Download A) ATB inhibiting bacterial cell wall synthesis

Antibiotic therapy
(presentation provided by
Prof. MUDr. J. Beneš, CSc.)
History of antibiotics
1910
1932
1928/41
1944
1945
1947
1948
1952
1954
1955
1957
1959
salvarsan
prontosil
penicillin
streptomycin.
cefalosporin C
chloramphenicol.
chlortetracyclin.
erythromycin.
spiramycin.
vancomycin.
kanamycin.
rifampicin.
P.Ehrlich, S.Hata
E.Domagk
A.Fleming,H.Florey,E.Chain
S.A.Waksman
G.Brotzu
I.Ehrlich
B.M.Buggar
J.M.Mc.Guire
S. Pinnert-Syndico
M.H.Cormick
H.Umezawa
P.Sensi
--. = drugs produced by Streptomycetes
History of antibiotics II
1960
1960
1962
1966
1968
1981
1982
1990
1991
2000
ampicillin
methicillin
cefalotin
doxycyclin
co-trimoxazol
amoxicillin/clavulanic acid
ciprofloxacin
azithromycin
clarithromycin
linezolid
many drugs are semi-synthetic
Groups of antibiotics
A) ATB inhibiting bacterial cell wall synthesis
(peptidoglycan synthesis)
B) ATB inhibiting bacterial DNA metabolisms
C) ATB inhibiting bacterial proteosynthesis
D) ATB inhibiting bacterial metabolic
pathways
E) ATB damaging bacterial cell membranes
Groups of antibiotics
A) ATB inhibiting bacterial cell wall
synthesis (peptidoglycan synthesis)
beta-lactams
penicillins
cefalosporins
monobactams
carbapenems
glycopeptides
Beta-lactams
penicillins
monobactams: aztreonam
cefalosporins
carbapenems: imipenem
Penicillin
strong effect
no interactions
no toxicity
dosage: therapy of tonsillitis
erysipelas
endocarditis
1,5 mil.U./day
6-12 mil.U.
12-30 mil.U.
G+ cocci: streptococci, pneumococci, enterococci
G+ rods: B. anthracis, C. diphtheriae, L. monocytogenes
G- cocci: Neisseria spp.
others: anaerobes, spirochetes
Penicillins
Penicillin G
strong and nontoxic - but ..
narrow spectrum
half time 30 min
acid labile (not orally)
anti-staphylococcal penicillins
methicilin, nafcilin, oxacillin
broader spectrum penicillins
(E. coli, H. influenzae, ..., enterococci)
ampicillin, amoxicillin
longer effect:
- procain PNC (24 h)
- benzathin PNC (3 weeks)
oral forms:
- penicillin V
- penamecillin
anti-Pseudomonas penicillins
CARB, TIC, AZL, MEZ
piperacillin
Mechanisms of resistance

inactivation of antibiotic (exoenzymes)
 cleavage of the molecule
 adding a side chain

