L2-Cell Wall Inhibitors 1, 2, 3 PDF

Intended Learning Objectives : By the end of this chapter, the student should be able 2.6 to: 4-Predict the s...

Intended Learning Objectives : By the end of this chapter, the student should be able 2.6 to: 4-Predict the spectrum of B lactam drugs by its mechanism of action Bacterial cell wall inhibitors 5-Recall the differences between different groups of penicillin and cephalosporines. (1, 2, 3) All are 6-List the spectrum of beta lactam antibiotics Cidial 7-Discuss clinically significant pharmacokinetic features of some cephalosporines. 8-Explain the rationale behind combining penicillin 9-Recognize the use of other beta-lactam antibiotics in penicillin hypersensitivity 10-List the adverse effects of beta lactam antibiotics Non −Lactams Cell Wall Inhibitors 1- Polypeptides or (cyclic peptide) :Bacitracin and cycloserine −Lactams: 2- Glycopeptide :vancomycin They share a -lactam ring in their molecular me isimpo mn 3-Lipoglycopeptide : Dalbavancin, Oritavancin jff structure. eisitivity ffper Telavancin, and Teicoplanin antibiotic 4- Lipopeptides: Daptomycin – Penicillins firstdisconord – Cephalosporins 5- Fosfomycin – Monobactams (Aztreonam):only Gram-negatives it– Carbapenems (Imipenem) :Tienamycin, very wide spectrum onlymenacillin 1stgen cephalosporinaresafeforpregnancy  BETA-LACTAMS antimicrobials 1-Penicillins All beta-lactams have a few things in common: 2- Seizures can result from very high doses of any 1-All beta-lactams can cause hypersensitivityErinc beta-lactam, and some cause other neurologic effects. reactions, ranging from mild rashes to drug fever to Accumulation to toxic levels can occur when the dose acute interstitial nephritis (AIN) to anaphylaxis. There of a beta-lactam is not properly adjusted for a is cross-reactivity between some agents (e.g., patient’s renal function. excreted byrenal mn gotof piniellin penicillin and cephalosporin), but it is difficult to predict exactly how often that will occur. Did you check your patient’s renal function???? can'tgivecephalosporin if paitantisallergictorenacilin bothshareBlaetanring epilepsy It seems that similarities between side chains of beta- don't use it on lactams are responsible for cross-reactivity. RÉnal dysfunction orSave for children and pregnant woman  2 3- All beta-lactams share a mechanism Steps of :Cidal 4- All beta-lactams can be destroyed by beta-lactamases, enzymes produced by bacteria to destroy beta-lactams. Inhibition of late steps in synthesis of cell wall = linking of peptidoglycan and transpeptidation by: -Some beta-lactams such as penicillins are easily destroyed, whereas others such as carbapenems are stable against most beta-lactamases. forsiblings WhichbeforformationofCellwall 1- They penetrate bacteria then form complexes with -Whenever a beta-lactam is developed, a beta-lactamase capable of (Irreversibly inhibit ) enzymes - trans- and targets hydrolyzing it inevitably emerges. carboxypeptidases (PCP= penicillin binding proteins) in bacterial cell membrane), which control synthesis of peptidoglycan – component of cell-wall of microorganisms (final steps of cell wall synthesis)=formation of peptide ESBLs: :extended-spectrum beta-lactamases (microorganisms – bridges between adjacent stands of peptidoglycan i.e resistant to cephalosporins and monobactams) prevents cross linking of the glycan strands leading to fromtheBactria leading to swelling and lysis, killing the organism. -Lactamase can be overcomed by : 1. Give a -Lactamase inhibitor at same time for mother 2-Involves activation of autolytic enzymes in the cell wall, and Clavulanic Acid & Sulbactam….etc boasgard results in lysis of organism. 2. Modify the antibiotic structure to make it more resistant 5- All beta-lactams lack activity against atypical 6-All but one of the currently available beta-lactams lack activity against methicillin-resistant organisms such as Mycoplasma pneumoniae T.no cellwall Staphylococcus (MRSA). So, Add vancomycin or another and Chlamydia pneumoniae. agent if this bacterium is suspected. lactams mostcommoncanproducehugeamountofBeta The available beta-lactams, only the cephalosporin Add another drug to your regimen if you are (ceftaroline and ceftobiprole ) has anti-MRSA activity. concerned about these organisms, as in cases of community-acquired pneumonia (CAP). N.B If 1952 – 100 % Staphylococcus infections were cured by penicillin has pneumonia and wedon'tknow 1 patent combination atypical typical microbial 1982 – only 10 % infections weuse of therapy otheranti At nowadays ?................... 