Antibiotics

1. Antibiotics

3. I-Antimetabolites

4. Folate Antagonists Folate-derived cofactors are essential for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication. Therefore, in the absence of folate, cells cannot grow or divide. To synthesize the critical folate derivative, tetrahydrofolic acid, humans must first obtain preformed folate in the form of folic acid as a vitamin from the diet. In contrast, many bacteria are impermeable to folic acid and other folates and, therefore, must rely on their ability to synthesize folate de novo. The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit this de novo synthesis of folate.

6. Cont; Sulfonamides -One of the first groups of antibiotics -Bacteriostatic in action -Prevent synthesis of folic acid required for synthesis of purines and pyrimidines. -Does not affect human cells or certain bacteria that can use preformed folic acid -Examples: Short acting: sulfadiazine, sulfamethazine Intermediate acting : sulfamethoxazole Long acting : sulfathiazole , sulfasalazine

9. F. Spectrum of Activity -Broad range of Gm+ and Gm- -They are also active against some protozoa as toxoplasmosis and chloroquine-resistant malaria when combined with pyrimethamine (which interferes with folic acid synthesis by inhibiting the enzyme dihydrofolatereductase). G. Resistance - common due to: 1) an altered dihydropteroate synthetase. 2)decreased cellular permeability to sulfa drugs 3) enhanced production of the natural substrate, PABA.

10. H. Uses 1- Respiratory and urinary tract infection. 2-Ulcerative colitis 3-Skin wounds and skin burns. 4-Toxoplasmosis and malaria. 5-in burn units,they have been effective in reducing burn-associated sepsis, because they prevent colonization of bacteria (silver (sulfadiazine given topically). 6-Sulfonamides are as efficacious as oral penicillin in preventing streptococcal infections and recurrences of rheumatic fever among susceptible subjects 7-For some sexually transmitted infections (e.g. trachoma, chlamydia) I. Side effects -Hypersensitivity reactions (e.g., rashes and drug fever) in a small number of patients. Other cause allergic reactions include photosensitivity. -Stevens-Johnson syndrome is also associated with sulfonamide use; it is characterized by fever, malaise, erythema ,and ulceration of the mucous membranes of the mouth and genitalia.

11. -High concentration of sulfonamides with aqueous solubility which is sufficiently low, the free drug or its metabolites may form crystals and cause bleeding or complete obstruction of the kidneys. i-Combinations of sulfa (for lowering the dosage of individual agents) ii- A lot of fluids intake iii-Alkalinization of the urine (to increase excretion) to reduce the chance of crystalluria -Sulfonamides compete for sites on plasma proteins that are responsible for the binding of bilirubin. As a result, less bilirubin is bound, and in the newborn, the unbound bilirubin can be deposited in the basal ganglia, causing kernicterus, a toxic encephalopathy. For this reason, sulfonamides should not be administered to newborns or to women during the last 2 months of pregnancy or lactating females.

13. D. Antibacterial spectrum -The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. It is active against most gram-positive and gram negative organisms. There is little activity against anaerobic bacteria.However, trimethoprim is 20-to 50-fold more potent than the sulfonamide.

14. E. Uses Trimethoprim may be used alone in the treatment of acute UTIs and in the treatment of bacterial prostatitis and vaginitis is used in the treatment of genitourinary, GI, and respiratory tract infections. F. Resistance Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity for trimethoprim. Overproduction of the enzyme may also lead to resistance, because this can decrease drug permeability. G. Adverse effects Trimethoprim can produce the effects of folic acid deficiency. These effects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having very poor diets. These blood disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria.

15. III-Cotrimoxazole The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole shows greater antimicrobial activity than equivalent quantities of either drug used alone .The combination was selected because of the similarity in the half-lives of the two drugs. Rationally, by blocking the first stepin folic acid synthesis, there is no real reason to block further steps. However, there are some bacteria which can inhibits the initial blockage, and so this may be the rationale for the use of such combination. -There is synergy between the two drugs - the combined effect is greater that the expected sum of their activities -Individually the drugs are bacteriostatic; however, in combination they are bactericidal -The use of two drugs will delay the emergence of resistance.

