ANTIBIOTICS
Assistant Prof. Dr. Shamil H. AL-Nuaimi M B ch B, M Sc, Ph D牤⽳桳灡硥汭砮汭埬滍㛣븐ျᚼ～繬⍬⋲选肶᠑ᙱⱻ襨喲ꑓ削鶎孳彴孤螡羽츦䨛탶˅ƶ풙蜌쳟㍼⾤Ⳟ앳툖첺裨德㢵㪓䤶Ꞧ缑罻킼傉쭆꾈ٯ繟共巴냁뭘ᅾ駱䗷�뷂蔲郔욥싦橣춧䫂딧ḗ�땩髎좹ἴ铀豞醋冥뭼夘▖缑駍㤖岶﷿꿺鿵㼌꺿갿捿㽏ﯢ䀘俯㲿枽�鞬噖ꀄ䴍眼㸵濱◰㱖栃魌殼ۓН荮͓洦챚瘀亓ꓯ癷횝閺ᘂ糭셳텇ꙟ缶됩藁鯨攴㧩즢孀嚭ꘈꇻ嘔꙲햾裂र炞錥襽ꍫℨ嘘쌷轫礙ạㄗ鈩蔯量�톂謐鬐㍛覞ق넅㨘蕟Ꝥ∛蕔貁织䍋涂嚥ᆂ⟤瘗媈ﴁ쌨�₅֨蒢餗偎ᅴ汯萴ꊚ揎㥯摋⽺㫇퀉뺶궊䌔敽쇧橂뾴謌숦�셐❺ঞ䔽賙ᵊ魣衖ꊦ馂⚼图剧ᾎᢷ仏緫ａ۲㎎⪿⩤瑢瞡鋰ꊺ곣糈물礑傦ᵐ渰갦炓㐿娢譻ᥞ꓅院⏨矜嬣貓螚埨搏幱姦빮⇜ᆤ몗盱�픉ꤻᨒ斞㗄ꂶ泖㦳槐ำ츣틦섢ݔ汔ᚵʕ楞쟪笪�⦄ᐥ성夛퉣丰뫞応⤫䖂걂㴴릵铉岪�ꌸ蒲繞奾俵搤䭟ꦦ㶌䎢䱋ꗩ켝ޒ儶붥ओ�攅틀ઌ㭶赁칷ẉ唐逪�擩날왡盖涃ꇋ徾䒆ҕẾ訇ꗯ㝜➔ꃦ誩ɧ⨩ঞ坢쵳쥖϶�䏶៍⧹䁄蛣䟛ဢ㸫≫ꐜ␟蠨읚愳橻㫬뛾ἷ蓏㎃䮡뢗⭣܈≰붰ų菓胞䜃⌧աຮ묟ࠥᣛ噟蒷迿퐑躼茗뽏᭒ɮи矰ఏ坃︌Ͽ倀͋ᐄࠀ℀㌀離핈豈ༀ搀獲搯睯牮癥砮汭轄仁ッ䐐䣯菼䢵၃ᕕ囪䑐隔�㝦䩱䝬榶뿒蹐ᦣ톽깛팧༖l Ȫ牤⽳桳灡硥汭砮汭䭐ȁ-!䣹Хщٛ牤⽳潤湷敲浸偬ՋЀЀ崀ကࣰ瘀 态ᘕ༏ᄀ泰쌀ࠋ Penicillins and Cephalosporins
Beta-lactam antibiotics
Drugs with structure containing a bata-lactam ring; include the penicillins and cephalosporins. This ring must be intact for antimicrobial action. Beta-lactamases: Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the lactam ring of certain penicillins and cephalosporins.Penicillin- binding proteins (PBP): Bacterial cytoplasmic membrane proteins that acts as the initial receptors for penicillins and other beta-lactam antibiotics Peptidoglycan , Murein (NAM, NAG): Chain of polysaccharides and polypeptides that are Cross-linked to form the bacterial cell wall.