0 Due to (MRSA) )– ((methicillin/oxacillin-resistant Staphylococcus aureus MRSA causes 19 000 deaths annually in USA Resistant staphy aureus  absor tea PENICILLINS io Pharmacokinetics (ADME)  History:……………. Absorption: see below in the preparations Narrow Coccitre ve Bacillitre ve Puff Antibacterial spectrum:…………… spirochetesActinomyce Distribution: *Gram-positive cocci, e.g. streptococci, pneumococci good throughout the body. They cross the placental and staphylococci. barrier but none is teratogenic (safe in pregnancy). *Gram-negative cocci: gonococci and meningococci. Penetration into either bone or CSF is insufficient for *Gram-positive bacilli: anthrax bacillus, C. diphtheria therapy (only with inflammation of these sites). and clostridia. meningitis *Gram-negative bacilli: shigella, salmonella, etc. don'tcrossthemeningesexciteon *Spirochetes: treponema pallidum. do to increasethe permeability ofBBB *Actinomyces. *PREPARATIONS OF PENICILLINS: Excretion: Bad urineorder I. BENZYL PENICILLIN= Penicillin G (natural very shortdura Elimination of most penicillins occurs rapidly and is penicillin) administratedVery4 mainly renal, 90% being through Through the firstpenicillin organic acid (tubular) secretory system of the Drawbacks : kidney and by glomerular filtration. Probenecid A-Active against gram positive bacteria (streptococci, inhibits the secretion of penicillins by competition meningococci, aerobes). narrowspectrum and thus can increase blood levels. B-It is sensitive (destroyed) by penicillinase enzyme (B lactamase). C-Short acting preparation e.g. (6 hours) I.M or I.V Penicillins are excreted into breast milk and saliva. D-Not given orally. To overcome short duration:  Long-acting preparations: onlyIMorwillcausepyhf.gg as penciling To overcome the drawback of the short duration of action of benzyl on To overcome injection route : samedeferthat isoral penicillin, which necessitates its frequent parenteral administration, long acting preparations of benzyl penicillin were prepared. These *Oral preparations: if preparations are given only intramuscularly and never intravenously. These penicillins are stable in acid medium and hence The long acting penicillins include: 1-Procaine penicillin-G: 12-24 hours for of treatment Gout escape destruction in the gastric juice. They include: This is a combination of procaine and benzyl penicillin. It consists of Phenoxymethyl penicillin (penicillin V). me 100.000 units of procaine penicillin + 100.000 units of benzyl penicillin. procaine Phenethicillin. Ospen 2-Fortified procaine penicillin: 24 hours It consists of 300.000 units of procaine penicillin + 100.000 units of benzyl penicillin-Given once daily IM. eeks3-Benzathine penicillin: nuoneRheumaticfeverprophlaxyix This preparation produces low blood levels lasting from few days to 4 weeks depending on the dose. It should not be used in acute infections because the blood levels are low. So it is used in chemoprophylaxis of rheumatic fever. II. ANTISTAPHYLOCOCCAL PENICILLINS or The only indication is infection by -lactamase producing staph. PENICILLINASE RESISTANT PENICILLINS They have low activity against other gram-positive and inactive Within a few years of penicillin becoming widely against gram-negative bacteria. They include: available, staphylococcal strains began to produce beta lactamases, rendering penicillin useless in these 755nF Methicillin. infections. The basic structure of penicillin was Cloxacillin, Dicloxacillin, Flucloxacillin. modified to resist these destructive enzymes, leading if Nafcillin: It is more active than methicillin and cloxacillin. Excreted on the bile to the anti-staphylococcal penicillins. This Most antistaphylococcal penicillins are eliminated from the modification gave these drugs activity against body in large part by the liver and do not need to be adjusted staphylococci that produce penicillinases, but it did in cases of renal dysfunction. not add to the poor gram-negative activity of the natural penicillins. These drugs are interchangeable therapeutically. Therefore, S aureus that is susceptible to methicillin (which is no longer used) is susceptible to oxacillin, nafcillin, and the rest.  