Lec10

Antimicrobial Agent

What is an Antibiotic?
“Antibiotic” is from antibiosis, meaning against life.It is a Substances produced by various species of microorganisms: bacteria, fungi, actinomycetes — to kill or suppress the growth of other microorganisms.Today the term antibiotic extends to include synthetic antibacterial agents: sulfonamides and quinolones. *

* Antimicrobial spectrum : the scope that a drug kills or suppresses the growth of microorganisms. Narrow-spectrum: The drugs that only act on one kind or one strain of bacteria. (isoniazid ) Broad-spectrum: The drugs that have a wide antimicrobial scope. (tetracycline, chloramphenicol )
Definitions

classification

Antimicrobial drugs can be classified in a number of ways. These include: 1) by their chemical structure (for example, β-lactams or aminoglycosides),.2) by their mechanism of action (for example, cell wall synthesis inhibitors).3) by their activity against particular types of organisms (for example, bacteria, fungi, or viruses).

classification according to their mechanism of action:

Antimicrobial agents are among most commonly used and misused of all drugs:


Classification of some antibacterial agents by their sites of action. (THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid)



Factors that determine susceptibility and resistance of microorganism to antimicrobial agents
1- concentration of antibiotic at site of infection 2- host defenses 3- local factors : - low PH - high protein concentration - anaerobic conditions

Bacterial resistance is attributed to 3 general mechanisms

1-failure of the drug to reach its target: - small polar molecules , including many antibiotics enter cell of bacteria through protein channels called porins , loss of porin can slow drug entry. - if target is intracellular and need active transport across the cell membrane , resistance can result from mutation that prevent transport.

Bacterial resistance is attributed to 3 general mechanisms

2-the drug is inactive due to: - production of enzymes that modify or destroy the drug . - failure of bacteria to activate the prodrug . 3- target alteration : - mutation

Bacterial resistance

Selection of antimicrobial agents
1-testing for microbial sensitivity to antimicrobial agents. 2-phamacokinitic factors which include: a-drug concentration b-location of infection and route of drug administration c- antibiotic access to sites of infection d- dose of drug e- renal and hepatic function of the host.

Selection of antimicrobial agents

3- host factors: *status of defense mechanism. 4-local factors: a-pus at site of antibiotics action will reduce effects of drugs because pus contain phagocytes , cellular debris and proteins that interact with drug and reduce it is action . b- decrease PH found in abscess will decrease action of drugs. c- presence of foreign body or prosthetics, decrease effect of drugs.

Selection of antimicrobial agents

5- other factors : a-age new born and elderly have impaired mechanism of drug elimination . b-genetic factors and interindividual differences c-pregnancy and lactation d-drug allergy


Advantages of combinations of antimicrobial agents
1-Therapy of sever infection in which a cause is unknown. 2-treatment of polymicrobial infection 3-enhancement of antibacterial activity of drug (synergism) 4-prevention of emergence of resistance microorganisms.

Disadvantages of combination of antimicrobial agents

1- increased risk of toxicity 2-eradication of normal host flora. 3-increase cost.

Superinfection

The appearance of bacteriological and clinical evidence of anew infection during chemotherapy of a primary one *It is due to removal of the normal flora which produces antibacterial substances and competes for essential nutrients. *The broader spectrum and longer period of antibiotic treatment , the greater the risk of superinfection.

Antibiotics loading dose

Is 2 or 4 times the maintaince dose , given to achieve high antibiotics blood levels quickly. It is necessary to use loading dose with orofacial infections because such infections begin and peak rapidly.

Penicillin and cephalosporin

P consist of a thiazolidine ring (A) connected to a β-lactam ring (B)to which is attached aside chain (R)P nucleus itself is the chief structural requirement for biological activity.Fig 44-1 p729 goodman

Penicillin and cephalosporin

Mechanism of action:-P acted on rapidly dividing organisms -it is structural analogue of D-alanine which is involved in steps of cell wall synthesis of bacteria.-peptidoglycan provide rigid mechanical stability to bacterial cell wall,P and C will inhibit last step in peptidoglycan synthesis by inhibition of transpeptidase enzyme which is responsible for transpeptidation reaction involving removal of D –alanine to allow the formation of complete cell wall of bacteria.