Penicillins
A- Classification: - All penicillins are derivative of 6-aminopenicillanic acid and contain a beta-lactam ring structure that is essential for antibacterial activity. - Penicillin subclasses have additional chemical structure that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.C- Mechanism of Action and Resistance: # Beta-lactam antibiotics are bactericidal drugs. # They act to inhibit cell wall synthesis by the following steps: (1)binding of the drug to specific receptors (PBP). (2)inhibition of transpeptidase enzymes. (3)activation of autolytic enzymes that cause lesions in the bacterial cell wall.
B- Pharmacokinetics: # Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability. # They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion, the later process being inhibited by probenecid. # Ampicillin and nafcillin are excreted partly in the bile.
# Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity. # The formation of beta-lactamases (penicillinases) by most staph. And many gram-negative organisms is thus a major mechanism of bacterial resistance.
# Structural changes in target PBPs is another mechanism of resistance and is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci.
# In some gram-negative rods (e.g. Pseudomonas aeruginosa ) changes in the porin structure in the outer membrane may contribute to resistance by impeding access of penicillins to PBPs.
#Inhibitors of these bacterial enzymes (eg. Clavulanic acid, sulbactam, tazobactam) are sometimes used in combination with penicillins to prevent Their inactivation.
D. Clinical uses: 1. Narrow spectrum, penicillinase- susceptible agents: (prototype is penicillin G) # Clinical use include therapy of infections caused by : - Streptococci. - Meningococci. - Gram positive bacilli. - Spirochetes.
# Resistant m.o. : - Several strains of pneumococci. - Most strains of Staph. Aureus. - Strains of N. gonorrhoeae # It is the drug of choice for syphilis. # Activity against enterococci is enhanced by aminoglycisides. # Penicillin V is an oral drug used mainly in oropharyngeal infections.
2- Very narrow spectrum, penicillinase- resistant drugs: - includes methicillin (prototype), nafcillin and oxacillin. - used in the treatment of staphylococcal infections. - MRSA are resistant to members of this subgroup and may be resistant to multiple antimicrobial drugs.
3- Wider spectrum, penicillinase-susceptable drugs: a. Ampicillin and amoxicillin: - Their indications similar to penicillin G as well as infections due to enterococci, Listeria monocytogenes, E. coli, Proteus merabilis, Haemophilus influenzae , and Moraxella catarrhalis , though resistant strains occur.
- When used in combination with inhibitors of penicillinases ( clavulanic acid, etc.) their antibacterial activity is enhanced.
- In enterococcal and listerial infections ampicillin is synergistic with aminoglyciside.
b- Piperacillin and ticarcillin: - Have activity against several G- rods including pseudomonas, enterobacter and in some cases Klebsiella spp. - most members have synergism with aminoglycosides. - they are susceptible to penicillinases and often used in combination with penicillinase inhibitors.
E. Toxicity: 1. Allergy: include urticaria, severe pruritus, fever, joint swelling, haemolytic anemia, nephritis, and anaphylaxis.
- About 5-10 % of persons with a past history of penicillin reaction have an allergic response when given it again.
- Methicillin causes nephritis more than others. - nafcillin is associated with neutropnia. - Complete cross-allerginicity between different penicillins should be assumed. - Ampicillin frequently causes maculopapular skin rashes that may not be an allergic reaction.
2. Gastrointestinal disturbances: - Nausea and diarrhea may occur with oral penicillins, especially with ampicillin which has been implicated in pseudo- membranous colitis. - Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram- positive organisms or yeasts.
