Carbapenemici I carbapenemici sono antibiotici β- lattamici dotati di un’unica struttura del nucleo, ove all’atomo di zolfo è stato sostituito un atomo di carbonio e l’anello a 5 atomi è insaturo. Sono derivati dall’acido olivanico (sintetizzato nel 1976) che è un inibitore delle β-lattamasi. 1

Carbapenemici Nel 1978 è stata isolata la tienamicina, prodotta da Streptomyces cattleya, un composto che è risultato chimicamente molto instabile, mentre il suo derivato ottenuto l’anno seguente (1979) N- formidoil-tienamicina nota come imipenem, è entrato in uso da tempo. Successivamente è stato commercializzato il meropenem, sviluppato nel 1987. 2

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Carbapenemici I carbapenemici sono i farmaci che esprimono il più ampio spettro antibatterico in vitro non solo nell’ambito dei β-lattamici, ma anche includendo le altre classi di antibiotici. Essi infatti inibiscono molti cocchi aerobi ed anaerobi nonché un gran numero di specie gram-negative. 4

Carbapenemici La potenza in vitro dei carbapenemici si osserva nei confronti dei microorganismi produttori di β- lattamasi a spettro esteso o che mostrano resistenze multiple ad altri antibiotici, su questi patogeni i carbapenemici dimostrano attività antibatterica. 5

Carbapenemici Sono invece considerati resistenti Enterococcus faecium, Stenotrophomonas maltophilia, Burkholderia cepacia, gli stafilococchi resistenti all’oxacillina (meticillina), corinebatteri e i patogeni intracellulari. 6

The enhanced activity of carbapenems is due to several factors are smaller molecules than cephalosporins and are zwitterions (i.e. they have both positive and negative charges in solution), both of which properties facilitate rapid penetration across the Gram-negative outer membrane have high affinity for essential penicillin-binding proteins (PBP-2, PBP-4, PBP-3 and PBP-1b) from a broad range of bacteria are resistant to a broad range of -lactamases from Gram-positive and Gram-negative bacteria. 7

Carbapenemici La selezione spontanea di microorganismi resistenti ai carbapenemici appare inoltre un evento molto raro. Sono dotati di una veloce capacità di ingresso nei batteri ed una immediata ed alta affinità con il bersaglio. 8

Carbapenemici Parenterali Imipenem, meropenem, panipenem, biapenem, doripenem (S-4661), ertapenem, Tomopenem (CS- 023), razupenem (PZ-601), ME 1036 In studio: E 1036, E-1010 e BMS-181139, J-111,347, SM 197436 Orali Tebipenem, sanfetrinem, In studio:DZ-2640, CS-834 e GV-129606 9

Enterobacter, spp. ecc) che fermentano invece il glucosio. Raggruppamento dei principali carbapenemici sulla base dello spettro d’attività I bastoncini gram- non fermentanti includono i ceppi come Pseudomonas, Stenotrophomonas, Burkholderia e Acinetobacter, che sono diversi dalle Enterobacteriaceae (E.coli, K.pneumoniae, Enterobacter, spp. ecc) che fermentano invece il glucosio. 10

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Ertapenem Ertapenem (formerly MK-0826 and L-749, 345) is a carbapenem that shares the broad spectrum of imipenem and meropenem against Enterobacteriaceae, Gram-positive organisms, and anaerobes, but is less active against non- fermenters Carbon 1 carries a -methyl group, protecting against hydrolysis by renal dehydropeptidase I. Ertapenem has a trans hydroxyethyl on the 6-position and this configuration is critical to -lactamase stability in carbapenems. 12

Ertapenem Like meropenem, ertapenem binds most strongly to penicillin binding protein (PBP-2) of E. coli, as compared to PBP-3, and has good affinity also for PBP-1a and 1b In contrast, imipenem binds primarily to PBP-2, then 1a and 1b, and has only weak affinity for PBP-3 . Inactivation of PBP-1a and b achieves rapid bactericidal action without the prior filamentation that occurs with agents such as third-generation cephalosporins, which binds primarily to PBP-3 13

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P. aeruginosa, S. maltophilia and E. faecium Panipenem Panipenem (RS-533), introduced into clinical practice in Japan in 1993, was the second approved carbapenem. It is susceptible to hydrolysis by DHP- I and thus requires the co-administration of an inhibitor of this enzyme, betamipron. This drug, is approved in Japan, China and South Korea. Broad spectrum of activity similar to imipenem but poor activity against P. aeruginosa, S. maltophilia and E. faecium 15

