paleilacie cig > polsnt so srageia actin of actamases has created jenewed i Early attempts to SH Yas f Dunston: consisting of « GlaciaTiae-resistant penicil (e<,methilin or exci) se 6 Competitive inhibitor and af-tctamase=sensTve perllin(eg arsplellin or carbene the organisms, met with limited success, a OK Factors that may contribute to the failure of such combinations to achieve synergy include {@) the failure of most lipophilic penicillinase-resistant penicillins to penetrate the cell envelope of Gram-negative bacilli in effective concentrations. J+ 0s the reversible binding of penicillinase-resistant penicillins to B -lactamase, requiring high concentrations to prevent substrate binding and hydrolysis, Tithe ind lactamases by some penicillinase-resistant penicillins ‘The discovery of a naturally occurring, mechanism basedGahibitor which causes =rest in B lactam Fe Cop oo aint i © This interest has led to the design and synthesis of additional mechani:m based @ lactamase inhibitors, such as , and the of naturally eccurring B -lactams, such as the {lyienaiye/ns, Which both inhibit -lactamases and interact wk Pass. Knowles has described two classes of B-actamase inhibitors: ge ee ee on fe st sulbactam) > ae a St ; |) inhibitors that do not (e.g., the carbap: nems). Seer Sy thant. eointermediate is formed by reaction of the j me. For normal substrates, ing the substrate and intermediate formed e is diverted by With the B-lactamases, an cy Jactam with an active- ine hydroxyl group of the enzy! the acyl-enzyme intermediate readily undergoes hydrolysis, destroy freeing the enzyme to attack more substrate, The acytenzyme i When a mechanism-based inhibitor |s attacked by the enzym itomerism to a more stable imine form that hydrolyzes more slowly to free the enzyme (transient inhibition). Because these inhibitors are also substrates for the enzymes that they inactivate, they are sometimes referred to as “suicice substrates”. Retake sederstiiun wee oN = geste”Because class | inhibitors cause prolonged inactivation of certain -lactamases, they x, a0 particularly usefur i? @mbinatiombwith extended -spectrum, G-lactamase-sensitive is eo penicillins to treat infections caused by B-lactamase—producing bacteria. "Three such avy ie) Gulla : marketed for this purpose. nA lass tLinhibitor apenein derivative imipenem, has potent antibacterial, 2 activity radaltion to its ability to cause transient inhibition of some B lactamase SSS “Bfactamases inactivation by class | inhibitors appear to be related to the molecular } properties of the enzymes. B -Lactamases belonging to[zaun A] large and somewhat heterogenous group of i ‘some with narrow (e.8., penicillinases or cephalosporinases) and JIBS ‘with broad (i.e. general B -lactamases) specificities, are generally inactivated by anic wah CuTEaCTAMDY and are currently class | Inhibitors. Aine group of chromosomally encoded serine fi -lactamases belonging f A TeiBe Br ordiy tor cephalosporins are, however, resistant to inactivation by class § wi bitore, A sinall group of Zn2-requiting metalio-B -lactamases ({;0u0 D)with broad Sibstrate specificities are also not inactivated by class ! inhibitors. ovens eed \wot ooded <5) lot Der aeue HA 4 imadinded oy pakClavulanate Potassium <5 - Oo Clavulanic acid is aN antibiotic isolated from, Streptomyces clavulgeris. SWMCHiEStY, i is y @ {-oxovemary lacking the 6-acylamino sd2 in of penicillins but possessing a 2. Om m ve ene moiety at C-2. en 2 Clavulanie aeid exhibits very weak antibacterial activity, comparable and, therefore, is not useful as an antibiotic It's, however, a; at aureus ® actamase and plasmid-mediated -lactamases claborat negative bacilli (IMETATOTY of amoxicillin and the potassium salt_of clav lanic acid are available {Augmentin ip various fixed-dose oral dosage forms intended for the treatment of skin, respiratory, ear, and Utinary tract Infections caused by -lactamase~producing bacterial strains. These combinations are effective against B lactamase-producing strains of » E colt K. pneumoniae, Enterobacter; H. influenzae, which are resistant to amoxicillin alone. Clavulanic acid is ( 2515>\It cannot undergo penicilianic acid formation bees lacks an amide side chain. 7jos al sulbadhan 9 2 ore > mmturebeys Sop oedtes eat ‘wlbactam © [Aino eS cee LS tess > AS), ley oo abe} Sulbactam is penicillanic acid or (Gisdowopenietane acid.) This synthetic ; penicillin derivative 1 GOsa REE OF * aureus B Jactamase as well as many B - 72 lactamases elaborated by Gram-negative bacilli. Sulbact. ym has we: intrinsic Se" antibacterial activity(but ois, ies the activity offampteltte soR-arbeaa inst cms] " B -lactamase=producing 5. aureus and members of the Enterobacteriacese femily.it <> does not, however, synergize with either nicilin_or ticarcilin against A, << eruginosa strains resistant to these agents. e. ey of sulbactam to penetrate the cell envelope is 3 postile SeplaAstion for the lack of synergy, Fixed-dose combinations of ampicillin sodium and aoe sodium, marketed under the trade name Unasyn as sterile powders for injection. These combinations are recommended for the treatment of skin, tissue, intra-abdominal, and gynecological infections caused