Penicillin and cephalosporin

other proteins necessary for cell division and cell shape also are target of P and C So P and C promote formation of cell wall deficient microorganism of different shapes which can not maintain their internal osmotic pressure and burst

According to the mechanism of action of P and C:

1-High blood levels of β-lactams are required for optimum success ,since not all bacteria divide at the sometime.2-P kill bacteria slowly

Mechanism of bacterial resistance to P and C

1-By mutation that decrease affinity of P binding protein for P and C 2-inability of drug to penetrate to site of action 3-bacteria can destroy β-lactams by the action of β-lactamase (larger amount of this enzyme is produced by gm +ve bacteria4-microorganism that adhere to prosthetic device e.g. prosthetic heart valves produce biofilms which are less sensitive to P and C 5-intracellular bacteria which survive inside host cells are less sensitive to P and C

Lecture 4

Penicillin G

Penicillin G and V

Antimicrobial activity: 1-P G (benzyl penicillin) and P V (phenoxymethyl derivative) have similar effects for aerbic gm +ve bacteria 2-P G is 5-10 times more active against anaerobes 3- they are effective against most streptococci 4- more than 90% of staphylococci are now resistant to P G

Absorption of penicillin

Oral administration *for P G -1/3 oral dose absorbed -max concentration in blood are attained within 1hr -food interfere with absorption (should be given 30 min before or 2 hr after meal) *for P V -better absorption and higher blood level than P G

Absorption of penicillin

Parenteral administration (P G )I.M injection give peak concentration in plasma within 15 – 30 mint1/2 30 minRepository preparation of P G increase duration with low level of drug

E.g. penicillin G procaine: P G combined with procaine , dose of 300 000 units contain ~ 120 mg procaine which exerts L.A effect when injected E.g. penicillin G benzathin : Suspension of salt obtained by combinding ammonium base and P G and provides slow release (duration will be 26 days)

Distribution of penicillin

P G widely distributed 60% bound to albumin Significant level found in liver , bile , kidney , joint fluid Not enter CSF unless there is meningeal inflammation

Excretion of penicillin

P G -rapidly eliminated by kidney -60-90% of I.M dose is eliminated by urine -the reminder is metabolized to penicilloic acid -infants and neonates have incomplete development of renal function thus they have lower P clearance

Therapeutic uses of penicillin

Therapeutic uses of penicillin
1-pneumococcal infection caused by S. Pneumoniae 2-streptococcal infections like pharyngitis which is caused by S. Pyogenes , Rx by one of the following: *P V 500mg\6hr\10 days *600 000 units of P G procaine I.M once daily \10 days *single injection of 1.2 million units of P G benzathine


3-streptococcal toxic shock : life threatening infections are best treated by penicillin + clindamycin 4- arthritis ,meningitis , endocarditis treated by P G \ i.v\12-20 million units\daily\for 2-4 wk 5-infections with anaerobes like pulmonary and periodontal infections respond well to P G

Mild to moderate infections: PG or PV 400 000 units\4 times daily Sever infections: 12-20 million units of PG i.v 6-meningococcal infections , actinomycosis and gas gangrene , PG is drug of choice 7-syphlis ,PG is highly effective


8-gingivostomatitis produced by synergistic action of leptotrichia buccalis and fusospirochetes that are present in the mouth: Rx by PV 500 mg \6hr\for several days


Penicillinase – resistant penicillin These P resist hydrolysis by staphylococcal penicillinaseTheir use is restricted to treatment of infection caused by staphylococci that elaborate this enzymeThey are less effective than PG against P – sensitive microorganismIt include:

Penicillinase – resistant penicillin 1-isoxazolyl: e.g. oxacillin , cloxacillin and dicloxacillin 2-nafcillin

Aminopenicillins

It include: -Ampicillin ,Amoxicillin they are bactercidal for gm +ve and gm –ve bacteria

