neonates its Vd is relatively
large (if compared to children of adults) . but
decreases with the age This fact also modifies
the dosage regimens
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Fig.2
birth
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Fig.3Plasma concentrations of gentamicin in 6
immature neonates with the low body weight on
day 4 of the postnatal lifePlasma concentration
after one dose (a 30-min i.v. infusion) of
gentamicin at the steady state are described by
four points.
The newborns were given a reduced dose (2.0
mg/kg every 18 hours). Let us compare Cpeak and
Ctrough identified with those recommended by tab.
5 The figure shows that in 5 patients the Ctrough
plasma concentrations are very high and predict
toxicity the dose reduction
was not individualized enough
54
Fig.3. Plasma concentrations of gentamicin in 6
immature neonates with the low body weight on
day 4 of the postnatal life
Plasma concentrations in log
h after i.v. inf.
weeks
gestational age
55
How to predict the indidividual dosage
regimen? using PC programmes for instance MW
Pharm Remind of clinical pharmacology in year
5 Welcome !
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impairment of renal function and plasma
concentrations Fig. 4-6demonstrate the range
between the red and green levels the therapeutic
window In h e a l t h y m a n gentamicin
is given at a dose of 80 mg every 8 hours
(three-times a day) fluctuation of gentamicin
plasma concentrations (Cpl) reaches the steady
state (Css) after the third dose - where the
rate of gentamicin administration the rate of
gentamicin elimination In case of r e n a l i
m p a i r m e n t, Cpl of gentamicin is much
higher and does not reach Css within 72 hours
The drug accumulates in the body and this fact
predicts toxicity!
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LINCOSAMIDES
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LINCOSAMIDES
Clindamycin is effective against G-pos.cocci,
including many PNC-resistant staphylococci ,
and many anaerobic bacteria such as Bacteroides
species.
Given orally or parenterally C. is widely
distributed in tissues (including bone) and
body fluids but not cross the blood-brain
barrier. Adverse effects GIT disturbances.
Indications infections caused by Bacteroides
organisms, staphylococcal infections of
bones and joints. It is also used topically as
eye drops, for staphylococcal conjunctivitis.
62

GLYCOPEPTIDE ANTIBIOTICS
63
GLYCOPEPTIDE ANTIBIOTICS
vancomycin
Effective against multiresistant staphylococcal
infections IV 60-min infusion, pseudomembranous
colitis - orally
Adverse effects red man syndrom, nephrotoxicity,
neurotoxicity TDM teicoplanin less toxic,
with a longer duration of action
64

POLYPEPTIDE ANTIBIOTICS

65
POLYPEPTIDE ANTIBIOTICS
Bacitracin
is most active against G-pos. organisms including
staphylococci producing ß-lactamase.
B. has serious toxic effects on the kidney and is
therefore only used topically for infections of
mouth, nose, eye and skin.
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POLYMIXIN ANTIBIOTICS
polymixin B colistin - polymixin E
have a selective rapid bactericidal action on
G-neg bacilli, especially pseudomonas and
coliform organisms.
They are not absorbed from the GIT. Adverse
effectsneurotoxicity and nephrotoxicity. Indicat
ions gut sterilisation and topical
treatment of eye or skin infections.
67

FLUOROQUINOLONES
68
FLUOROQUINOLONES
Inhibit topoisomerase II, the enzyme that
produces a nega- tive supercoil in DNA
permitting transcription or replication
ciprofloxacin, ofloxacin, norfloxacin, pefloxacin
Broad spectrum agents, the type agent
ciprofloxacin effective against both G-pos.and
neg.organisms. The excellent activity against
Enterobacteriaceae. High incidence of
staphylococcal resistance.
Indication infections with aerobic G-negative
rods and cocci.
69

METRONIDAZOLE
NITROFURANTOIN
70
METRONIDAZOLE

is active against anaerobic bacteria such as
Bacteroides, clostridia and some streptococci.
Indications serious anaerobic infections.
71
NITROFURANTOIN
Spectrum against a range of G pos. and neg.
organisms. The development of resistance is rare.
Given orally it is rapidly and totally absorbed
from the GIT and very rapidly excreted by the
kidney by both glomerular filtration and tubular
secretion thus it reaches antibacterial
concentrations in the urine but not in plasma. In
renal failure, toxic levels can be obtained.
Indications urinary tract infections, drug is
more active in acid urine. Adverse effects GIT
disturbancies, hypersensitivity reactions
involving the skin and bone marrow (leukopenia).
72

ANTIMYCOBACTERIAL DRUGS
73
ANTIMYCOBACTERIAL DRUGS
Drugs used to treat tuberculosis
Drugs used to treat leprosy
A particular problem with both these conditions
is that after phagocytosis, the microorganisms
can survive inside macrophages unless they are
activated by cytokines produced by Th1
lymphocytes.
74
Drugs used to treat tuberculosis
TBC due to Mycobacterium tuberculosis
The first-line drugs Isoniazid, rifampicin,
ethambutol, pyrazinamide The second-line drugs
STM, cycloserin, capreomycin,
75
Usage to avoid emergence of resistant organisms,
three drugs are used initially, then two drugs
later

• a first phase of about two months is consisting
  of three
• drugs used concomitantly isoniazid, rifampicin,
• pyrazinamide (plus ethambutol if the organism is
  suspec-
• ted to be resistant)
• a second, continuation phase, of 4 months,
  consisting
• of two drugsisoniazid and rifampicin.
• Longer-term treatment is needed in some
  situations
• (in patients with meningitis, bone, joint
  involvement,
• drug-resistant infections).

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First-line drugs Isoniazidkills actively growing
mycobacteria within host cells. Given orally it
penetrates necrotic lesions, also the CSF. Slow
acetylators (genetic polymorfism in metabo- lism)
respond well. I. has low toxicity but pyridoxine
deficiency increases risk of neurotoxicity. No
cross-resistance with other agents. Rifampicin
is a potent, orally active drug. It penetrates
CSF. Adverse effects are infrequent (but serious
liver damage has occured). It induces hepatic
drug-metabolising enzymes. Resistance can develop
rapidly. Etambutol is given orally and can
penetrate CSF. Adverse effects are uncommon,
optic neuritis can occur. Resistance can develop
rapidly.
77
Pyrazinamide resistance can develop rapidly.
Adverse effectsincreased plasma urate, liver
toxicity with high doses.
Second-line drugs Capreomycin is given i.m.
Adverse effects include damage to the kidney and
to VIIIth nerve. Cycloserine given orally it
penetrates the CSF. Streptomycin given i.m.
Adverse effects ototoxicity (mainly vestibular,
and nephrotoxicity. Infrequently used now.
78
Drugs used to treat leprosy
due to Mycobacterium leprae
For tuberculoid leprosy dapsone and
rifampicin for lepromatous leprosy dapsone,
rifampicin, clofazimine Dapsone
sulphonamide-like and may inhibit folate
synthesis. Adverse effects are fairly
frequenthaemolysis of red cells,
methemoglobinemia, nausea and vomiting, anorexia,
fever, allergic dermatitis, neuropathy. Syndrome
resembling infectious mononucleosis, which can be
fatal, has occasionally been seen. Clofazimine
is a dye which is given orally and can accumulate
by sequestring in macrophages. Action is deleayed
for 6-7 weeks (t1/2 8 weeks). Adverse effects
red skin and urine, GIT disturbances.