16. Mechanism of action • Resistance • -The bacteria by gentic mutation they do not need to make folic acid they utilize already formed folic acid. • -Overproduce the target e.g. To overcome trimethoprim, bacteria can overproduce DHFR to overcome the inhibition of trimethoprim. • -Bacteria produce mutated DHFR

17. Side effects TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Uses TMP-SMX is used in the treatment of infection caused by ampicillin-resistant Shigella and for antibiotic-resistant Salmonella. -Successful in treatment of traveler’s diarrhea due to susceptible E. coli. -Because trimethoprim accumulates in the prostate, TMP-SMX is used to treat prostatitis caused by sensitive organisms. - Used n Pneumocystis jiroveci pneumonia occur in HIV patients.

18. Uses of Cotrimoxazol

19. II-Protein Synthesis Inhibitors

20. Reason For Selective Toxicity A number of antibiotics exert their antimicrobial 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 in human).

21. Inhibitors of bacterial protein synthesis, Overview • These agents are bacteriostatic, protein-synthesis inhibitors that target the ribosome • Examples: tetracyclines, aminoglycosides, macrolides, chloramephnicol Tetracyclines Chloramphenicol Θ Θ (P-site) (A-site) Θ Macrolides, clindamycin

22. 1-Aminoglycosides They are highly polar with polycationic structure. These characters prevent adequate absorption of these antibiotics after oral administration. Therefore, all aminoglycosides (except neomycin )must be given parenterally to achieve adequate serum levels. Note: The severe nephrotoxicity associated with neomycin precludes parenteral administration, and its current use is limited to topical application for skin infections or oral administration to prepare the bowel prior to surgery. The bactericidal effect of aminoglycosides is concentration and time dependent; that is, the greater the concentration of drug, the greater the rate at which the organisms die. They also have a postantibiotic effect (residual bactericidal activity persisting after the serum concentration has fallen below the MIC). Because of these properties once-daily dosing with the aminoglycosides can be employed. The aminoglycosidessynergize with β-lactam antibiotics and vancomycin because of the latter's action on cell wall synthesis, which enhances diffusion of the aminoglycosides into the bacterium producing synergistic bactericidal effect in vitro against enterococci, streptococci and staphylococci

23. Mechanism of action • Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of G-ve bacteria to enter the periplasmic space. Their transport across the cytoplasmic membrane depends on electron transport (membrane electrical potential is required to drive permeation of these antibiotics) • This active transport is rate-limiting and can be inhibited by divalent cations (e.g., Ca2+ & Mg2+), a reduction in pH and anaerobic conditions. The last two conditions impair the ability of the bacteria to maintain the membrane potential, which is the driving force necessary for transport. Thus the antimicrobial activity of aminoglycosides is reduced markedly in the anaerobic environment of an abscess for example. • Once inside the cell, aminoglycoside binds irreversibly to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA, leading to accumulation of abnormal initiation complexes, so-called streptomycin monosomes, blocking further translation of the message 1-Aminoglycosides

24. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to: • premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein (B) = nonsense • incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins (C)=misense • The resulting aberrant proteins may be inserted into the cell membrane, leading to altered permeability and further stimulation of aminoglycoside transport. This leads to leakage of small ions, followed by larger molecules and, eventually, by proteins from the bacterial cell. This progressive disruption of the cell envelope, as well as other vital cell processes, may help to explain the lethal action of aminoglycosides

26. 2-Any organism resistant to one aminoglycoside is not resistant to all Resistance 1-Resistance can occur by altering the 30s ribosome binding site of the drug / low affinity of the drug. 2- Impaired intracellular transport: Decrease the transport of the AB. 3- Inactivation by microbial enzymes :Bacteria can produce deactivating enzymes as phosphotransferases, adenyltransferases and acetyltransferases Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance is not an invariable rule. Note: 1- Amikacin is less vulnerable to these enzymes than are the other antibiotics of this group

27. Pharmacokinetics • They are highly polar cations and therefore are very poorly absorbed from the GIT • All aminoglycosides are absorbed rapidly from intramuscular sites of injection • Because of their polar nature, they do not penetrate into most cells, the CNS and the eye • The elimination of aminoglycosides depends almost entirely on the kidney • The half-lives of aminoglycosides in plasma are similar (2-3 h in patients with normal renal function) • The half-life for tissue-bound aminoglycoside has been estimated to range from 30 to 700 h