All -SPECTRUM PENICILLINS =AMINO PENICILLINS: except III. Broad They can be given orally (acid resistant) and by injection (IM and Though the antistaphylococcal penicillins improve on the gram-positive IV). They include: coverage of natural penicillins, they do not add to their gram-negative coverage. Aminopenicillins are more water soluble and pass through porin 1-Ampicillin Excreted onbile channels in the cell wall of some gram-negative organisms. It is concentrated in bile, so it is effective in gall bladder disease and typhoid fever Salmonella). But when given orally, low Act on G +ve and G –ve bacteria. more broadly active against gram- absorption, so,Atsuperinfection and cause diarrhea. negatives *Pro-drugs of ampicillin:tester e.g. pivampicillin, talampicillin, and bacampicillin. They can be given orally (acid resistant) and by injection (IM and IV). These are esters of ampicillin which themselves are They are -lactamase susceptible. microbiologically inactive but after oral administration they are de-esterified in the gut mucosa or liver to release ampicillin to the systemic circulation. However, they are susceptible to beta-lactamases, and resistance to them Advantages Iiiistinalabsorbtion is common. Aminopenicillins are rarely active against staphylococci, or because these almost always produce penicillinases. These drugs also do 1-They are better absorbed from the gut than ampicillin itself, not have useful activity against Pseudomonas aeruginosa. so gives higher levels in blood and tissues. 2-Because they are inactive when present in the lumen of the Their spectrum like penicillin G plus gram negative bacteria e.g. H. gut, they have no effect on the gut flora and less G.I. upset (less influenza, Salmonella, Proteus, and Shigella. superinfection). topreventsuperinfectionftp.newjffffcham 2-Amoxycillin: VI-ANTIPSEUDOMONAL PENICILLINS: Surgicalwoundinfection like ampicillin but differs in: IffyThey are broad-spectrum, but should only be used for pseudmonas infection and ampicillin resistant proteus. 1-Better absorption from intestine, so it has higher Also they have activity against anaerobic gram negative bacteria e.g. Bacteroids fragilis (a common pathogen in plasma and tissue levels. 1 intra-abdominal sepsis) IT srkontyphoidfever 2-More active against Salmonella and Streptococcal fecalis (ampicillin more on shigella and H. influenza). They are -lactamase susceptible. 3-Can penetrate mucoid and purulent sputum, so it is They have synergistic effect when they are used with useful in chronic bronchitis. aminoglycosides. 4-Less diarrhea as side effect. Superinfection *Examples: Q typhoidfever (Carbencillin, Ticarcillin , Azlocillin, Mezlocillin, and Onlytwodrugsofpenicilin treat Piperacillin) Bodybard N.B BodyGard PENICILLIN/BETA-LACTAMASE INHIBITOR COMBINATIONS Agents: Example: is 1- ampicillin/sulbactam 1-Clavulinic acid combined with amoxycillin 2- amoxicillin/clavulanate Lyn (Augmentin) , this extends the spectrum of 3- piperacillin/tazobactam amoxycillin to include -lactamase producing 4- others………………………………… organisms. N.B New beta-lactamases with the ability to destroy many types of beta lactams are continually being discovered and are becoming more Amoxicillin/clavulanate is used for upper and lower prevalent. respiratory tract infections when beta-lactamase– The beta-lactamase inhibitors (sulbactam, clavulanate, avibactam , producing organisms are found or suspected. tazobactam …………………………………………..) counter beta-lactamases; these drugs mimic the structure of beta-lactams but have little antimicrobial activity on their own. They bind to beta-lactamases irreversibly, preventing the beta-lactamase from destroying any beta- lactams that are co-administered and enabling the therapeutic beta- 2-Other -lactamase inhibitors include sulbactam, lactam to be effective. which can combine with ampicillin to extend its spectrum (Unasyn). N.B use Roslé Empiric therapy with (piperacillin/tazobactam). When considering the activity of a beta-lactamase inhibitor Because they have activity against aerobes and combination, remember that the beta-lactamase inhibitor only frees anaerobes, they are a good empiric choice for mixed infections, such as1intra-abdominal up the beta-lactam drug to kill the organism—it doesn’t enhance the activity. Therefore, the combination products are active only against the bacteria that the beta-lactam in the combination has intrinsic activity against in the absence of beta-lactamase production. For infections,2diabetic ulcers, and3aspiration example, ampicillin/sulbactam is active against beta-lactamase pneumonia. producing E coli because ampicillin alone is active against non-beta- lactamase producing E coli. However, it has no useful activity against P aeruginosa, because ampicillin lacks activity against this organism. In contrast, piperacillin/tazobactam is active against P aeruginosa because piperacillin itself is active. Keep in mind the rule that beta-lactamase inhibitors restore activity, not add to it, to set them straight.  Therapeutic uses of penicillins: treatmentorprophylaxis B-Prophylaxis: prophylactically in the following A. Treatment of infection: Penicillins may be used in the treatment of: conditions: Fonsolitis 1-To prevent recurrence of rheumatic fever. 