inhibition of ATB entry in the G- bacteria cell

changes in the target structure

alternative metabolic pathway

efflux

combination of several mechanisms
Inhibitors of beta-lactamases
sulbactam
clavulanic acid
clavulanic acid + amoxicillin = Augmentin, Amoksiklav, ....
sulbactam
+ ampicillin = Unasyn (only i.v.)
+ cefoperazon = Sulperazon (only i.v.)
tazobactam + piperacilin = Tazocin (only i.v.)
Cefalosporins
I. gen
II. gen
III. gen IV. gen
streptococci
+++
+++
++
+++
staphylococci
+++
++
+
+++
G- rods (E. coli)
+
++
+++
+++
Pseudomonas
-
-
some
(ceftazidim)
++
anaerobs
+
+
+
+
Generations vary in anti-bacterial spectrum, resistance against βlactamases, and pharmacokinetics (penetration in tissues, half-time)
Penicillins and cefalosporins
PENs more effective against G+, CEFs against GCEFs I. gen ≈ PEN + OXA
wound infections, profylaxis in surgery (i.v., orally)
CEFs II. gen ≈ aminoPEN + β-lactamase inhibitor
UTI, abdominal a respiratory infections (i.v., orally)
CEFs III. gen ≈ anti-Pseudomonas PENs
G- sepsis, meningitis (ICU needed, i.v.)
CEFs IV. gen
nosocomial infections/sepsis (ICU, i.v.)
Conclusions: beta-lactams
Bacterial killing:
rapid, strong, no post-ATB effect
Pharmacokinetics:
short half time (t1/2 0,5-2 hod)
good levels in plasma and ECF, not in cells
Toxicity, side effects:
nontoxic ATB, good for children, pregnant women
allergy (PENs > CEFs)
dysmicrobia (candidoses, post-ATB colitis)
Indications:
Acute infections >> chronic infections
Severe infections, sepsis >> mild infections
Glycopeptides
- vancomycin
- teicoplanin, daptomycin
large molecule not permitting transport through an outer wall of Gramnegative bacteria, inhibitor of cell wall synthesis
bactericidal against most Gram-positive bacteria incl. MRSA
not absorbed from GIT, active only in blood and extracellular
fluid (no transport into cells), elimination in urine
possible nephrotoxicity, blood levels should be measured !
Conclusion:
- reserve ATBs against (multi) resistant Gram-positive bacteria
- good for treatment of sepsis and severe acute infections if
not possible to treat with other ATBs (e.g.: endocarditis,
osteomyelitis, pneumonia)
Glycopeptides
Vancomycin
 Indications: peroral therapy of colitis caused
by Clostr. Difficile as a result of antibiotic
therapy or parenteral ther. of infect. caused
by MRSA
 ADV. EFF.: nephrotoxicity, (ototoxicity)
 Teicoplanin similar to vancomycin

Groups of antibiotics
B) ATB inhibiting bacterial DNA metabolism
(fluoro) quinolones
rifampicin
Fluoroquinolons
I. gen.: weak effect; limited spectrum (Gram-neg. only);
limited absorbtion; effective only in UTI
NAL, OXO, PIP;;
norfloxacin
II. gen.: fluoroquinolons, systemic distribution;
broader spectrum (+ staphylococci, chlamydiae,
Mycoplasma spp., Mycobacterium spp.)
ciprofloxacin, ofloxacin, PEF, LEVO
III. gen.: excellent absorbtion, half-time 6-20 hrs;
high concentrations in lungs;
broader spectrum (pneumococci); higher cost
moxifloxacin, ...
Characteristics of fluoroquinolones
broad spectrum (Gram-negative bacteria, staphylococci,
intracellular bacteria)
bactericidal
good pharmacokinetics: good absorbtion from GIT
good penetration in tissues and cells
elimination in various routes
low cost
adverse events:
GIT complaints: nauzea, anorexia
allergy, fotosensibilization
CNS: dizziness, agitation, insomnia, seizures
connective tissues: tendinitis, tendon ruptures
arrythmia, torsade de pointes
not allowed for children and pregnant women
interaction with other drugs (P450, CYPIA2)
theophyllin, warfarin, H2 blockers, ...
resistance can develop very easily
Torsade de pointes
ATB rezistance (%) in invasive isolates E. coli
in the Czech Republic in 2000-2006
25
20
15
10
5
0
2001
2002
2003
2004
2005
2006
(n=1189)
(n=1598)
(n=1777)
(n=1982)
(n=2257)
(n=1045)
red line – fluoroquinolones, black line – aminoglycosides, blue line – 3rd gen. cefalosporins
Appropriate usage of FQ
(with respect to ATB policy)