Ampicillin

It is the protype of the group Well absorped orally Food delay absorption Renal impairment prolong t1/2 It undergo enterohepatic circulation Excreted in the feces

Amoxicillin

More rapid and complete absorption from GIT Have twice peak plasma concentration than ampicillin Food not interfere with absorption Less incidence of diarrhea Excreted in urine


Aminopenicillins
Therapeutic indications: 1-uper respiratory infection 2-UTI 3-meningitis 4-salmonella infection

Antipseudomonal Penicillin

Carboxypenicillin and ureidopenicillinTheraputic uses: -gm –ve bacterial infections, including infection acquired in hospitals e.g. piperacillin -bacteremia , pneumonia -infection following burns

Untoward reactions to penicillin

1- hypersensitivity reactions :it include *rash,urticaria,fever, bronchospasm,vasculitis,serum sickness, dermatitis and anaphylaxis *allergy to one P increase the risk of reaction if another P is given *allergy can be mild ,moderate , severe (lead to death) *Anaphylactic reaction to P and angioedema are the most serious reaction to P , usually are mediated by IgE Ab

Anaphylaxis

Among all drugs ,P are the most responsible for this type of reactionCan occur at any age Their incidence is 0.004 – 0.04 % , and 0.001 % of patients treated by P die from anaphylaxisThe most dramatic reaction is sudden hypotension and deathIn other cases their will be broncoconstriction , abdominal pain , nausea, vomiting , weakness , skin purpuraManagement: - history - skin test , if available -treatment with another antibiotics

Untoward reactions to penicillin

2-toxic effects: A- bone marrow depression granulocytopenia hepatitis B- irritative responses -I.M --------- pain , inflammation -I.V --------- phlebitis - orally------- nausea , diarrhea - PG procaine ---- procaine reaction , include dizziness, tinnitus, headache , hallucination - accidental injection into sciatic nerve cause severe local pain and dysfunction -intrathecal injection of P produce encephalopathy (avoid it ) -parenteral administration of large dose of PG ( more than 20 million units \ day) may produce : lethargy , confusion , twitching , seizures

Untoward reactions to penicillin

3- P change the composition of microflora which can be reestablished shortly after therapy is stopped , sometime superinfection results

Therapeutic uses in dentistry

Oral route is preferable (PV)Amoxicillin is better than PV PG is reversed for severe infection or when oral route is compromisedOral infections are caused by β-lactamase producing microoorganism should be treated by Penicillinase – resistant penicillin Periodontal infection caused by gm+ve and gm-ve , aerobic and anaerobic need combination of amoxicillin + metronidazole


Lecture 5

Cephalosporins

Cephalosporins
Chemistry: C produced from 7-aminocephalosporanic acid by the addition of different side chains Mechanism of action: C and cephamycins inhibit bacterial cell wall synthesis (similar to P )

Cephalosporins

Classification Classified by generations: First generation e.g. cephalothin , cefazolin Good activity against gm+ve bacteria Modest activity against gm-ve bacteria Most mouth anaerobes are sensetive (except B. fragilis group which is resistant)

Cephalosporins

Classification: Second generation -e.g. cefoxitin , cefotetan, cefmetazole -increased activity against gm-ve microorganism -active against B. fragilis

Cephalosporins

Classification:Third generation-ceftazidime,cefoperazone-less activity against gm+ve-more activity against β-lactamase producing strains

Cephalosporins

Classification: Fourth generation -cefepime -have extended activity -useful for treatment of serious infection in hospitalized infection

General features of cephalosporin

Excreted by kidney Penetrate CSF Cross placenta Penetrate aqueous humor of eye

Therapeutic uses of cephalosporin in dentistry

Good activity against many orofacial pathogens Limited activity against oral anarobes

Adverse effects of cephalosporin

Hypersensitivity reaction(simillar to penicillin ,so patients sensitive to P should not receive C ,cross sensitivity)Renal toxicityDisulfiram – like effects , if taken with alcohol it block alcohol oxidation and lead to accumulation of acetaldehydebleeding


