Antimicrobial Agents

1. Antimicrobial Agents cell wall inhibitors

3. Penicillin Penicillin is a group of antibiotics derived from penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are B -lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive organisms.

4. Chemical structure of penicillins Penicillin core structure, where "R" is the variable group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.

5. Why are penicillins more effective against gram-positive organisms than gram-negative organisms? The structure of the bacterial cell wall in gram-positive organisms contains only a layer of peptidoglycans attached to the inner membrane, and leaves the PBPs relatively exposed. In a gram-negative organisms, the drug must enter through pores (porin) in order to reach the inner space between the double membrane and attach to PBPs.

6. The cell envelope of gram negative bacteria

7. Mechanism of Action of penicillins • Penicillins are bactericidal drugs. • They act to inhibit cell wall synthesis by the following steps: 1. Binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane. 2. Inhibition of the transpeptidation reaction that cross-links the linear peptidglycan chain constitunts of the cell wal. 3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall. • NB: Penicillins exert a bacteriocidal action on growing or multiplying germ.

10. Resistance to Penicillins I. Production of b-lactamases This family of enzymes can inactivate penicillins by hydrolyzing the b-lactam ring The production of b-lactamases is considered the principal cause of bacterial resistance to b-lactam antibiotics Examples of bacteria that produce b-lactamases are staphylococcus aureus and many strains of H. influenzae, Neisseriaand Pseudomonas

12. II. The occurrence of modified penicillin-binding sites • Modified PBPs have a lower affinity for b-lactam antibiotics, requiring clinically unattainable concentrations of the drug to effect its bactericidal activity • Example: penicillin resistance in Streptococcus pneumoniae (pneumococcus) is caused by altered PBPs • Decreased permeability to the drug • Decreased penetration through the outer membrane prevents the drug from reaching the target PBP • This occurs with G-ve organisms, which have an outer membrane that limits penetration of hydrophilic antibiotics. This is of particular relevance in determining the extraordinary resistance of Pseudomonas aeruginosa to most antibiotics.

14. Classification of Penicillins

15. Types of penicillin and their antimicrobial activity • Penicillins (e.g., penicillin G): These have greatest activity against gram–positive organisms, gram-negative cocci, and non-β-lactamase producing anaerobes. They are susceptible to β-lactamase • Antistaphylococal penicillins (e.g., nafcillin): These penicillins are resistance to staphylococcal β-lactamase. They are active against staphylococci, streptococci but not against enterococci, anaerobic bacteria, and gram negative cocci and rods. • Extended-spectrum penicillins (ampicillin and the antipseudomonal penicillins):These drugs retain the antibacterial spectrum of penicillin and have improved activity against gram-negative organisms. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamase.

16. Pharmacokinetics • Oral absorption of penicillins varies, depending on their stability in acid, protein binding and adsorption to food stuffs in the gut. • Penicillins can also be given by IV and IM injections. • Penicillins are polar compounds and are not metabolized extensively. They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion; the latter process is inhibited by probenecid(this would prolong serum penicillin levels) • Because renal dysfunction will compromise the elimination of penicillin, dosages may need to be reduced in patients with renal insufficiency. • The plasma half-lives of most penicillins vary from 30 min to 1 hr. • Most penicillins cross the blood brain barrier (BBB) only when the meninges are inflamed.

17. Clinical Pharmacokinetics • Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis) • They are actively excreted unchanged by the kidney, but the dose should be reduced in severe renal failure

18. Clinical uses of the penicillins • Penicillins are given by mouth or in more severe infections, intravenously, and often in combination with other antibiotics. • Uses are for sensitive organisms. Including for example: • Bactrial meningitis: benzylpenicillin • Bone and joint infections: flucloxacillin • Otitismedia,Bronchitis, Pneumonia,Urinary tract infections: amoxicillin • Gonorrhea: amoxicillin (plus probenecid) • Syphilis: procaine benzyl penicillin • Serious infections with pseudomonas aeruginosa: ticarcillin, pipracillin • treatment with penicillins is some times started empirically, if the likely causative organism is one thought to be susceptible to penicillin, while waiting the results of laboratory tests to identify the organism and determine its antibiotic susceptibility.

19. Clinical uses of penicillins • 1-Narrow-spectrum penicillinase-susceptible agents: A. Penicillin G is the prototype of a subclass of penicillins that have a limited spectrum of antibacterial activity and are susceptible to beta-lactamases. • Used for therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes. • Most strains of pneumococci are now resistant to penicillins (penicillin-resistant streptococci pneumoniae [PRSP] strains). • Most strains of staphylococcus aureus and a significant number of strains of neisseriagonorrhoeae are resistant via production of beta-lactamase.