1-Streptococcal infections, e.g.1wound sepsis, puerperal fever acute throat infections,4subacute bacterial endocarditis,.. etc. 3 2-Staphylococcal infections of skin, mucous membrane and bone. 2-To prevent gonorrhoeal ophthalmia in neonates. f 3-Pneumococcal infections e.g. pneumonia and empyema. 3-To prevent subacute bacterial endocarditis due to 4-Syphilis and gonorrhoea. Penicillin G remains the drug of choice bacteraemia resulting from operative procedures for syphilis. such as 1dental extraction,2tonsillectomy…etc. in 5-Meningococcal infections. empirictherapy patients with congenital or acquired valvular disease 6-Typhoid and paratyphoid fevers: ampicillin and amoxycillin. 7-Pseudomonas infection. anti Pseudomonaspenicillin or immunocompromised patient. 8-Other uses: *Actinomycosis, Anthrax and H. influenza infections. take6capsules of *Diphtheria, tetanus and gas gangrene (Penicillin may be used arthromithine 5 choice together with the specific antitoxins). metronidazole 4 ca whichofthefollowingdrugwrong 2amoxyclin 2tetracycline 3 *Peptic ulcer………………………….. Q premonia ifthecauseisHpylori Adverse effects for of Mycoplasma treatment trees 949,4 offendonthe effect Chink the Penicillins are among the most widely used and least toxic antibiotics available. 1-Hypersensitivity (10% of patients): deft I hate To Isusbid.ie in hypersensitivity reactions are common with prolonged course, history of other allergic disease and with procaine penicillin. Allergy generally occurs to all forms of penicillins at once. Allergic reactions occur in 0.7% – 8% of treatments 10% of allergic reactions are life-threatening and 10% of these are fatal Types: Allergy from 1-Early (Type I reaction-anaphylactic): Immediate - within 20 minutes apprehension, pruritis, numbness, choking,, edema, severe fall in blood pressure occurs, Penicillin with bronchoconstriction, angioedema (including larynx) and sometimes death due to loss of fluid from the intravascular compartment. , loss of consciousness, death mechanisamunknown except on emergencycase Anaphylactic shock usually occurs suddenly, in less than an hour after the drug has been given even orally, but within minutes if it has been given IV. I canusepencilin 2-Accelerated (1-72 ) hrs after administration :mainly hives iskinRash 3-Delayed (Type III reaction, serum sickness): it occurs after 2-12 days in the form of fever, malaise, arthralgia, skin rash and angioedema. if thereisallarsia ftp.ffjf ff antiphsomdonal n  9 I butforrnthekdditii.iiesof.it Prevention: 4-Cation toxicity: iiifromthepenicillin *Never give penicillin if there is history of penicillin allergy. Large doses of the sodium or potassium salt of penicillin-G in patients with *Test for hypersensitivity renal insufficiency can result in excessive blood levels of these cations. i 5-Procaine penicillin: Treatment: ECAA It produces mental changes, convulsion, pulmonary infarction (due to Epinephrine = antihistamine (e.g. accidental IV administration). chlorpheniramine)corticosteroids and aminophylline. sreiaiesoftoixiii.is inflammatic 6-Herxheimer reaction in late syphilis: Bactriacidal madye strong treatbycorticosteroid.am.in i iii 2-Neurotoxicity: 7-Masking of infection (syphilis and gonorrhea): the him forgonorrhea trement Convulsions, coma, and death has followed intrathecal syphilisdoctorwill give injections of penicillin. It occurs after high doses and in renal cnn.mn nn 8-Other Adverse effects: failure. Both carbenicillin and ticarcillin may interfere with platelet aggregation and; occasionally, cause bleeding problems. 3- Broad spectrum penicillin as ampicillin cause iiiiiiiiiii.iii.io superinfection (oral monilliasis =thrush =candidiasis) (fungal 9-Resistance (due to B-lactamase enzyme) infection) Pseudomembranous colitis with late diarrhea (CDAD) 10-G.I.T upset :(diarrhea with ampicillin) Interactions proteine thepeptidelinking block blog.apygeinesyntnis 11-Interstitial nephritis (Methicillin ) 1-Penicillins with bacteriostatic drugs (e.g. tetracycline, chloroamphenicol, erythromycin): since penicillin act by inhibiting cell wall synthesis, but drugs which decreases protein synthesis, interfere with the action of penicillin. 12-Thrombophlebitis (IV) 2- Combined use of penicillin and an aminoglycoside antibiotic (such as gentamicin) on the enterococcus. In this example, inhibition of cell wall anesthesia synthesis by penicillin permits better penetration of the cell wall by the 13-Painful injection (IM) add local aminoglycoside and more effective inhibition of protein synthesis than either drug alone. But All penicillins impair the antibacterial action of aminoglycosides when 14-bleeding tendency the 2 drugs are mixed together in vitro. This inactivation is likely to occur in patients with severe renal impairment. 