Other β-lactam antibiotics Carbapenems-have broader spectrum than other imipenem: -disrupt cell wall synthesis and kill microorganism. -resist hydrolysis by β-lactamase -active against wide variety of aerobic and anaerobic microorganism -used for treatment of :

UTI Lower respiratory tract infection Abdominal and gynecological infection Skin, soft tissue,bone,joints infections


Aztreonam -active only against gm –ve bacteria -have no activity against gm +ve bacteria and anaerobic organism -given I.M or I.V - half life 1.7 hr -excreted in urine -dose for severe infection is 2 gm \ 6-8 hr

Other β-lactam antibiotics β-lactamase inhibitorsthose are certain molecules that can inactivate β-lactamases there by protecting β-lactam antibiotics that are their substrates.They include :


1-clavulanic acid: -irreversibly bind to β-lactamase of gm+ and gm- microorganisms -it is combined with amoxicillin for oral administration (Augmenten) -it is combined with ticarcillin for parentral administration (timentin)

2- sulbactam which is combined with for i.v and i.m use (unasyn) 3-Tazobactam which is combined with piperacillin for parenteral preparation (Zosyn)

Lecture 6

Aminoglycosides
Mechanism of action:-they are bactericidal ,act on 30S ribosomal subunit and interfere with reading of microbial genetic code and inhibit protein synthesis-residual bactericidal activity persist even after serum concentration has fallen and this allow once – daily dosing regimen


Aminoglycosides diffuse through aqueous channels formed by porin proteins in outer membrane of gm-ve bacteria and it is driven by the membrane electrical potential (interior negative), therefore action of aminoglycosides is blocked or inhibited by reduction in pH (acidic) or anaerobic conditions e.g. abscess

Resistance to aminoglycosides

Occur due to: 1-failure of drug to penetrate intra- cellularly 2-low affinity of drug for bacterial ribosome 3-drug inactivation

Absorption of aminoglycosides

They are highly polar and poorly absorbed from GIT Toxic level may result from sustained topical application to large wounds , burns , or cutaneous ulcers ,this due to rapid absorption It is rapidly absorped after i.m injection

Distribution of aminoglycosides

-do not penetrate into most cells ,CNS and eye (except streptomycin ) -volume of distribution = volume of extracellular fluid -low conc. In secretion and tissues -high conc. In renal cortex and inner ear -drug can accumulate in fetal plasma and amniotic fluid


Dosing of aminoglycosides
Current practice is to administer the total dose as single injection ,because: -less toxic -equal efficacy to multiple dose -provide longer period -less cost -more easy

Dosing of aminoglycosides

Practice of single dose should be avoided in : -renal problem -neonate and pediatric patients -bacterial endocarditis

Elimination of aminoglycosides

-t1\2 2-3 hr -excreted by kidney -toxicity can be treated by hemodialysis or peridialysis

Untoward effects of aminoglycosides

1- ototoxicity :irreversible ,repeated dose can lead to deafness 2-nephrotoxicity :mild , reversible Why ototoxicity is irreversible while nephrotoxicity is reversible? 3-neuromuscular blockade and apnea with large dose

streptomycin

Used for Rx of certain unusual infections in combination with others Given by deep i.m or i.v Dose : 15mg\kg\day 1000mg\ single daily dose 500mg\ twice daily Indicated for Rx of; bacterial endocarditis plaque TB

Gentamicin(garamycin)

For gm –ve bacillary infectionGiven parentally , topicalDose:3-5mg\kg\dayindications: *UTI *pneumonia *meningitis *bacterial endocarditis *sepsis

Amikacin

It has broadest spectrum Dose 15mg\kg\day

neomycin

Broad spectrum P. aeruginosa are resistant to it Given oral, topical Uses: topical for skin and mucous membrane infections e.g.burns,wound,ulcer Poorly absorbed from GIT Excreted by kidney

neomycin

Side effects -hypersensitivity -renal damage -deafness -orally can cause intestinal malabsorption and superinfection

General notes on aminoglycosides

Combined with Penicillin or cephalosporin for serious gm-ve infections Should not be used more than few days, why? Never mix with P in same solution (inactivation) Aminoglycosides have no uses in orofacial infections unless dictated by culture and sensitivity tests.