enteric fever, extra-intestinal salmonellosis
zoonoses (tularemia, brucellosis etc.)
prostatitis
acute exacerbation of chronic bronchitis
lower respiratory tract infections in cystic fibrosis
common UTI
gastroenteritis, enterocolitis
biliary infections (+ prophylaxis)
uretritis (STD)
nosocomial infections, sepsis
Rifampicin
Broad spectrum: Gram-positive and -negative bacteria,
including intracellular pathogens – but it is registered for
therapy of mycobacterial infection
Resistance can develop very easily, it should not be used in
monotherapy !
Good absorbtion from GIT if taken without food. Good
distribution into tissues and cells. The drug is metabolized
in liver (cytochromes P450). Elimination in urine.
Adverse events: hepatotoxicity, drug interactions
Groups of antibiotics
C) ATB inhibiting bacterial proteosynthesis
macrolides (+ azalides + ketolides)
lincosamids
tetracyclines
chloramphenikol
oxazolidinons
+ aminoglycosides
Macrolides
12-chain: veterinary drugs
14-chain: erythromycin, clarithromycin, roxithromycin
16-chain: spiramycin – less interaction potential than above
azalides (15-chain): azithromycin
ketolides: telithromycin
• streptococci, pneumococci, Branhamella catarrhalis,
Bordetella pertussis, Legionella spp.
• oral anaerobic flora, actinomycetes
• mycoplasmata, chlamydiae
• Borrelia burgdorferi and other spirochetes
• Campylobacter spp., Helicobacter spp. (clarithromycin)
(+ mycobacteria)
erythromycin molecule
Macrolides
Advantages
• excellent penetration in
many tissues and cells
• high concentration in
leucocytes
• leucocytes transport the
antibiotic into the site
of infection
• absence of toxicity
• comfort dosage
Disadvantages
•
•
•
•
•
static effect on bacteria
weak effect
drug interactions (P450)
ERY: nauzea, vomiting
resistance develops easily
Macrolides
Usage:
- mild infections, mucosal infections
- infections in young persons
with good immunity
- infections with intracellular pathogens
(respiratory infections, urogenital infections)
Not recomendable:
- usage in severe infections (sepsis)
- usage in persons with decreased immunity
- frequent usage (→ resistance)
Lincosamides


lincomycin
clindamycin
Partial absorbtion from GIT, good penetration into tisues and
cells, metabolization in liver, elimination in bile in urine
Spectrum:
• only Gram-positive microbes (streptococci and staphylococci)
• anaerobes
• protozoa (Toxoplasma, Plasmodium, Entamoeba)
No toxicity, can be used in children or pregnant women –
but there is a risk of post-antibiotic colitis (Clostr. difficile)
Lincosamides


