1. ATB II. part

2. CARBAPENEMS IMIPENEM, MEROPENEM synthetic beta-lactam ATB
imipenem is compounded with cilastatin to protect it from
metabolism by renal dehydropeptidase.
Spectrum: Imipenem/cilastatin is the broadest spectrum beta- lactam antibiotic currently available. It is active against pencillinase-producing gram-positive and gram-negative organisms, anaerobes, and pseudomonas aeruginosa
The drug plays a role in empiric therapy. Meropenem has antibacterial activity similar to that of imipenem.

3. CARBAPENEMS
- administered i.v., penetrates well into CNS. - excreted by GF and undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule to form an inactive metabolite that is potentially nephrotoxic MEROPENEM – it is not cleaved in the kidney !! Adverse effects: nausea, vomiting, and diarrhea. High levels of especially imipenem may provoke seizures.

4. MONOBACTAMS - AZTREONAM
unique because the beta-lactam rings is not fused to
another ring
narrow antimicrobial spectrum precludes its use alone in empiric therapy
is resistant to the action of beta-lactamases.
Spectrum: G- primarily against the enterobactericeae; effectiveness against Pseudomonas aeruginosa and other aerobic gram-negative bacteria

5. MONOBACTAMS - AZTREONAM
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 beta-lactam - an alternative for patients allergic to penicillin.

6. OTHER AGENTS AFFECTING THE CELL WALL
VANCOMYCIN, TEICOPLANIN (similar, longer acting) - the emergence of staphylococci resistant to most antibiotics except vancomycin led to the reintroduction of this agent. Use - infections caused by methicillin-resistant staphylococci (MRSA), and pseudomembranous colitis caused by Clostridium difficile or staphylococci.

7. VANCOMYCIN
Slow i.v. infusion - treatment of systemic infections or for prophylaxis.
Vancomycin is not absorbed after oral administration - treatment of antibiotic-induced colitis due to C. difficile.
Metabolism – minimal ( % excreted by glomerular filtration) – adjust dosage in renal failure – accumulation of the drug.
Adverse effects: at the infusion site (fever, chills, and/or phlebitis), flushing ("red man syndrome"). Shock as a result of rapid administration. Rashes. Ototoxicity and nephrotoxicity – more common when administered with other drug (e.g., an aminoglycoside) that can also produce these effects.

8. PROTEIN SYNTHESIS lNHIBITORS
A number of ATBs exert their antimicrobial effects by targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosome.

9. PROTEIN SYNTHESIS INHIBITORS
TETRACYCLINES
Demeclocycline
Doxycycline
Minocycline
Tetracycline
AMINOGLYCOSIDES
Amikacin
Gentamicin
Neomycin
Netilmicin
Streptomycin
Tobramycin
MACROLIDES/KETOLIDES
Azithromycin
Clarithromycin
Erythromycin
Telithromycin
CHLORAMPHENICOL
CLINDAMYCIN
QUINUPRISTIN/DALFOPRISTIN
(according to Lippincott´s Pharmacology, 2006)
LINEZOLID

10. TETRACYCLINES
related compounds - consist of 4 fused rings with a system of conjugated double bonds.
DOXYCYCLINE, MINOCYCLINE
Entry into susceptible organisms - both by passive diffusion and by an energy-dependent transport protein mechanism.
They bind reversibly to the 30S subunit of the bacterial ribosome
Doxycycline

11. TETRACYCLINES
Broad spectrum antibiotics - also effective against intracellular organisms - drugs of choice for rickettsial, mycoplasma and chlamydial infections Widespread resistance limits their clinical uses – inability of the organism to accumulate the drug. Any organism resistant to one tetracycline is resistant to all - cross over resistance mechanism

12. TETRACYCLINES
Absorption: Doxycycline and minocycline completely absorbed
Dairy foods in the diet decrease absorption because of the formation of nonabsorbable chelates of the tetracyclines with calcium ions.
Nonabsorbable chelates are also formed with other divalent and trivalent cations (e.g. those found in magnesium and aluminium antacids, and in iron preparations).

13. TETRACYCLINES Distribution:
concentrate in the liver, kidney, spleen, and skin and
bind to tissues undergoing calcification (e.g.,teeth, bones),
Penetration into body fluids is adequate. Though all enter the CSF, levels are insufficient for therapeutic efficacy, except for MINOCYCLINE
Teratogenic - all TTCs cross the placental barrier and concentrate in fetal bones and dentition.
very good penetration into ischemic tissues (abscess ...)