Lecture 7

Sites of action of different antimicrobial agents

Sulfonamides, Trimethoprime, Sulfamethoxazole, Quinolones

Chemistry -derivatives of para-aminobenzenesulfonamide -they are insoluble in water -their sodium salt are soluble in water

Sulfonamides, Trimethoprime, Sulfamethoxazole, Quinolones

Mechanism of action -They are bacteristatic agents, -competitively inhibit dihydropteroate synthase This enzyme responsible for incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid (the precursor of folic acid)


Sulfonamides, Trimethoprime, Sulfamethoxazole, Quinolones
All sulfonamides are synthetic analogs of PABA , and this structural similarity make sulfonamides compete with PABA in steps of folic acid synthesis of bacteria.

Sulfonamides, Trimethoprime, Sulfamethoxazole, Quinolones

SO: -bacteria which synthesize their own folic acid will be sensitive to sulfonamides while those depend on performed folic acid will not affected -mammalian tissues receive performed folic acid and not affected

Synergistic of sulfonamides

Trimethoprine exerts a synergistic effects with sulfonamides , it inhibits microbial dihydrofolate reductase selectively and potently , this enzyme reduce dihydrofolate to tetrahydrofolate

Resistance to sulfonamides

Originated by mutation and not confer cross – resistance to other types of antibiotic

Sulfonamides

Rapid ,well absorption from GIT Peak plasma level after 2-6 hr Widely distributed through out the body Reach CSF in effective concentration Cross the placenta Metabolized by liver: their metabolites have no antibacterial activity , yet retain the toxic potential of the parent substance Eliminated by urine, small amount eliminated by feces , bile, milk.

Sulfonamides

According to rapidity of absorption and excretion , sulfonamides are classified into:


Rapidly absorbed and eliminated sulfonamides

Rapidly absorbed and eliminated sulfonamides

Rapidly absorbed and eliminated sulfonamides
Sulfadiazine

Poorly absorbed sulfonamides

Sulfonamids for topical use
Sulfacetamide - Used for ophthalmic infection in very high aqueous concentration which is not irritating to the eye.

Sulfonamids for topical use

Silver sulfadiazine Inhibit growth of all pathogenic bacteria and fungi Used topically to reduce infection in burn patients Not used for Rx of established deep infection.

Sulfonamids for topical use

mafenide



Sulfonamides therapy
UTI Nocardiosis(infection due to nocardia species) Toxoplasmosis Used for prophylaxis of streptococcal infections

Sulfonamides adverse effects

1-disturbances of UT and crystalluria which lead to nephrotoxicity ( new agents are more soluble)2- hypersensitivity : rashes , angiodema , and Stevens – Johnson syndrome.3- Haematopoietic disturbances:hemolytic anaemia in patients with Glucose 6 – phosphate dehydrogenase deficiency and agranulocytosis

Sulfonamides adverse effects

4 – miscellaneous reactions : *anorexia , nausea , vomiting *Kernicterus in new born (displacement of bilibubin from albumin )

Sulfonamides interaction

Anticoagulants Sulfonylurea Phenytoin

Trimethoprim - sulfamethoxazole

Trimethoprim - sulfamethoxazole
Antibacterial spectrum: they have synergistic interaction and most gm + and gm – are sensitive to them.

Trimethoprim - sulfamethoxazole

Mechanism of action: action on 2 steps of the biosynthesis of tetrahydrofolic acid of bacteria.