20. B. Penicillin V is the acid resistant form of penicillin which is marketed as oral dosage form. • All oral penicillins are best given on an empty stomach to avoid the absorption delay caused by food. • Penicillin V is less active than penicillin G against Neisseria species. It is satisfactory substitute for penicillin G against Streptococcus pneumonia and S. pyogenes. • It is the first choice in the treatment of odontogenic infections. C. Procaine penicillin G{ Depot form }(is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent .This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection) is best suited to the single-dose outpatient treatment of very sensitive organisms (e.g., penicillin-sensitive N. gonorrhea and group A streptococci) D. Benzathine penicillin is another long-acting preparation given IM. It is used for prophylaxis of rheumatic fever and for treatment of syphilis.

21. odontogenic infections

23. 2. Very-narrow-spectrum penicillinase-resistant drugs: • Methicillin is the prototype but rarely used owing to its nephrotoxic potential in addition to Nafcillin and oxacillin. • Their primary use is in the treatment of known or suspected staphylococcal infections. • Methicillin-resistant (MR) staphylococci (S aureus [MRSA] and S epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs. • They are resistant to bacterial penicillinase. • Nafcillin and the isoxazolyl penicillins (oxacillin, cloxacillin, dicloxacillin) are lipophilic in nature, with a high degree of efficacy against staphylococcus.

24. 3. Wider-spectrum penicillinase-susceptible drugs: A. Ampicillin and amoxicillin (aminopenicillins) : These drugs has a wider spectrum of antibacterial activity than penicillin G and have improved activity against gram-negative organisms but remains susceptible to penicillinase. • Their clinical uses are similar to penicillin G as well as infections resulting from enterococci, Listeramonocytogenes, Escherichea coli, Proteus mirabilis, Haemophilusinfluenzae, and Moraxellacatarrhalis. • When used in combination with inhibitors of pencillinases (e.g., clavulanic acid), their activity enhanced. • In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides. • Amoxicillin may be given orally to pediatric and geriatric patients.

27. B. Piperacillin and ticarcillin (Anti-Pseudomonal Penicillins): • These drugs have activity against several gram-negative rods, including Pseudomonas, Enterbacter, and in some cases Klesiella species. • Most of these drugs have synergistic actions when used with aminoglycosides in the treatment of systemic Pseudomonas. • Piperacillin and ticarcillin are susceptible to penicillinase and are often used in combination with penicillinase inhibitors (e.g., tazobactam and clavulanic acid) to enhance their activity. • These antibiotics have a broader spectrum of gram-negative activity than do the aminopenicillins, and include activity against most strains of P. aeruginosa • These antibiotics are used in the treatment of urinary tract, lung, and bloodstream infections caused by ampicillin-resistant enteric gram-negative pathogens.

29. Adverse reactions Penicillins are among the safest drugs, and blood levels are not monitored. However, the following adverse reactions may occur. 1. Hypersensitivity :This is the most important adverse effect of the penicillins. The major antigenic determinant of penicillin hypersensitivity is its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. Approximatelyfive percent of patients have some kind of reaction, ranging from maculopapularrash (the most common rash seen with ampicillin hypersensitivity) to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis. Cross-allergic reactions occur among the β-lactam antibiotics. To determine whether treatment with a β-lactam is safe when an allergy is noted, patient history regarding severity of previous reaction is essential.

30. maculopapular rash periorbital area

31. 2. Diarrhea: This effect, which is caused by a disruption of the normal balance of intestinal microorganisms, is a common problem. It occurs to a greater extent with those agents that are incompletely absorbed and have an extended antibacterial spectrum. As with most antibiotics, pseudomembranous colitis may occur. 3. Nephritis: All penicillins, but particularly methicillin, have the potential to cause acute interstitial nephritis. [Note: Methicillinis therefore no longer available.] 4. Neurotoxicity: The penicillins are irritating to neuronal tissue, and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are particularly at risk. When indicated, dosage adjustments for patients with renal dysfunction further minimize the risk for seizure

32. injected intrathecally

33. Hematologic toxicities: Decreased coagulation may be observed with high doses of piperacillin, ticarcillin and nafcillin (and, to some extent, with penicillin G). Cationtoxicity: Penicillinsare generally administered as the sodium or potassium salt. Toxicities may be caused by the large quantities of sodium or potassium that accompany the penicillin. For example, sodium excess may result in hypokalemia. This can be avoided by using the most potent antibiotic, which permits lower doses of drug and accompanying cations. Treatment with aqueous penicillin G has a high potassium load, which must be taken into account while monitoring electrolytes. The same is true for ticarcillin which has a high sodium load.