15-hypokalemia with carbenicillin  CEPHALOSPORINS Characters: They have been grouped into “ 5 generations” that largely correlate with their spectrum of activity. 2- cephalosporins cephalosporins have some cross-allergenicity with penicillins However, using any cephalosporin in a patient with a penicillin allergy is a matter of balancing risks and benefits. emergencycase The cephalosporins are generally more resistant to beta- lactamases than penicillins are. Beta-lactamases that are active against penicillins but inactive against cephalosporins are called penicillinases. Beta- lactamases that inactivate cephalosporins (cephalosporinases) CEPHALOSPORINS Pharmacokinetics : Antibacterial spectrum sina.m IProbenicid1decrease renal penicillin and cephalosporin excretion and pm st nd rd f.wsdram th Increase duration of action They are divided into 1 , 2 , 3 , and 4 generations. In general, the activity against gram-positive bacteria 1-Cefoperazone (third generation) are primarily excreted in bile and excretedingbile its serum level is not greatly influenced by renal failure. decreases from first to third generation while activity fortreatmentofSalmonellatyphoidfever against gram-negative organisms increases. 2-Cefotaxime on other hand is excreted mainly by kidney, so dose off adjustment is needed in renal insufficiency. only don'tuseit 3- Ceftriaxone has the characteristic of having dual modes of mF elimination via both renal and biliary excretion. It does not need to be adjusted for renal dysfunction, but it does effectively treat UTIs. not forchildren willcauseJunate  notcross unreliable cross I. FIRST GENERATION CEPHALOSPORINS fortreatment They are active against aerobic gram-positive cocci THE 1 Gst 2nd G my 3 G rd ofth 4 G meningitis and some aerobic gram-negative bacilli. BY rum They do not cross the meninges and are therefore not +ve> -ve +ve = -ve -ve > +ve +ve = -ve used in treatment of meningitis. Pseudomonas X Pseudomonas √ They are -lactamase sensitive : gram re is easypentrition Examples of this class include: parentral and oral ofanyantimicrobial Cephalothin , Cephradine, cefazolin, cefalexin- cefadroxil) tretment alternative ofmaxodin in tonstitis I. FIRST GENERATION CEPHALOSPORINS II. SECOND GENERATION CEPHALOSPORINS They are active against aerobic gram-positive cocci They have extended spectrum including few and some aerobic gram-negative bacilli. anaerobes and gram-negative. They do not cross the meninges and are therefore not used in treatment of meningitis. not evenonmengitis They are relatively resistant to -lactamases. They are -lactamase sensitive : Unreliable corss 85 stop Examples of this class include: Examples of this class include: cedar not zenad Cefuroxime, cefoxitin, cefamandole , cefaclor and Q Yghi.CH rettmhehtaf'mYnng is ( cefotetan) which has added activity against firstandsecondGeneration f anaerobes IV.  positive infection notused for tonski is gram THIRD GENERATION CEPHALOSPORINS -They are excellent gram negative organisms including Pseudomonas and anaerobic microorganisms with Ceftriaxone has two problems that make its use in diminished gram positive activity. but less vs. neonates problematic: staphylococci fever 1-It interacts with calcium-containing medications to infectionand Salmonita typhoid on Billarytract form crystals that can precipitate in the lungs and -Highly resistant to -lactamase. kidneys, which has led to fatalities, and on Gonrrhearesistent -Penetrate blood brain barrier and attain high concentrations in CSF, therefore they are used in gram- 2- it can lead to biliary sludging with resultant negative bacterial meningitis except cefoperazone. hyperbilirubinemia. dunce Examples of this group include: I ceftriaxone, cefotaxime, Cefoperazone, cefixime So, Avoid ceftriaxone for neonates—cefotaxime is a , (Long half life ) and ceftazidime which has added safer drug for these young patients. activity against Pseudomonas aeruginosa. IV. FOURTH GENERATION CEPHALOSPORINS Browdsestspectrum 5th generation cephalosporins or ANTI-MRSA Like 3rd generation but more resistant to B lactamases CEPHALOSPORINS Ceftaroline There is only one fourth-generation cephalosporin: cefepime. ceftobiprole Changthestructer Cefepime is the broadest spectrum cephalosporin, with activity Its structure has been engineered to bind to the penicillin- binding protein 2a of MRSA, so, ceftaroline can bind to É against both gram-negative organisms, including Pseudomonas, and gram-positive organisms and anerobes. One way to penicillin-binding protein 2a, a type that is expressed by MRSA. remember its spectrum is to think that cefalothin (1st) + This characteristic is responsible for its anti-MRSA activity. which ceftazidime (3rd) = cefepime (4th). has low affinity for other beta-lactams. E Adverse Effects It is often used as an alternative to vancomycin or daptomycin Generally, similar to those of other beta-lactams, but for MRSA infections. cefepime may be associated with more neurotoxicity (non convulsive status epilepticus). than most other beta-lactams. Adverse Effects: A person allergic to penicillin, about 10% chance of being Similar to those of other beta-lactams, with possibly a higher allergic incidence of neutropenia seen with prolonged administration.  