Trimethoprim - sulfamethoxazole
Absorption, distribution and excretion - peak level after 2hr (in blood) for trimethoprim and 4hr for sulfonamide. - t1/2 is 11hr for trimethoprim and 10 hr for sulfonamide - excreted in urine

Trimethoprim - sulfamethoxazole

Therapeutic uses 1- UTI 2- bacterial RTI 3- GIT infections

Trimethoprim - sulfamethoxazole

Adverse effects 1- narrow margin of toxicity in bacteria and in human with folate deficiency 2- skin reaction 3- nausea and vomiting 4- glossitis and stomititis (common) 5- headache 6-depression , hallucinations 7-permenant impairment of renal function

Protein Synthesis Inhibitors

Macrolides
Examples: Erythromycins, Clarithromycin, Azithromycin Usually bacteriostatic DOC for penicillin-allergic

Macrolides

Antibacterial Activity/Use
Most effective against gm+ cocci and bacilli Gm+ microorganisms accumulate 100x more Emycin than gm- Clarithromycin and Azithromycin have expanded gm- coverage

Antimicrobial spectrum

Good for bacteria associated with atypical pneumonia (e.g. with mycoplasma, leigonella)

Kinetics

AbsorptionEmycin base is incompletely absorbed and its inactivated by stomach acids, so esterase have been createdEstolateEthylsuccinateClarithromycin – absorbed rapidly, but bioavailability is only ~50% due to high first pass metabolismAzithromycin- antacids interfere with peak levels. Food reduces peak levels but not bioavailability

Kinetics

Distribution Emycin Some esters are highly protein bound Azithromycin Extensive tissue distribution High drug concentration within cells, even phagocytes

Resistance

Efflux by an active pump Ex. Group A strep, Strep pneumoniae Methylation of ribosome Inducible/constitutive expression of a methylase enzyme Mutations of ribosome At 50 S; affects gm+ cocci Hydrolysis of macrolides By esterases produced by Enterobacter

Antibacterial Activity/Use

Most effective against gm+ cocci and bacilli Gm+ microorganisms accumulate 100x more Emycin than gm- Clarithromycin and Azithromycin have expanded gm- coverage


• Mechanism of action Bind to 50S ribosomal subunit—same site as chloramphenicolInhibits the translocation step where a newly synthesized peptidyl tRNA moves from the A site to the P site


Uses, continued
Mycoplasma pneumoniaeLegionnaires diseaseChlamydiaDiptheriaStreptococcus (pharnygitis, prophylaxis of rheumatic fever)StaphylococcusMycobacteriaIe. Avium in HIV – clarithromycin or azithromycinProphylaxis of endocarditis

Adverse effects

Cholestatic hepatitis – primarily with Emycin estolateGI distressProlonged QT interval – P450 inhibitor-Emycin and Clarithromycin cause toxicity when given with many drugs, including carbamazepine, digoxin, warfarin, theophylline

Drug interactions

Due to inhibition of P450s Prolonged activity of warfarin, phenytoin, rifampin, HIV retroviral protease inhibitors

Tetracyclines

Tetracyclines
Chlortetracycline was introduced in 1948. It was the first broad spectrum antibiotic—effective against gm+/-, ricketsia, MycoplasmaOther drugs: tetracycline, minocycline, doxycycline

• Mechanism of action Inhibits protein synthesis by binding to the 30S ribosomal subunit. This prevents access of aminoacyl tRNA to A site Bacteriostatic

Resistance

Cross resistance Decreased accumulation Decreased influx Increased efflux Decreased access to ribosome Enzymatic inactivation of drug

Kinetics

AbsorptionImpaired by dairy products, di-/tri-valent cations, cholestyramineWide range of plasma concentrations due to variable absorption patterns among individualsDistribution – wide; includes prostate, bone marrow, done, dentine and enamel of teethExcretionPrimarily renalWith decreased renal function, drugs accumulateAlso recirculated via enterohepatic recirculation

Uses

Rocky Mountain Spotted Fever – ricketsiasMycoplamsa pneumoniaChlamydiaAcneLyme’s disease-Borrelia burgdorferi – spirochetesCholera, Leptospirosis, Protozoal infections

Therapeutic Uses

Contraindication: 1. TET should not be used in pregnant women and children under 8 years . 2. Tetracycline during 1st trimester of pregnancy can cause birth defects 3. Should not be given to patient with severe liver and renal disease.