14. Adverse effects
Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa.
calcified tissues - deposition in the bone and primary dentition occurs 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 !!!
Hepatotoxicity.
Phototoxicity:

15. Adverse effects Vestibular problems: e.g., dizziness, nausea, vomiting
Superinfections: candida (e.g. in the vagina) or resistant staphylococci in the intestine. Pseudomembranous colitis due to an overgrowth of Clostridium difficile has also been reported.
dysmicrobia - hypovitaminosis B and K

16. AMINOGLYCOSIDES Effective in the empirical treatment of infections
suspected of being due to aerobic gram-negative
bacilli, including Pseudomonas aeruginosa –
Bactericidal, effective only against aerobic organisms
(anaerobes lack the oxygen-requiring transport system).
To achieve an additive or synergistic effect,
aminoglycosides are often combined with a b-
Iactam antibiotic, or vancomycin, or a drug active
against anaerobic bacteria.

17. AMINGLYCOSIDES All aminoglycosides are bactericidal - 30S.
The exact mechanism of their lethality is unknown, because
other antibiotics that affect protein synthesis are generally
bacteriostatic.
Commonly used aminoglycosides:
AMIKACIN, GENTAMICIN, TOBRAMYCIN and STREPTOMYCIN
Streptomycin - used to treat tuberculosis (kanamycin also effective),
plague, tularemia.
Other aminoglycosides: NEOMYCIN, NETILMICIN,
KANAMYCIN

18. AMINGLYCOSIDES
The bactericidal effect is concentration and time dependent They also have a postantibiotic effect - once-daily dosing with the aminoglycosides can be used . The exceptions are pregnancy, neonatal infections, and bacterial endocarditis, in which they are administered every eight hours.

19. The post antibiotic effect (PAE)
the continued suppression of antibacterial growth after the administration of antibiotic has ceased and serum concentrations have fallen below the minimum inhibitory concentration.
Factors that affect the duration of the post antibiotic effect include
- duration of antibiotic exposure
- bacterial species
- culture medium
- class of antibiotic

20. AMINOGLYCOSIDES Distribution:
All have similar pharmacokinetic properties.
penetrate most body fluids well except for the CSF
(penetration is poor even when the meninges are inflamed!).
accumulate in the renal cortex and in the endolymph and perilymph of the inner ear – nephrotoxicity and ototoxicity - TDM
All cross the placental barrier and may accumulate in fetal plasma and amniotic fluid.

21. AMINOGLYCOSIDES Elimination: metabolism does not occur in the host.
all aminoglycosides are rapidly excreted into the urine (short t1/2), predominantly by glomerular filtration (CLCR)
accumulation occurs in patients with renal failure, and requires dose modification.

22. AMINOGLYCOSIDES
Adverse effects It is important to perform TDM of gentamicin, tobramycin, netilmicin, and amikacin to avoid conc. that cause dose-related toxicities Patient factors (e.g. age, previous exposure to aminoglycosides – functional acummulation, gender, renal disease) tend to predispose to adverse reactions. The elderly are particularly susceptible to nephrotoxicity and ototoxicity !!

23. AMINOGLYCOSIDES
1. Ototoxicity: Vestibular and cochlear - directly related to high peak plasma levels and the duration of treatment. ATBs accumulates in the endolymph and perilymph of the inner ear, and toxicity correlates with the number of destroyed hair cells in the organ of Corti. Patients simultaneously receiving other ototoxic drug (e.g., diuretics furosemide, bumetanide, ethacrynic acid or cisplatin) - particularly at risk.

24. AMINOGLYCOSIDES 2. Nephrotoxicity:
Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated transport processes - this results in kidney damage
(from mild, reversible impairment to severe, acute tubular necrosis, which can be irreversible).

25. AMINOGLYCOSIDES 3. Neuromuscular paralysis:
mostly after direct intraperitoneal or intrapleural application of large doses of aminoglycosides.
mechanism responsible is a decrease in the release of acetylcholine from prejunctional nerve endings .
Patients with myasthenia gravis are particularly at risk.
Prompt administration of calcium or neostigmine can reverse the block.
4. Allergic reactions: Contact dermatitis - a common reaction to topically applied neomycin.

