Micro 8 And 9 Summary

UNIVERSITY Of JORDAN

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Faculty OF Medicine

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ILECTURE NO: I DATE:-

8+9

SV~~Qr

19/10/tOO

DONE, BY:

~DR.:

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Miral, AI.. , • as,,,,

Antimicrobial Drugs Types of Antimicrobial Drugs:

I. Those that inhibit the synthesis of the CELL WALL: 1) B-Lactam drugs: -Two types: Penicillin and Cephalosporin -Narrow-moderate spectrum: affect mainly gram +ve, anaerobic bacteria, and less of gram -ve aerobic bacteria. Penicillin: -6 C

-First drug to treat gonorrhea, but the gonorrhea bacterium has become resistant to penicillin. -Up to 90016 of Staphylococcus is considered resistant to penicillin -composed of 2 rings: 1) B-Lactam ring 2) 5-Thiazolidine Ring -the amino group and the carboxyl group on the side chain carbon can be modified· A) Penic;illin G:J194o:=1941) -Bactericidal -NarrQw.spe,ctrum: gram +ve aerobic bacteria, mainly gram +ve cocci (streptococcus, staphylococcus- first drug to treat them) -Cannot be ta~en Qralfv, Only IV or 1M "

B) Penicillin V: (after 2 years from penicillin G) -Bactericidal -Narrow spectrum: gram +ve aerobic bacteria, mainly gram +ve cocci (streptococcus, staphylococcus), facultative anaerobic bacteria especially that found in the intestine. -Taken orally, or by IV, 1M

C) Ampicillin + Amoxicillin: (1965) -Bactericidal -Broad spectrum: gram +ve and gram -ve bacteria especially Enterobacteriacea D) Methicillin: (1961) -Anti penicillinase, bactericidal -Narrow spectrum: gram +ve, staphylococcus -Not stable and will be inactivated at room temperature -Can be very toxic during the treatment -Not used anymore

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E) Oxacillin: (1960s) -Antipenicillinase, bactericidal -Narrow spectrum: gram +ve, staphylococcus F) Cloxacillin + Fluoroxacillin: (1960s)

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-To-Oxacillin they have added atom or F atom to produce these drugs -A-ntipenicillinase, bactericidal - ---- -Narrow spectrum: gram +ve resistant to penicillin, staphylococcus NOTE: MRSA (Methicillin Resistant Staphylococcus aureus -7 resistant to all types of BLactam drugs) G) Augmentin: -(Amoxicillin + Clawlanic acid [a chemical structure and not a drug, B-Lactamase inhibitor]

-7 Co-amoxiclav -Anti penicillinase, bactericidal -Broad spectrum: gram +ve bacteria and gram -ve bacteria like pseudomonas -Used for respiratory and urinary tract infections H) carbencillin + Piperacillin + Ticarcillin: (mid 1970s) -Carboxyl penicillin drugs -7 carboxyl group binding to their side chain -Mainly against gram -ve Pseudomonas spp. (anti-pseudomonas drugs) which cause nosocomial infections -IV 11M I) Monobactam: (represented by Aztreonan) - (19905) -Monobactam ring + B-Lactam ring -Anti penicillinase, bactericidal -Mainly gram -ve aerobic bacteria such as pseudomonas -IV I 1M only, and only in serious infections, and nosocomial infections -Used to treat meningitis and septicemia cau~ed by_gram -ve bacteria

J) carbapenem: (represented by Imipenem and Meropenem) - (mid 19905), Entrapenem (2000) -Carbapenem ring + B-Lactam ring -Antipenicillinase, bactericidal -Broad spectrum: mainly gram -ve Enteric bacteria, a'1d gram +ve bacteria resistant to penicillin -IV I 1M only, and only in serious infections, and nosocomial infections -Used against: Pseudomonas aeruginosa, Acinetobacter spp., E.coli, K1ebseilla, Enterobacter spp. -Used to treat meningitis and septicemia caused by gram -ve bacteria

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*The action of penicillin drugs: Penicillin drugs consist of small molecules that cause the formation of pores in the bacterial cell wall to allow it to be absorbed and carried. If the bacteria is capsulated, the drug will also cross the capsule and reach the surface of the cell wall. As the penicillin reaches the last layer of peptidoglycan, it will be recognized as a foreign molecule and the bacteria will _directlv pr~~uce a substance called Penicillin Binding Protein (PBP). PBP is an enzyme that will attach to penici-llin and this attachment will activate other importanf-en~ymes within the . -.' - - ,-ceil wall known as "autolytic enzymes" which are found between the cytoplasmic membrane and the peptidoglycan layers -7 damage and lysis of the peptidoglycan layers -7 due to rise in the osmotic pressure inside the cytoplasmic membrane -7 the cell will eventually burst and die. Penicillin affects only the growing cells because it interferes in the development of the cell wall, so once the cell wall is built it will be difficult to affect the bacteria. '.