lincomycin
clindamycin
Usage:
infections due to streptococci, staphylococci, anaerobes
mild to moderate infections – not sepsis
subacute or recurrent infections
•
•
•
•
infections in mouth cavity
wound infections, skin and soft tissue infections
infections of bones and joints
pneumonia after aspiration
+ malaria, toxoplasmosis, amebosis
Tetracyclins
1. generation: tetracyclin, oxytetracyclin
2. generation: doxycyclin, minocyclin
3. generation: tigecyclin
Good absorbtion from GIT, good penetration into tissues and
cells, metabolization in liver, elimination into bile and urine.
Long half-time.
Spectrum:
• very broad originally (various Gram-positive and –negative
pathogens, anaerobes, chlamydiae, mycoplasmata)
• but many resistant strains nowadays
• never effective against Pseudomonas spp., enterococci,
Bacteroides fragilis
Tetracyclins
1. gen. tetracyclin, oxytetracyclin
2. gen. doxycyclin, minocyclin
3. gen. tigecyclin
Indications:
• infections caused by mykoplasmata, chlamydiae, rickettsiae
- especially „atypical pneumonia“
- STD like uretritis, prostatitis
• zoonoses (lyme borreliosis, tularemia, brucellosis, ...)
Adverse events: nausea, vomiting
hepatotoxicity
storage in bones and teeth (= not allowed for
pregnant women and children up to 8 years)
Candida superinfections
Aminoglycosides
streptomycin
neomycin
gentamicin, tobramycin, ..
amikacin, isepamicin, ..
Mode of action:
• inhibition of proteosynthesis
• damage of cell wall in Gram-positive and –negative bacteria
→ synergy with beta-lactams and glycopeptids
Spectrum:
• Gram-negative rods (E. coli, Pseudomonas spp, ...) and
staphylococci → direct bactericidal effect
• Streptococci and enterococci: only synergic with other ATB
Aminoglycosides do not affect anaerobes, intracellular
pathogens, and encapsulated bacteria!
Aminoglycosides
streptomycin
neomycin
gentamicin, tobramycin, ..
amikacin, isepamicin, ..
for tuberculosis treatment
for external usage only
sepsis (community-acquired)
sepsis (nosocomial)
Adverse events:
• nephrotoxicity (cumulative)
• ototoxicity (especially high doses)
• neurotoxicity (when combined with myorelaxant drugs)
Usage:
narrow therapeutic window, serum levels should be monitored
once daily dosing in most situations
Groups of antibiotics
D) ATB inhibiting bacterial metabolic pathways
1/ inhibition of folic acid synthesis
- sulphonamides
- trimethoprim
2/ unspecific inhibitors of bacterial metabolism
- nitroimidazols (metronidazol)
- nitrofurantoin
Sulphonamides and trimethoprim
Inhibition of folic acid synthesis
(→ lack of thymin)
Gram-positive bacteria: pneumococi, staphylococci
Gram-negative bacteria: E. coli and other enterobacteria
plus: Pneumocystis jiroveci
sulphonamides also active against Toxoplasma gondii and
Plasmodium spp.
enterococci are always resistant in vivo, independently on
results of in vitro tests
sulphamethoxasol + trimethoprim = co-trimoxazol (5 : 1)
Good absorbtion from GIT, good penetration into tissues;
metabolization in liver → various drug interactions;
elimination via urine above all
Co-trimoxazol





urinary tract infections
diarrhea due to enteric bacteria
enteric fever
mild to moderate infections caused by pneumococci and
staphylococci
pneumonia due to Pneumocystis jiroveci
(including HIV/AIDS prophylaxis)
Adverse events:
mainly sulphonamides
allergy, incl. Stevens-Johnson syndrome
 drug fever
 myelotoxicity
Drug interactions: warfarin, hydantoin, salicylates, indomethacin ..

Nitroimidazoles
metronidazole, ornidazole, tinidazole
 anaerobic bacteria incl. Bacteroides fragilis

protozoa: Trichomonas, Entamoeba, Giardia
Excellent absorbtion and tissue penetration. Metabolization in liver.



infections due to anaerobic bacteria, especially in
abdominal cavity
postantibiotic colitis (Clostridium difficile)
protozoal infections (see above)
Adverse events: GIT intolerance, disulphiram effect, encephalopathy
Acquired rezistance is rare.
Nitrofurantoin
„urinary antiseptic agent“
therapeutical concentrations only in urine
short half-time, metabolization in various tissues
Spectrum: E. coli and other enterobacteria, + enterococci



urinary tract infections - therapy
urinary tract infections – long term prophylaxis
external usage: vaginal globules, pastae in dermatology
Adverse events: GIT intolerability, allergy
Acquired rezistance is very rare!
Groups of antibiotics
E) ATB damaging bacterial cell membranes
- colistin
Colistin
bactericidal against various Gram-negative bacteria,
including Pseudomonas spp.
ultimum refugium in therapy of multiresistant infections
a) parenteral application:
nephrotoxicity, neurotoxicity
b) external application:
used in dermatology
MUDr. P. Potměšil, PhD.