Bacterial don'talloy carnotis Gram ve Bacteria Cephalosporins SIDEROPHORE CEPHALOSPORIN Cefiderocol is a unique drug. It works to prevent peptidoglycan cross-linking, as other beta-lactams do. It has the basic structure of a cephalosporin but with a side chain that complexes with iron and is recognized by bacteria as a 1st 2nd 3rd 4th Next siderophore, which bacteria actively uptake. generation generation generation generation generation (Bacteria need iron to grow. Siderophores are substances that many bacteria secrete into their environment to complex with free iron, then actively Gram transport across their cell walls to the interior of the cell). Gram positive Gram positive negative activity activity activity > Broadest activity >Gram =Gram Gram positive spectrum of against When cefiderocol complexes with iron, bacteria recognize it as a siderophore negative negative action (MRSA) and actively transport the complex into the cell, where it can work to prevent + cell wall synthesis. activity activity Pseudomonas Cefiderocol’s siderophore side chain allows for active uptake into bacteria, avoiding some mechanisms of resistance, such as porin changes. m iii T.ESiicioram ve infection 2 ComplicatedUIT Phemonica accured Cefiderocol is an expensive antibiotic that has utility against 3 hospital many of the most resistant gram-negative organisms in practice, including those resistant to carbapenems. CEPHALOSPORIN/BETA-LACTAMASE INHIBITOR Cefiderocol used for treatment of: COMBINATIONS 1- complicated UTIs and ceftazidime/avibactam, ceftolozane/tazobactam 2- hospital acquired pneumonia. 3-Also, treatment of many types of infections caused by resistant gram-negative infections. Cefiderocol should be used only in patients with resistance to other antibiotics. Of course, cefiderocol resistance occurs. Those bacteria never quit, so susceptibility testing still needs to be performed. Therapeutic uses of cephalosporins Adverse effects 1-Allergic reactions, 1-Severe undiagnosedempric therapy sepsis especially in such as rash, urticaria, fever, serum sickness, hemolytic anemia, and immunosuppressed patient. 4thDecits broadspectrum eosinophilia. Because of the similarities in structure between the cephalosporins and penicillins, it is not surprising that patients, who are 2-Treatment of infection of respiratory tract, urinary tract, hypersensitive to penicillin occasionally exhibit similar sensitivity when skin, soft tissue, bones and joints due to susceptible treated with a cephalosporin (cross resistance). Therefore, it is organisms. important to inquire about both penicillin and cephalosporin hypersensitivity, especially the immediate variety, before administering 3-Gram-negative bacterial meningitis may be treated by any of these agents. cefotaxime (third generation) and Ceftriaxone that reach the C.N.S. 2-Nephrotoxicity is potentiated by the simultaneous use of diuretics (e.g. thiazide) or 4-Biliary infection: 3rd generation (cefoperazone or nephrotoxic agents such as aminoglycosides. It is less with oral ceftriaxone). preparations. 5-Gonorrhoea due to penicillin-resistant Gonococci. It is rare3-Superinfections with Pseudomonas, Klebsiella, Enterobacter, E. coli, treated by single IM injection of ceftriaxone. Proteus, Serratia and Candida have been reported leading to diarrhea. 6-Pseudomonal infection. 3rdand4thgeneration 2 3- MONOBACTAMS e.g. Aztreonam (I.V- I.M) 4-Hypoprothrombinemea, thrombocytopenia on hospital and/or platelet dysfunction It is monocyclic -lactams (monobactams). -Is are new adverse effects of selected extended- effective against aerobic gram negative bacteria only spectrum cephalosporins.. Including Pseudomonas, E. coli , K. pneumoniae, P. mirabilis, H. influenzae,M. catarrhalis, Enterobacter, Citrobacter,Providencia, Morganella, Salmonella, 5-A disulfiram-like reaction Shigella) has also been noted with some of these agents, such as cefoperazone if it is given with alcohol because they block the second step in alcohol oxidation which No effect on G+ve or anaerobes. results in the accumulation of acetaldehyde. (An alternative to an aminoglycoside).  