Adverse effects

DermalPhotosensitivityOnycholysis and pigmentation of nailsGastric distressHigh drug concentrations reach bowel so intestinal organisms are markedly alteredNausea, vomiting, diarrhea—lessened with foodPseudomembranous colitis, yeast infectionsHepatotoxityJaundice, abdominal pain, itchingTetracycline is the least hepatotoxic

Adverse effects, continued

Renal toxicity May aggravate renal disease Doxycycline has fewer renal effects Teeth Chelates to calcium in bone and teeth Risk to fetus Brown discoloration of teeth that is permanent in children; contraindicated in children < 8 years Hypersensitivity Rashes, angioedema, anaphylaxis

Adverse effects, continued

Other Pseudotumor cerebri Long term use can cause blood disorders like leukocytosis



Chloramphenicol

Chloramphenicol

• Mechanism of action : Binds to 50S ribosomal subunitPrevents the amino acid end of aminoacyl tRNA from entering the acceptor site on 50S ribosomal site, therefore there can’t be an interaction between peptidyltransferase and the amino acid so no peptide bond can be formedBlocks linkage by peptidyl transferase of new amino acids onto the growing peptide chainBacteriostatic

Antimicrobial actions

Gm +: ie. S. pneumoniae Gm-: H. influenzae, N. meningitidis, Proteus, Pseudomonas Anaerobes: Bacteroides Other: Ricketsia, Chlamydia, Mycoplasma

Resistance

Modification of drug via acetylation** Can no longer bind ribosomes Other: Decrease permeability into microorganism Mutations in ribosome sensitivity

Kinetics

Distributed: even to CNSMetabolism:Hepatically via glucuronide conjugationsCan lead to severe, life-threatening problems when liver isn’t fully functional


Use
Only when benefits clearly outweigh the risks Reserved for serious infections like meningitis and typhoid

Adverse effects

Chloramphenicol inhibits mitochondrial membrane protein synthesis and many adverse effects come from this Bone marrow Dose-related toxicities that are common, predictable, and reversible Anemia Leukopenia Thrombocytopenia Idiosyncratic aplastic anemia Fatal pancytopenia

Adverse effects, continued

Optic neuritis – 3-5% of children due to loss of retinal ganglionic cellsGray baby syndromeEspecially in premature infantsSigns: vomiting, refusal to eat, rapid and irregular breathing, abdominal distension, cyanosis, loose & green stools. Ashen gray color, hypothermiaResults from: failure to conjugate with glucuronide due to inadequate liver glucuronyl transferase and accumulation due to inadequate renal function

Drug interactions

Due to inhibition of P450s Prolonged activity of warfarin, phenytoin, rifampin, HIV retroviral protease inhibitors

Clindamycin

• Mechanism of action : Binds to 50S subunit

Clindamycin

Resistance Methylation of ribosome

Clindamycin

Kinetics Distribution: Wide, including bone, but not CNS Accumulates in leukocytes and macrophages 90% protein bound Uses/Antibacterial effects Active against anaerobic microorganisms especially B. fragilis Used for severe infections caused by B. fragilis, ie. intraabdominal infections, peritonitis, pelvic infections

Adverse effects

COLITIS!!! Clostridium difficile pseudomembranous colitis Abdominal pain, fever, diarrhea, mucus, blood This antibiotic is the single biggest culprit-10% incidence 20% experience 1 relapse after treatment with po vanco or metronidazole 5% Continually relapse

Inhibition of Protein Synthesis by Antibiotics

Figure 20.4

Other Miscellaneous Antibiotics

Metronidazole
MOA: Inhibits DNA synthesis, degrades existing DNA, and causes DNA breakage. Inhibits nucleic acid synthesis, resulting in cell deathCrosses classes—both antibacterial and antiparasiticUses: Trichomonas vaginalis, Gardnerella vaginalis, H. pylori, amebiasis, giardia, Clostridium, P. acnes, anaerobic infections

Adverse effects

Minor—ThrombocytopeniaPlatelet counts should be monitored in those with bleeding disordersIncidence increases with duration of therapy

Polymyxin B

MOA: cationic detergent. The drug interacts with phospholipids, disrupting cell membranes, altering permeability Uses: Gm- bacteria including P. aeruginosa Only used topically because of severe nephrotoxicity



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