Selected topics about antibiotics/antivirals
Some important interactions or
adverse effects of selected antibiotics




Ciprofloxacin cannot be used with agomelatine
(newer antidepressant)
Clarithromycin (e.g. for respiratory infections)
should not be used with buspirone (anxiolytic) or
dosage of buspirone should be reduced
Tetracyclines (e.g. Doxycyklin for borreliosis) make
complexes with Ca, Al, Fe and Mg cations (take
doxycyclin 2-3h before or 4-5h after use of food
supplements, milk products, antacides etc.)
Macrolides can cause damage of vestibulocochlear
nerve or hepatic impairment in high and longterm
dosage
Antibiotics used in eradication
of Helicobacter pylori infection







Amoxycillin
Clarithromycin – contraindicated with statins
that lower cholesterol (simvastatin etc.) or
with antineoplastic agents lapatinib, dasatinib
(azitromycin)
Metronidazol
Antibiotics have to be used together with
proton pump inhibitor = PPI (omeprazol,
pantoprazol etc.)
1/ Amoxicillin + metronidazol + PPI
2/ Claritromycin + PPI
Antibiotics used for therapy of acne
I. Topical use
1/ Erytromycin, or erytromycin in combination with
zinc (Zineryt lot.)
2/ Clindamycin, or clindamycin in combination with
benzoylperoxide (Duac gel)
3/ Metronidazol - acne rosacea
4/ Chloramphenicol
5/ Acidum fusidicum – (Fucidin cream)
II. Peroral therapy
A/ Tetracyclines
1/ Doxycyclin (some forms of acne)
2/ Tetracyclin
B/ Macrolides
1/ Erytromycin
2/ Azitromycin – less effective than tetracyclines but can be better
tolerated, pulse therapy recommended
C/ Clindamycin
Antibiotics for therapy of borreliosis
(caused by borrelia burgdorferi)
Doxycycline (tetracycline)
 Cefuroxim-axetil (cephalosporin II. gen.)
 Azitromycin (macrolide)

Pharmacotherapy of HIV infection
drugs are applied in combinations – combined
antiretroviral therapy (cART)
A) Inhibition of HIV entry
1/ maraviroc
- peroral antagonist of CCR5
receptor (chemokine coreceptor for HIV entry)
B) Inhibition of HIV replication
1/ reverse transcriptase inhibitors
zidovudine
tenofovir,stavudine,zalcitabine,
didanosine, nevirapine, efavirenz
2/ inhibitors of HIV integrase.
- patients have to be scrreened
for CCR5 genotype before
prescription
2/ enfuvirtide
- inhibiton of HIV fusion with cell
- only s.c.
Raltegravir
3/ HIV protease inhibitors
ritonavir, nelfinavir, fosamprenavir,
saquinavir, indinavir
Acyclic nucleoside phosphonates
(ANP)

(N-(2-fosfonometoxyalkyl) purines).

Antivirals effective against DNA viruses and
retroviruses.
Approved are:

tenofovir (HIV),
adefovir (HBV) and cidofovir (CMV).

(Tenofovir increases production of cytokine
IL-10 and chemokines MIP-1α, MCP-3 that
can block HIV entry/replication thus
tenofovir has low risk of resistence).
Therapy of chronic viral hepatitis B/C
Hepatitis B
1/ tenofovir or entekavir
first line choice for
longterm use today
because of very good
efficacy and low
resistance
2/ other drugs: adefovir,
lamivudine, telbivudine
or pegylated interferon
alfa

Hepatitis C
1/ standard therapy is
combination of
peg. interferon-alfa +
ribavirin
2/ New drugs
Boceprevir, telaprevir

Possible ATB for selected
nosocomial infections



Pseudomonas aerug.:
1/ ticarcillin
Resistent Staph.
Aureus:

1/ Vancomycin +
rifampicin or
gentamicin
2/ Teicoplanin
(for Vanc. resistent
Staph. A.)
(co-ticarcillin not actually
registered in Czech Rep.)




2/ ceftazidim +
aminoglycosides
3/ imipenem,
meropenem
4/ fluoroquinolones