26. MacroliDES bind irreversibly to a 50S subunit of the bacterial
ribosome
mechanism of action is inhibition of the translocation step of protein synthesis
are bacteriostatic
consist of a large macrocyclic lactone ring, rings are usually 14-, 15-, or 16-membered
ERYTHROMYCIN CLARITHROMYCIN AZITHROMYCIN

27. MacroliDES Administration: absorbed orally Distribution:
Food interferes with absorption of Erythro and Azithromycin but can increase that of clarithromycin.
Azithromycin - available for IV infusion,
but IV erythromycin - high incidence of thrombophlebitis,
- i.m. inj. are painful.
Distribution:
well in all body fluids except the CSF.
Erythro - diffuses into prostatic fluids and has the unique characteristic of accumulating in macrophages.
all drugs concentrate in the liver.
inflammation allows for greater tissue penetration.
Also clarithromycin, azithromycin, and telithromycin are widely distributed in the tissues. 27

28. MacroliDES Metabolism:
are extensively metabolized with exception of AZI.
inhibit the oxidation of a number of a drugs through its
interaction with the CYP-450 system.
Interference with the metabolism of drugs such as theophylline and carbamazepine has been reported for clarithromycin. Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity.
Excretion:
Erythro and azithro concentrated and excreted in an active form in the bile. Partial reabsorption occurs vienterohepatic circulation.
Inactive metabolites are excreted into the urine.
In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver (Adjust dosage in compromised renal function!).
Interference with the metabolism of drugs such as theophylline and carbamazepine has been reported for clarithromycin. Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity. 28

29. MacroliDES Adverse effects: Epigastric distress
- common - can lead to poor compliance for Erythro Clarithro and azithro - better tolerated by the patient, but GIT problems are also most common side effects.
Cholestatic icterus
Ototoxicity: transient deafness - erythromycin,
especially at high dosages.

30. Chloramphenicol
broad-spectrum antibiotic- a wide range of G+ and gram– organisms
because of its toxicity – systemic use is restricted to life- threatening infections or is use by local administration
- excellent activity against anaerobes
- mostly bacteriostatic or bactericidal - to H. influenzae)
life-threatening infections (H. influenzae,Bacteroides fragilis and
eningitis where PNCs cannot be used).
In typhoid fever: amoxycillin and cotrimoxazole less toxic. .

31. Chloramphenicol Mechanism of action:
It binds to the bacterial 50S ribosomal subunit and inhibit
protein synthesis at the peptidyl transferase reaction.
Because of the similarity of mammalian mitochondrial
ribosomes to those of bacteria, protein synthesis in these
organelles may be inhibited at high circulating
chloramphenicol levels - producing bone marrow toxicity or
finally multiorgan insufficiency!!

32. Chloramphenicol Administered intravenously or orally.
Completely absorbed after the oral route - lipophilic
Widely distributed including the CSF - it readily enters the normal CSF.
Excretion
- conversion in the liver to a glucuronide that is secreted
by the renal tubule.
Only about 10% of the parent compound are excreted by
glomerular filtration.
It is also secreted into breast milk.

33. Chloramphenicol Adverse effects
Anemia: Hemolytic anemia in patients with low levels of glucose 6-phosphate dehydrogenase. Other types of anemia - include reversible anemia (is dose-related and occurs concomitantly with therapy) and Aplastic anemia (pancytopenia), which is idiosyncratic and usually fatal !!! - is independent of dose and may occur after therapy has ceased !!!

34. Chloramphenicol
Gray baby syndrome: in neonates if the dosage is not properly adjusted. Low capacity to glucuronylate chloramphenicol and they have underdeveloped renal function - a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes - poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term "gray baby") and death. Adults who have received very high doses of the drug can also exhibit this toxicity.

35. Chloramphenicol Potential teratogenic effects
Dysmicrobia, GIT disturbances, diarrhea, hypovitaminosis B and K
Interactions - it inhibits some hepatic P450 and blocks
the metabolism of drugs (warfarin, phenytoin, tolbutamide) -
elevation of their concentrations - potentiation of their effects.

36. CLINDAMYCIN mechanism as macrolides antagonism when co-administered
infections caused by anaerobic bacteria - Bacteroides fragilis
also active against non-enterococcal, gram-positive cocci
Note: Clostridium difficile is resistant to clindamycin.

37. Given orally (well absorbed) or parenterally
Distributes well into all body fluids except the CSF.
penetration into bone occurs even in the absence of inflammation
It undergoes extensive oxidative metabolism - to inactive products
excreted into the bile or urine by glomerular filtration
Therapeutic levels of the drug are not achieved in the urine
accumulation
in patients with either severely compromised renal function or hepatic failure.

38. CLINDAMYCIN - AE skin rashes
the most serious adverse effect is potentially fatal pseudomembranous colitis !! (caused by overgrowth of Clostridium difficile) - vancomycin
GIT disturbances
impaired liver function
vancomycin is usually effective in the treatment. (Vancomycin should be reserved for a condition that does not respond to metronidazole).