28. Spectrum and Uses Aminoglycosides act bactericidalon dividing and non dividing micro-organisms.They are in general active againstaerobic Gram-negative including Pseudomonas aeruginosa. The exact mechanism of their lethality is unknown because other antibiotics that affect protein synthesis are generally bacteriostatic They have little activity against anaerobic microorganisms Their action against most G+ve bacteria is limited, and they should not be used as single agents to treat infections caused by such bacteria

29. Therapeutic Uses: • Aminoglycosides are used in combination with a penicillin or a cephalosporin for the therapy of serious G-ve microbial infections (e.g., P. aeruginosa, Enterobacter, urinary tract infections, bacteremia, infected burns, pneumonia) • Because of their toxicity with prolonged administration, aminoglycosides should not be used for more than a few days unless deemed essential for a successful or improved outcome • Once the microorganism is isolated and its sensitivities to antibiotics are determined, the aminoglycoside should be discontinued if the infecting microorganism is sensitive to less toxic antibiotics

30. Streptomycin (or gentamicin) is the drug of choice for the treatment of tularemia • Streptomycin and gentamicin are effective agents for the treatment of all forms of plague • Treatment of tuberculosis, streptomycin always should be used in combination with at least one or two other drugs to which the causative strain is susceptible • Neomycin and framycetin, whilst too toxic for systemic use, are effective for topical treatment of the conjunctiva or external ear. • Respiratory tract infections. • GIT infections as amebiasis (mostly neomycin).

31. Adverse effectsAll aminoglycosides are ototoxic and nephrotoxic. -Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. • Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate nephrotoxicity and should be avoided. -Ototoxicity can manifest itself either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage, evident by vertigo, ataxia, and loss of balance.

32. Copnt.: Adverse effects -Also they produce a curare-like effect with neuromuscular blocking effect that results in respiratory paralysis. The mechanism responsible is a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis are particularly at risk.This paralysis is usually reversible by calcium gluconate or neostigmine. -Hypersensitivity occurs infrequently.

33. 2- TETRACYCLINES They are safe, inexpensive ,broad-spectrum, bacteriostatic antibiotics, that are effective against aerobic and anaerobic gram-positive and gram-negative bacteria as well as against organisms other than bacteria (ex. Protozoa). .

34. 4 6 5 7 -The basic tetracycline structure consists of four benzene rings with various substituent on each ring.

35. Cont. Tetracyclines • Oxytetracycline is a natural product produced by Streptomyces rimosus. • Tetracycline is a semisynthetic derivative of chlortetracycline, produced by Streptomyces aureofaciens • Demeclocycline is the product of a mutant strain of Strep. Aureofaciens • Methacycline, doxycycline and minocycline all are semisynthetic derivatives

36. Tetracyclines are classified as: • short-acting :chlortetracycline, tetracycline, oxytetracycline (2) intermediate acting :demeclocycline and methacycline (3) long-acting :doxycycline and minocycline The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing.

37. A newly approved tetracycline analog, tigecycline, Is a semisynthetic derivative of minocycline. Many tetracycline-resistant strains are susceptible to tigecycline. It has broad spectrum. Tigecycline was developed to overcome the recent emergence of tetracycline “resistant organisms that utilize efflux and ribosomal protection to infer resistance WHY???.

38. Mechanism of action -Tetracyclines enter microorganisms in part by passive diffusion (through cell wall) and in part by an energy-dependent process (active transport through cell membrane). Susceptible cells concentrate the drug intracellularly. -Once inside the cell, tetracyclines bind reversiblyto the 30Ssubunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNAto the acceptor site on the mRNA-ribosome complex. This prevents addition of amino acids to the growing peptide. -Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis.

40. Mechanisms of resistance • Decreased intracellular accumulation due to either decreased influx or increased efflux by an active transport protein pump … (the most important) • Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome • Resistance is primarily plasmid-mediated and often is inducible • Any organism resistant to one tetracycline is resistant to all.