the Legff to producepenicillinallergy g _post surgical ftp.egggertioncephlosporinbut 1 thisone Used in : 1-Gram-negative infections, including Pseudomonas, particularly in patients I I 4- CARBAPENEMS e.g. imipenem/cilastatin, meropenem, ertapenem i.ru with a history of beta lactam allergy. CidalBroadest-spectrum antibacterial drugs against most aerobic and anaerobic bacteria (Gram-positive and gram-negative) with the exception of Free2-Aztreonam can be administered via inhalation to patients with cystic fibrosis to prevent exacerbations of infection. occasional Pseudomonas strains. They possess a beta-lactam ring and share the same mechanism of action Side effects : of beta lactams with higher ability to induce seizures. (Neurotoxic in high 1- Abnormal liver enzymes doses)– (not used in meningitis= imipenem) 2- Little hyper-sensivity reaction Bacteria not covered by carbapenems include MRSA, VRE, coagulase- 3R characters: of 1-Risk (low)of cross allergy with penicillin. Minimal risk of reaction in those negative staph, C. difficile, S. maltophilia, Nocardia allergic to penicillin. Can be used in penicillin allergy Imipenem is metabolized in the kidney to a nephrotoxic product. 2-Replace extended spectrum penicillin & cephalosporins Cilastatin blocks the renal dehydropeptidase that catalyzes this reaction and prevents this metabolism from occurring so, inhibit necrosis of 3-Resist B-lactamase enzyme (Aztreonam is stable to most -lactamases). tubules and increase urinary active drug concentration cause nephrotoxictkidneyprotictivebyblocking characterestics : Adverse effects The ease of penetration (due to its low molecular 1-Allergy :Carbapenems may rarely elicit an allergic weight) with charge characteristics that allow them to reaction in patients with a history of penicillin allergy. G use porins in the outer membrane of G-ve bacteria to access the PBPs ak 2-Blood disorders. 3- Neurotoxic in high doses. 4- G.I.T: nausea, vomiting, etc. Resistant to B lactamases Affinity to broad range of PBPs Meropenem: All of these imparts a broad-spectrum of antimicrobial activity against most aerobic and anaerobic bacteria 1-Stable in renal tubule (not affected by (Gram-positive and gram-negative). dehydropeptidase enzyme) So, Not need cilastatin 2-Safe in meningitis (no seizures) CARBAPENEM/BETA-LACTAMASE INHIBITOR COMBINATIONS : 1-meropenem/vaborbactam 2- imipenem/cilastatin/relebactam Non B lactam bacterial cell wall inhibitors cidal nsthfc8nusueseit Non −Lactams BACITRACIN Topic.at ifpI h'tinkp Mechanism of action Bactericidal-inhibits cell wall synthesis. inhibit early stage (dephosphorylation) of peptidoglycan 1- Polypeptides or (cyclic peptide) :Bacitracin and cycloserine -Not used systemically because it is Nephrotoxic 2- Glycopeptide :vancomycin Antimicrobial spectrum 3-Lipoglycopeptide : Dalbavancin, Oritavancin Bacitracin inhibits gram-positive cocci and a few gram-negative Telavancin, and Teicoplanin organisms. 4- Lipopeptides: Daptomycin Therapeutic uses: limited uses due to its side effects when used systemically (nephrotoxicity) 5- Fosfomycin it is mainly used topically alone or in combination with other antibiotics (Notably polymyxin-B and neomycin) or hydrocortisone (as anti-inflammatory) in the form of creams, ointments and aerosol preparations. for surgical wound 2 infection  VANCOMYCIN:(Bactericidal)(Natural) CYCLOSERINE Mechanism of action Structural analog of D-alanine Secondline treatment Glycopeptides bind peptidoglycan in the cell wall, ofTB for 6mounthsd.g Exclusively use in strains of Mycobecteria resistant inhibiting early stage (preventing further elongation of to first line anti tuberculous drugs peptidoglycan chains(transglycosylation) & cross linking of peptidoglycan. Serious dose related neuropsychatric toxicity i.e psychosis, tremors, convulsions Not absorbed orally giveitIM.IV Antimicrobial spectrum It has a narrow-spectrum activity (only against gram- positive bacteria). But Not for tonsillitis of Therapeutic uses Adverse effects 1-Vancomycin is also the drug of choice in patients in 1-The major adverse effect associated with vancomycin therapy whom pseudomembranous colitis (antibiotic associated is ototoxicity. colitis) has developed (oral) Q antifungal anfetresi.nl 2-"Red neck syndrome": More commonly, the intravenous 2-Methicillin-resistant Staphylococcus aureus infections, infusion of vancomycin can result in the occurrence of chills, (MRSA) infection e.g infective endocarditis (IV infusion) fever, hypotension and a maculopapular skin rash often involving the head and upper thorax due to histamine release. Now it is called vancomycin Infusion-related rapid reactions. This reaction can be prevented by slowing the infusion rate and is 3-Other infections due to susceptible organisms e.g. not a true allergy. Antihistamines can also ameliorate the streptococci, bacillus anthracis, corynebacterium reaction. diphtheria, clostridium tetani and difficile. Anaerobic infection orally 3- Nephrotoxicity. 