34. Summary of the adverse effects of penicillin

35. Cephalosporin antibiotics • Cephalosporin antibiotics are beta-lactam antibiotics, similar in structure and action to penicillin, were first isolated from “Cephalosporium” fungus. • Semisynthetic broad-spectrum cephalosporins have been produced, they vary in susceptibility to beta-lactamase. • First-generation cephalosporins are active predominantly against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria. • In general, the spectrum of activity of cephalosporins increases with each generation because of decreasing susceptibility to bacterial b-lactamases

36. Mechanism of action • Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases. • Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. • These agents bind to penicillin binding proteins. • Like penicillins, they must enter the cell wall through porins and attach to penicillin-binding proteins (PBPs). The binding of the drug to these proteins mediates an inhibition of cell wall synthesis and leads to autolysis.

37. Classification • The cephalosporins are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. • Many members of this group are in clinical use. • They vary in their antibacterial activity and are designated according to the order of their introduction into clinical use: First generation such as: cefradine, cefalexin, cefazolin and cefadroxil Second generation such as: cefuroxime, cefaclor, cefamandole, and cefoxitin. Third generation such as: cefotaxime, ceftazidime, cefixime, ceftriaxone and cefoperazone. • Fourth generation such as :cefepime, cefpirome. Fifth generation such as: Ceftaroline

38. 7-aminocephalosporanic acid nucleus

39. Structure of some cephalosporins

40. Pharmacokinetics • These agents are water soluble and relatively acid stable. • Several cephalosporins are available for oral use, but most are administered parenterally, intramuscularly (which may be painful) or intravenously. • After absorption, they are widely distributed in the body and some, such as cefotaxime,cefuroxime and ceftriaxone, cross the blood brain barrier. • Excretion is mostly via the kidney unchanged, largely by tubular secretion, but 40% of ceftriaxone is eliminated in the bile. • Most first- and second-generation cephalosporins do not enter cerebrospinal fluid even when the meninges are inflamed.

41. Administration and fate of the cephalosporins

42. Therapeutic advantages of some clinically useful cephalosporins

45. Clinical uses of the cephalosporins • Cephalosporins are used to treat infections caused by sensitive organisms. As with other antibiotics, patterns of sensitivity vary geographically , and treatment is often started empirically. • Many different kinds of infection may be treated, including: • Septicaemia (e.g., cefuroxime, cefotaxime) • Pneumonia caused by susceptible organisms. • Meningitis (e.g., ceftriaxone, cefotaxime) • Billiary tract infection • Urinary tract infection (especially in pregnancy or in patients unresponsive to other drugs) • Sinusitis (cefadroxil). • In general, first generation cephalosporin possess excellent activity against gram-positive aerobic bacteria and poor activity against gram-negative organisms.

47. First-Generation Cephalosporins • Cefazolin (parenteral), cephalexin (the first oral cephalosporin) and the long acting agent cefadroxil are examples of this subgroup. • They are active against gram-positive cocci, including staphylococci and common streptococci. • Many strains of E. coli and K. pneumonia are also sensitive. • Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions. • These drugs have minimal activity against gram-negative cocci, enterococci, mithicillin-resistant staphylococci, and most gram-negative rods. • They distribute widely throughout the body, but do not penetrate well into the CSF (not used for meningitis).

48. Second-Generation Cephalosporins • Drugs in this subgroup usually have slightly less activity against gram-positive organisms than the first generation drugs but have an extended gram-negative coverage. • Marked differences in activity occur among the drugs in this subgroup. • Examples of clinical uses include infections caused by the anaerobe Bacteroidsfragilis(cefotetan, cefoxitin) and sinus air, and respiratory infections caused by H influenzaeor M catarrhalis(cefamandole, cefaclor). • They are more resistant to b-lactamase than the first-generation drugs. • Cefoxitin is active against gram-negative organisms and anaerobes.

49. Third-Generation Cephalosporins • Characteristic features of third-generation drugs (e.g., ceftazidime, cefoperazone, cefotaxime) include increased activity against gram-negative organisms resistant to other beta-lactam drugs and ability to penetrate the blood brain barrier (except cefoperazone and cefixime). • Most are active against Providencia, Serratiamarcescens, and beta-lactamase-producing strains of H influenzae, Neisseria. • Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin resistant pneumococci (PRSP strains). • Individual drugs also have activity against Pseudomonas aeruginosa (ceftazidine) and B fragilis(cdftizoxime).

50. Fourth-Generation Cephalosporins • Cefepime is more resistant to beta-lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin resistant pneumococci. • Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins. • Fourth-generation agents are particularly useful for the empirical treatment of serious infections in hospitalized patients when gram-positive microorganisms, Enterobacteriaceae, and Pseudomonas all are potential etiologies