CEPHALOSPORINS:
A. Classification: - Derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. - They are designated first-, second-, third-, forth and fifth- generation drugs according to the order of their introduction Into clinical use.B. Pharmacokinetics:
- several are available for oral use but most administered parentrally. - The major elimination is by renal excretion via active tubular secretion, some may undergo hepatic metabolism. - Cefoperazone and ceftriaxone are excreted mainly in the bile. - Most 1st and 2nd generation do not enter the CSF fluid even when the meninges are inflammed.C. Mechanism of Action and Resistance:
- They bind to PBPs on bacterial cell membrane to inhibit cell wall synthesis by mechanism similar to those of the penicillins. - Cephalosporins are batericidal against susceptible organisms. - less susceptible to staph. Penicillinases. - some bacteria are resistant through the production of other beta-lactamases. - Resistance may resulted from decrease in membrane permeability and from changes in PBPs. - Methicillin resistant staph. are also resistant to most cephalosporins.D. Clinical Uses:
1. First generation drugs: - Cefazolin (parentral) and Cephalexin (oral) are examples of this subgroups. - They are active against G+ cocci, including Staph. and Strept., E. coli and K. pneumoniae. - Clinical uses include treatment of infections Caused by these organisms and surgical prophylaxis in selected conditions. - Have minimal activity against gram-negative cocci, enterococci, methicillin-resistant Staph, and most G-rods.
2. Second-generation drugs:
- Less active against G+ organisms than the 1st generation drugs but have an extended G- coverage. - Clinical uses include infections caused by Bacteroids fragilis (Cefotetan, cefoxitin) and by H. influenzae or Morexella catarrhalis (cefuroxime, cefaclor).3. Third Generation Drugs: (Cefoperazone, Cefotaxime)
- increased activity against G- organisms resistant to other beta-lactam drugs and ability to penetrate the blood –brain barrier (excpet cefoperazone and cefixime). - Most are active against enterobacter, providencia, Serratia marcescens and beta- lactamase producing strains of H. influenzae and Neisseria.
- Individual drugs also have activity against pseudomonas (cefazidime) and B. fragilis (ceftizixime). - Drugs in this subclass should usually be reserved for treatment of serious infections (e.g. bacterial meningitis). - Ceftriaxone (parenteral) and cefixime (oral),currently drugs of choice in gonorrhea - Likewise, in acute otitis media,a single injection of ceftriaxone is an effective as 10-days course of treatment with amoxicillin or cefaclor.
4. Fourth-generation drugs:
- Cefipime is more resistant to beta- lactamases produced by G- organisms, including enterbacter, haemophilus, and neisseria. - Cefipime combines the G+ activity of the 1st generation agents with the wider gram-negative spectrum of the 3rd generation cephalosporins.E. Toxicity: 1. Allergy: - Cephalosporin cause a range of allergic reactions from skin rashes to anaphylactic shock. They occur less frequently with cephalosporin than with penicillins. - Complete cross hypersensitivity between different cephalosporins should be assumed. - Cross- reactivity between penicillins and cephalosporins is incomplete (5-10 %). - Patients with a history of anaphylaxis to penicillins should not be treated with cephalosporins.
2. Other adverse effects: - They may cause pain at intramuscular injection sites and phlebitis after iv administration. - Increase the nephrotoxicity when combined with aminoglycosides. - Drugs containing a methylthiotetrazole group (cefoperazone, cefotetan, moxalactam) cause hypoprothrombineamia and may cause disulfiram-like reactions with ethanol. - Moxalactam also decreases platelet function and may cause severe bleeding.
Other Beta-lactam Drugs
A. Aztreonam: - is a monobactam that is resistant to beta-lactamases produced by certain G- rods, including klebsiella, pseudomonas and serratia. - has no activity against G+ bacteria or anaerobes.
B. Imipenem and meropenem:
- They are carbapenems ( chemically different from penicillins but retaining the beta-lactam ring structure) with low susceptibility for beta-lactamases. - The drug have wide activity against G+ cocci ( including some penicillin resistant pneumococci), G- rods, and anaerobes.- It is administered parenterally and is especially useful for infections caused by organisms resistant to other antibiotics. It is currently the drug of choice for infection due to enterobacter. - Imipenem is rapidly inactivated by renal dehydropeptidase I and is administered in fixed combination with cilastatin, an inhibitor of this enzyme.