by B-lactamase-producing strains of 5. % col, Klebsiella spp., P mirabilis, 8. frapis, and Enterobacter and Acinetobacter sop. F aTazobactam S << B10: Ade MAK Tazobactam is a penicillanic acid syne that is similar in structure to sulbactam. It is a spore potent lactamase Inhibligr than sulbactam and has a slightly broader i? spectrum of activity than clavulanic acidy It has very weak antibacterial activity. © Tazobactam is available in fixed-dose, injectable combinations with piperacillin, a YS broad-spectrum penicillin consisting of an S1 ratio of piperacillin sodium to tazobactam sodium by weight and marketed under the trade name Zosyn. ‘The p(Gimscokinetics-of the two drugs are very similar. Both are minimally protein bound, experience very little metabolism, have short half-lives (t1/2 1 hour). Approved indications for the piperacillin-tazobactam combination include the reatment of appendicitis, postpartum endometrtis, and pelvic inflammatory disease aused by - lactamase-producing £ coli and Bacteroides spp,, skin and skin soi, Structure infections caused by B -lactamase-producing 5. surcus, and pneumonia eo" caused by B -lactamase-producing strains of HM. influenzae. Ye Mtis «in active forms in the urine in high concentrations.(R.ACEE ORES UE ee es oe 4 as To Ses Saas org, ese senna eea ash cr Jha seh ves Neewivg Nebere, 4 Severed aw Pes ants = ‘Thienamycin is a {0 Blactam antibiol first isolated and identified from fermentation of \ cultures of Streptomyces cattleya. ocean 4 thionamycin are shared with the penicillins and cephalosporins: a ae ee containing a B -lactam and an equivalently attached 3-carboxy! tly attached S-carboxyl between C-2 and C3 | sou. The bicyclic system consists of a carbapenem containing 3 AP $Si\es (\.0..-it- ‘The double bond in the bicyclic_structure creates “| considerable rin reases the reactivity of the Bi -lactam to ring | oS) reactions > eee SENN Sr aie a The sicie chain is unique in two respects: | Git +2 simple(hydronyethygroup instead of the falar acylatmino she chain oriented to the bicyclic ring system rather than having Whe USuol erertation of the | —e i 2it penicilins and cephalosporins. Th feature isa inoetinytvoetha)fncton st CL rowFOpeTTES)ig_vitro. Wk is highly bic an oslve and Gram-negative bases eruarnosa, and 8, frags. Leesstant maT ATSTSy Most B -lactamases elaborated by Gram-ne a negative and Gram-positive. bacteria "an therefore, is effective against many strains resistant to peneliig a coshelocnorne ~ stant to penicillins and cephalosporins. sito lactamase’ appears tobe a function of tag hyaronethy soe cain ets) See As capone CO An unfortunate property of thienamycin is its(emmical ins.bi y)in-solution. tt is f€ and alain more susceptible to hydrolysis in both acidf€ a ine solutions than ot B ciated ecrn sa rere vnc se toned an endocyclic double bond] Another shortcoming is its susceptibility to hydrolyte_ nactvation by renal jropeptidase-I (Dlr) which causes it to have an imacceptably short half-life in vivo. ey Us eden’ &e oat om tos : ; yo ow Cae ak ee a eae= egy a “imipenem if ossaEenacmmy the most sucessful of series cof emia) (CoD derivatives of thienamycin im which the “group is converted to 3 Tron nucleophilic basic function, classi» is an inhibitor of DHP-I, The (Primaxin) provides 2 chemically and enzymatically st ble form of thienamycin that has clinically useful pharmacokinetic properties. C 1} of the drug is nonetheless short ty elev 1 hour) because of renal tubdar secretion oflimineneD. imipens Te the ihacterial properties of thienamycin. Its bactericidal 2) extraordinary anti ks from the inhibition of call wall synthesis associated with bonding :2 POPS vmipenem is very stable i mast -lactamases. 1's of inhibitor of B= Afamases from certain Gram- negative bacteria resistant to other 6 -lactam antibiotics (eg. |, & marcescens, and Enterobacter spp.) substituents at the > however, appear to affect primarily the spectrum of “ntibacterial activity of the carbaperem by Influencing penetration into bai [capability oF carbapenems to emer as \uitts SORT ( Af P| imipenem and biapenem), resulting from the combined features of a basic amine ee Pion attached to_the 2-nosition_and_the 3-carboxyl group, ¥ fi 4-4 \ molecules to enter bacteria via thet charged porin channels) Ri dmipenem-Cilastatin may (enable these oeMeropenei > LH ef ner tn. “4 oD eo Pe t y—, Wee t, to date, has undergone the al evaluation. It has ned been agaroved as Man for the treatment of infections caused by iply-resistant bacteria and for empirical therapy for serious infections, such as bacterial meningitis, septicemia, pneumonia, peritonitis. eas ma ‘Meropenem exhibits greater potenc) Meropenem is_a second-generation and gainst Gram-negative and anaerobic bacteria it an does imipenem, but it is slighth gainst ‘most Gram-positive species. It ( is Rot cifective against MRS, Meropenem is(not hydrolyzed DHP- and is resistant to most B -lactamases, including a few carbapenemases that hydrolyze carbapenem. ie Keene meropenem ig HOC active OTA It is provided as.a sterile lyophilized > power tobe made up in normal saline or '59 dextrose solution for parenteral (9 administration. 2 x poe ee? ins f= See