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Cephalosporin Drugs: -7C -Cannot treat MRSA -From orange filamentous fungus cephalosporium -amino group and side chains can be replaced -made of 2 rings: 1) B-lactam ring 2) 6-dihydrothiazine ring -40 types available in the market -First cephalosporin was isolated from sewage in Italy -somewhat resistant to staphylococcus penicillinase, however, this does not mean they are resistant to B-lactamase -are not effective against Enterococcus spp. (gram +ve) which cause URI or Anaerobes -mainly used in the 70s and 80s to teat RTI, UTI, intestinal infections, blood sepsis, wound infections, CSF infections -more complicated than penicillin A) First Generation: (beginning of 1960s) -Cephraidin-e + Cephalexin + Cephalothin:

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-Anti B-lactamase, Bactericidal -Narrower spectrum than other drugs, similar activity to Ampicillin + Amoxicillin -Given orally except Cephalothin -Used to treat RTI and UTI B) Second Generation: (between 1970-1980) Cefoxitin + Cefuroxime -Anti B-lactamase, Bactericidal -Broad spectrum: anaerobes and facultative anaerobes, gram +ve and gram -ve bacteria such as E.coli, K1ebseilla, Enterobacter which belong to the group Enterobacteriacea. -Mainly injectable drugs but are modified to be given orally -Used to treat blood, intestinal infections, RTI, UTI -Still used, especially in surgeries 3

C) Third Generation: (mid 19805 to mid 19905) Ceftriaxone + Cefotaxime (modified from Cefuroxime to be given orally) + Ceftazidime (shows effectiveness against pseudomonas aerugihosa (gram -vel -7 immunocompromised condition) -Bactericidal 1--

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_ -NO resistance to B:-~ctam.as.!! -Mainly against gram -ve bacteria _

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-Used in the treatment of pneumonia, septicemia, meningitis, streptococcus' pneumonia. D) Fourth Generation: (1995) Cefepime -Bactericidal, Anti B-lactamase -Mainly against gram -ve bacteria like pseudomonas + Enterobacter (immunocompromised condition)

2) Peptidoglycan Drugs: -large # of A.A. -bactericidal -resistant to penicillinase -affect the membrane bound phospholipid carrier -affect the cross-linking A.As -very toxic -used in intestinal operations -topical use -gram +ve bacteria Bacitracin: -Bactericidal -Gram +ve bacteria (mainly) and gram -ve bacteria -Topical treatment, ointments --

-Used in the treatment of skin infections or IV / 1M, or for long periods of time -7 severe uncontrollable

--~Sh~uld not i)-e- ~Venorally, side effects

3) Glycopeptide Drugs: -glucose + polypeptides -only in serious infections -Gram +ve like Enterococcus which are resistant to cephalosporins and penicillin / Oxacillin, MRSA -Very toxic and cause intestinal problems due to the fact that they interfere with the synthesis of the cell wall, not in association with PBPs but by interfering with enzymes responsible for cross linking of peptidoglycan layers. .-Used as injectable not oral forms

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A) Vancomycin: -IV 11M -used as a final solution, toxic on high does and has large side effects -in Jordan, all staphylococcus are susceptible to Vancomycin B) Teicoplanin: -Clostridia, staphylococcus, some bacilli II. Those that affect CELL MEMBRANE integrity:

1) Colistin I Polymixen E:

-Colistin originated from a large group called polymixen (topical and oral treatments except colistin which can be injected to treat systematic infections) -polyenes- complex polypeptides -very toxic -bactericidal -broad spectrum: gram +ve and -ve bacteria -amino and nitro groups -Colistin is the only effective drug against Acinetobacter, which causes septicemia -Topical treatment drugs, systemic, against MR-pathogens, Nephrotoxic 2) Antifungal Drugs: -Complex structures of F, N, H, CI groups -they are F.A. derived drugs -form a complex with ergosterol, needed in fungal cell wall synthesis -against yeast (Candida), filamentous fungi -toxic drugs A) Polyene: -Large circular molecule consisting of hydrophobic and hydrophilic regions Nystatin: -Oral and topical treatments (skin and hair infections) -Safe Amphotercin B: -For systematic infections -but toxic B) Imdazole group: Ketoconazole: . -Orally for systematic infections and topical treatments (Candadasis especially for children) Clotrimazole: -All forms

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topical treatment

C) Triazole group: -New, more effective, less toxic -For hospital use only Fluconazol: -Applied orally or topically -- - - -For systematic treatment usually .. Itraconazole: -For systematic use -Applied orally, topically, IV III. Inhibition to PROTEIN SYSNTHESIS: Note: the bacterial ribosome