41. Antimicrobial actions: • Tetracyclines are active against many G+ve & G-ve bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas • They are also active against some protozoa, e.g., amebas • The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, which are less rapidly effluxed by the pump that is responsible for resistance

42. Pharmacokinetics Substitutions on these rings are responsible for variation in thedrugs'individual pharmacokinetics, which cause small differences in their clinical efficacy. • Absorption after oral administration is approximately 30% for chlortetracycline ,60–70% for tetracycline, oxytetracycline, and methacycline; and 95–100% for doxycycline and minocycline. • Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations.The decreased absorption results from chelation with divalent and trivalent cations. • Tetracyclines are 40–80% bound by plasma proteins.Tetracyclines are distributed widely to tissues and body fluids except for CSF, where concentrations are 10–25% of those in serum. (Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcalcarrier state).

43. -Tetracyclines cross the placenta to reachthe fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to and damage growing bones and teeth. -Tetracyclines are excreted mainly in bile and urine. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels . Excretion into the urine, mainly by glomerular Filtration . Small % of the these drugs are excreted in feces. -Doxycycline, in contrast to other tetracyclines, is eliminated mainly nonrenaly , do not require dosage adjustment in renal failure. Thus it is one of the safest TET for the treatment of extrarenal infections, making it the tetracycline of choice for use in the setting of renal insufficiency. Minocycline is recovered from urine and feces in significantly lower amounts than are the other tetracyclines, and it appears to be metabolized to a considerable extent. Its renal clearance is low. The drug persists in the body long after its administration is stopped, possibly due to retention in fatty tissues. Nonetheless, its half-life is not prolonged in patients with hepatic failure

44. Spectrum & Clinical Uses -Tetracyclines are active against many Gram-positive and Gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and against some protozoa, as amebas. -Tetracyclines are sometimes employed in the treatment of protozoal infections, e.g., those due to Entamoeba histolytica or Plasmodium falciparum. • Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. • Tetracyclines are effective in treatment of Rocky Mountain spotted fever by rickettsia rickettsii. -Other uses include treatment of acne, They may act by inhibiting propionibacteria, which reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The relatively low doses of tetracycline used for acne are associated with few side effects -They are used in combination regimens to treat gastric and duodenal ulcer disease caused by H. pylori. -Although all tetracyclines enter the (CSF), their levels are insufficient for therapeutic efficacy, except for minocycline enters the brain in the absence of inflammation and also appears in tears and saliva so it is useful in eradicating the meningococcal carrier state, but not effective for CNS infections.

46. Adverse ReactionsTET can produce a variety of adverse effects ranging from minor inconvenience to life-threatening. -Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are not very common. -Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attributable to direct local irritation of the intestinal tract. These effects can usually be con- trolled by administering the drug with carboxy- methylcellulose, reducing drug dosage, or discont- inuing the drug.

47. -TET like other antimicrobial agents administered orally may lead to development superinfections, as Tetracyclines modify the normal flora, with suppression of susceptible organisms and overgrowth of pseudomonas, proteus, staphylococci, , clostridia (causing Pseudo membranous colitis ), and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis Diarrhea must be distinguished either: A. Normal -loose stools do not contain blood or leukocytes B. Pseudo membranous colitis -severe diarrhea, fever, stools containing shreds of mucous membrane and large number of neutrophils. As CI. difficile produces a toxin which is cytotoxic to mucosal cells.

48. --Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods to children under 8 years of age, similar changes can result. Tetracyclines can probably impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function

49. 3-Macrolides -The macrolides are a group of antibiotics with a macrocycliclactone structure to which one or more deoxy sugars are attached. Erythromycin was the first of these drugs to find clinical application, both as a drug of first choice and as an alternative to penicillin in individuals who are allergic to penicillin . -The newer members of this family include clarithromycin and azithromycin (semisynthetic derivatives of erythromycin). The structural modifications in these drugs: • improved acid stability • Enhanced absorption & tissue penetration • broadened the spectrum of activity -Ketolides and macrolides have very similar antimicrobial coverage. However, the ketolides are active against many macrolide resistant gram-positive strains .Telithromycin is a semisynthetic derivative of erythromycin, is the first ketolide antimicrobial agent that has been approved and is now in clinical use