4-Thrombophlebitis with fever and chills 4-may be used in penicillin allergy 5-Neurotoxic  2- Telavancin is a lipoglycopeptide that was modified from LONG-ACTING GLYCOPEPTIDES: vancomycin’s structure but with unique properties of improved activity against MRSA that is less susceptible to vancomycin, but dalbavancin, oritavancin: Long acting drugs it is used primarily for patients who do not respond to Are unique agents with slow their elimination. Both can vancomycin. (vancomycin R organisms) be dosed intravenously just once for the equivalent of 2 weeks of therapy since each has a half-life of over a week. Telavancin is more rapidly bactericidal than vancomycin because it has dual mechanism of action: Both drugs have strictly gram-positive activity that 1- The first as vancomycin. includes MRSA and streptococci. 2- The second mechanism where the drug interferes with the cell membrane also, disrupting membrane function. Used in Skin and skin structure infections caused by Telavancin side effects : gram-positive organisms. 1-Because the core structure of telavancin is essentially vancomycin, it may cause vancomycin infusion reaction as well. 2-Taste disturbances and foamy urine occur with telavancin. AF Nausea, vomiting, diarrhea, and rash were the most common adverse effects with both drugs. Daptomycin (lipopeptides) Uses: of Mehanism of action and spectrum : i i.ee Lipid portion of the drug inserts into the cell membrane of is effective for treating complicated skin and soft tissue infections. It is administered intravenously once daily and is excreted unchanged in urine; dose adjustments are required gram-positive organisms, weakening it leading to the leakage when given to individuals with severe renal insufficiency. of intracellular cations from the organism that maintain membrane polarization. The result is rapid depolarization and cell death. Instead of blowing the bacteria apart as beta lactams do, daptomycin leaves the dead bacteria intact Adverse effects : of 1- Skeletal muscle that can manifest as1muscle pain or don'tswell Bacteria 3 2 weakness, or possibly rhabdomyolysis. To monitor for this Daptomycin is active against many resistant gram-positive effect, creatine kinase (CK) concentrations should be checked organisms, including VRE and MRSA. It has been proven weekly while a patient is on therapy. This toxicity can be effective in staphylococcal endocarditis , an indication that decreased by administering the drug no more than once daily few antibiotics have. and by adjusting the interval in renal dysfunction. N.B: Though it penetrates lung tissue very well, daptomycin aBfq.ae 2- Eosinophilic pneumonia has been reported in patients on cannot be used to treat pneumonia. Human pulmonary daptomycin therapy surfactant binds to daptomycin, rendering it inactive. THE POLYMYXINS Adverse effects Q polymyxin B and colistin (polymyxin E) are used in the treatment bacterial diseases. 1- Nephrotoxicity. MOA: 2-Neurotoxicity. recognized by perioral paresthesia, Polymyxins bind to the outer membrane of gram-negative numbness, weakness, ataxia and blurred vision. bacteria (P. aeruginosa and coliform organisms in particular)., leading to disruption of membrane stability 3-These drugs precipitate respiratory arrest (due to and leakage of cellular contents. Neuromuscular blocking effect) especially both in patients given muscle relaxants during anesthesia and Therapeutic uses in persons suffering from myasthenia gravis. 1-In combination with neomycin, polymyxin B is used as a bladder irrigant to reduce the risk of catheter- associated infections. 2-Polymyxin B also is applied topically in combination with other antibiotics for infections of skin, eye or ear. Fosfomycin: Fosfomycin inhibits bacterial cell wall synthesis in a different way from beta-lactams and glycopeptides, preventing the production of the building blocks of peptidoglycanin in both Gram-positive and gram negative bacteria. Is a synthetic, broad-spectrum, bactericidal antibiotic with activity against large number of Gram-negative and Thank you Gram-positive organisms including E. coli, Klebsiella spp., Proteus spp., Pseudomonas spp., and VRE. Uses: is used in treatment of urinary tract infections. It is used only as a urinary antiseptic in uncomplicated cystitis. Given every 10-14 days. (ineffective for infections outside of the lower urinary tract).