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70s = 30s and 50s

1) Aminoglycosides: -many amino groups + glucose + oxygen + carboxyl -a group of drugs that share chemical, antimicrobial, pharmacological and toxic characteristics - originated from soil bacteria (Actinomyces) -bind to 30s subunit - prevents the formation of a complex with mRNA -7 increases cell membrane leakage -bactericidal -broad spectrum: gram +ve and -ve (mainly), facultative anaerobes th

-nephrotoxicity + ototoxicity-toxic to the 8 cranial nerve which affects hearing, blood level monitoring -cannot affect anaerobes, streptococci, intracellular bacteria -used for serious infections, hospital use -IV / 1M

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reason: not absorbed by the intestine

-Can be inhibited by bacterial enzymes: acelytate, phosphorylate, denylate

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which act

while the drug is passing through the cell membrane, produced during the growth of bacteria in the presence of the drug

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-may face some bacterial resistance by production of certain enzymes that affect mainly the -

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side chains A) Streptomycin: -Against tuberculosis + Enterobacteria B) Neomycin + Kanomycin: (1950s) -Used for the treatment of intestinal infections, nowadays used by mixing with other drugs

C) Gentamicin (sepsis, meningitis, active against p. aeruginosa, combined with penicillin) + Tobramicin + Netilmicin: (1970s) D) Amikacin: (1980s) -IV

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2) Tetracyclines: (mid 1950s) -bacteriostatic -Broad spectrum: gram +ve and -ve bacteria -derived from fat -Four fused rings (different R) + oxygen + hydroxyl .. -later modified - by the _additi<m, pf atoms like Fluorine (fluorotetracycline), oxygen (oxytetracycline),' chlorine (chlorotetracyclin~)~min~ group· (aminotetracycline) -10 types -7 same effect, differ only in the pharmacokinetics -function: 1) cause damage to the cell membrane [bacteria can develop resistance .-7 barriers (reduce active transport) -7 accumulation of drug in cell membrane], 2) bind to 305 subunit of bacteria ribosomes -7 prevent the attachment of amino-acyl tRNA to 305 -7 prevent protein synthesis -used in the treatment of cholera infection (intestinal), and respiratory and genital tract infections caused by intracellular microorganisms like Mycoplasma, Chlamydia, legionella. -Develop resistance by reduced active transport Doxcycline + Minocycline: -Most commonly used -Mostly orally or injected -Used in the treatment of cholera, respiratory and genital infections -Side Effect: enhance the growth of yeast and facultative anaerobic bacteria -Not recommended to be used by children under the age of 8 or pregnant women. 3) Chloramphenicol: (mid 1950s) -bacteriostatic -broad spectrum: gram +ve and gram -ve bacteria, however they are more effective than tetracyclines on gram -ve bacteria -attaches to 50s subunit of the ribosome blocking the formation of the peptide bond -very small, can easily penetrate the intracellular compartment. It can enter the spinal fluid to treat meningitis and to the brain (it can cross the blood brain barrier) and so used to treat CN~ infecti~s.

-Used in the'treatment of infections from skin, respiratory system, intestine (typhoid), meningitis, septicemia -problem: certain bacteria can develop resistance to it rapidly and others slowly -Toxic -It might suppress the bone marrow and lead to Aplastic Anemia 4) Macrolides: -large lactone ring (14 or 16 carbon ring + carboxyl + other side chains) -attaches to the 50s subuni,t of the ribosome -7 either inhibiting peptidyl transferase or translocation of the growing polypeptide -Narrow spectrum: only gram +ve bacteria (Antistapyhlococcus, Antistreptococcus)

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A) Erythromycin: -Narrow spectrum: mainly gram +ve bacteria -Mostly taken orally, less by IV -Short acting effect (6hrs), 3-4 tablets per day -Used in the treatment of respiratory infections in patients hypersensitive to either penicillin or cephalosporin _ _ _ B) Clarithromycin + Azithromycin: -Derivatives of Erythromycin but with longer terminal half life, Le. longer acting effect, same activity, different pharmacokinetics -Relatively nontoxic -Mostly active against gram +ve / intracellular bacteria -Used in the treatment of respiratory, urinary, vaginal infections like pneumonia, diphtheria, streptococcus, staphylococcus, Mycoplasma, Chlamydia, Legionella, pneumophilia infections, B-hemolytic streptococcus5) Uncosamindes:

-A.A -bacteriostatic -related to but not considered true macrolides -narrow spectrum: mainly against staphylococcus, streptococcus (gram +ve bacteria) -used in oral cavity and bone treatments -accumulate in high levels in bone -used by dentists -kill anaerobic bacteria while enhance the growth of facultative anaerobic bacteria (sporeforming Oostridium ditficile -7 found in small % in t,he intestine, normally resistant to this drug -7 increase in # -7 enterotoxin -7 affect mucosa of the large intestine and blood vessels there -7 bloody diarrhea -7 condition: Pseudomembranous Colitis) Clindamycin + lincomycin: -Treat infections in the oral cavity 6) Fusidic Acid: -Bacteriostatic -Gram +ve bacteria, staphylococcus -No effect on gram -ve bacteria or streptococcus -Applied topically, for skin infections, not used in systematic infections because it is ver:v toxic -Steroid antibiotic, prevents translocations of tRNA to ribosomes Metronidazole (Flagyl) -Anti-protozoa and aerobic bacteria

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IV. Inhibition to NUCLEIC ADD Svnthesis:

1) Nalidixic Acid, Nitrofurantoin (Nitrofurans): -Anti urinary drug -Excreted up to 99% in the urinary bladder (can spread up or down) ____-~ffe~_l!lainly gram -ve bacter~a_.such as E.coliwhich is responsible for 70-80% of urinary _ - tract infections _ -Affect DNAgyrase 7 type of DNS polymerase needed for the formation of double helix of DNA 2) Quinolones + Fluoroquinolones: (1980-1990) -Derivatives of Nalidixic Acid -Bactericidal -Broad spectrum: mostly to treat gram -ve bacteria in the beginning -Inhibits DNAgyrase -May develop resistance by altered DNAgyrase -Used in the treatment of intestinal, vaginal, respiratory, urinary, blood stream and soft tissue infections -Not used for infections in the CNS -Used against aerobic bacteria, protozoa (giardia), and amoeba A) Norfloxacin: -Used in the treatment of urinary (mainly) and respiratory infections B) Ciprofloxacin: -Used in the treatment of pneumonia, septicemia, urinary, respiratory, blood, intestinal, and soft tissue infections -MOST USED ANTIBIOTIC IN JORDAN

C) Levofloxacin: -Used mainly in the treatment of upper respiratory tract infections -Gram +ve and -ve bacteria including Mycoplasma and Chlamydia -Usually, nowadays it can escape resistance machinery of bacterial enzymes 3) Rifamycin I Rifampin: -Bactericidal -Specific; used against one or two types of infections -Rifampin is one type of Rifamycin that originated "from soil bacteria just like aminoglycosides but less toxic -Bind to RNA polymerase 7 prevent transcription -Broad spectrum: especially intracellular bacteria such as Mycobacteria, Chlamydia, Brucella (gram -vel -Used in the treatment of tuberculosis -Bacteria might develop resistance against these drugs by producing bacterial enzymes that produce a change in RNA polymerase B-subunit

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V. Inhibition synthesis oflMPORTANT METABOUl£S:

1) Sulfa drugs I Sulfonamides: (1934) -Amino groups + sulfur -Bacteriostatic -Broad spectrum: gram +ve and -41e bacteria -Taken orally or-as cream -Important analogue drug (structure related drug) _ ~Chemically

synthesized

-PABA (para-aminobenzoic acid) is an essentia_1 component in metabolic pathway for the synthesis offolic acid -7 needed for protein synthesis These drugs resemble PABA -7 compete with it -7 bind to enzymes -7 inhibit the production of folic acid -Mammals don't need PABA or its analogs, can tolerate sulfa drugs -No effect on human if applied in small doses, but since they must be applied in high levels (5-10g/day) -7 accumulate in kidney -7 toxic -7 kidney failure -Used in the treatment of simple respiratory infections by streptococcus and -urinary . infections by E.coli -As a result of side effects + developed resistance -7 new drug: Co-trimoxazole ~ sulfamethoxazole (modified sulfur drug) + trimethoprim (a related, not sulfa drug) -synergistic (additive) activity -broader spectrum: more effective on gram +ve and -ve bacteria except for anaerobes -used for urinary and respiratory tract infections 2) Antituberculosis Drugs: -restricted for treating Mycobacterium tuberculosis -7 inhibits mycolic acid in its cell wall -less effective on other organisms A) Izoniazid (INH) B) Streptomycin _.

. C) Ethambutol ---- - - ---- - ----- , 0) Rifampin

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E) Para-Amino Salicylic acid -These drugs are not used as single but synergistic drugs. For example treat with streptomycin for the first 4 months then shift to INH. -Usually, Streptomycin is used with INH And Rifampin with Ethambutol -Rapid resistance development -Treatment period of Mycobacterium tuberculosis using these drugs lasts up to 6-24 months -Unfortunately, a lot of mycobacterium tuberculosis has developed resistance against these drugs. (This was written based on 2007 and 2008 sheets) Best wishes, Miral AI-Nimri

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Figure 1.4 ClaSSification of some meaicallyirnportant bacterial families. .i

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