Panipenem

Doripenem Doripenem (S-4661), è un carbapenemico ad ampio spettro caratterizzato da notevole stabilità alle -lattamasi e resistenza all’inattivazione della diidropeptidasi renale. La sua attività è simile a quella di imipenem o ertapenem nei confronti dei cocchi gram- positivi e come meropenem sui ceppi gram- negativi ma 2- 4 volte superiore a imipenem su questi ultimi batteri 17

Doripenem 1. high affinity for PBP targets that are species-specific (PBP3 in P. aeruginosa, PBPs 1, 2 and 4 in S. aureus, PBP2 in E. coli 2. bactericidal action 3. a post antibiotic effect of 1.8 h (in vitro) to 4.3 h (in vivo) for P. aeruginosa 4. influx in Gram-negative species by OprD channels with efflux sensitivity via the MexAB-OprM system 5. pharmacokinetic parameters resembling meropenem 6. low risk of convulsive side effects 7. stability to wide variety of -lactamases 8. high level stability to human recombinant dehydropeptidase-I 9. clinical success from human trials in Japan 18

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Biapenem Biapenem (“RPX- 2003”) is a broad-spectrum carbapenem with in vitro activity against Gram-negative and Gram- positive bacteria similar to that of meropenem. Like other carbapenems, biapenem is not affected by the presence of ESBLs but is labile to hydrolysis by both serine and metallo- carbapenemases.

Tomopenem Tomopenem (CS-023, RO 4908463, formerly R- 115685) is a new parenteral carbapenem that binds with high affinity PBP1, PBP2 and PBP4 from S. aureus and PBP1a, PBP1b, PBP2 and PBP3 from E. coli. Tomopenem is more stable to hydrolysis by human renal dehydropepti-dase-I than meropenem or imipenem and is bactericidal against P. aeruginosa and MRSA and also has broad spectrum of activity against Gram-positive and Gram- negative bacteria, including penicillin-resistant S. pneumoniae, H. influenzae, and members of Enterobacteriaceae Tomopenem (CS-023, RO 4908463, formerly R-115685) is a new parenteral 2- substituted 1 -methyl carbapenem that has unique guanidine–pyrrolidine side chain and binds with high affinity to PBP1, PBP2 and PBP4 from S. aureus ATCC 6538P and PBP1a, PBP1b, PBP2 and PBP3 from E. coli NIHJ. CS-023 is more stable to hydrolysis by human renal dehydropepti-dase-I than meropenem or imipenem and is bactericidal against P. aeruginosa and MRSA and also has broad spectrum of activity against Gram-positive and Gram- negative bacteria, including penicillin-resistant Streptococcus pneumoniae, H. inluenzae, members of Enterobacteriaceae 21

Tomopenem It is 4- to 8-fold more potent against the isolates of meropenem resistant P. aeruginosa. The broad spectrum suggest the use for a wide range of infections. Tomopenem is distributed to the extracellular fluid where many infecting microorganisms reside. low protein binding ratio I t is 4- to 8-fold more potent against the isolates of meropenem resistant P. aeruginosa. The broad spectrum of in vitro activity of tomopenem suggest potential for therapy of a wide range of infections. However, further studies are warranted to determine its detailed clinical efficacy. Tomopenme is predominantly distributed to the extracellular fluid in body after intravenous administration. This limited distribution would be favorable property of an antimicrobial agent, since most infecting microorganisms resides in extra cellular space. A low protein binding ratio would also be favorable property for tomopenem, since the protein unbound, free form of CS-023 in plasma is a pharmacologically active fraction, which achieve rapid equilibrium with drug in extracellular fluid. 22

Razupenem Razupenem (SMP-601; PZ-601) is a novel broad-spectrum carbapenem. High affinity for PBPs enhances its activity against multidrug-resistant Gram-positive organisms including MRSA, and it retained the typical carbapenem-like spectrum against Gram-negative bacteria including Pseudomonas spp. Razupenem (SMP-601 (PZ-601) is a novel broad-spectrum carbapenem. High affinity for PBPs enhances its activity against multidrug-resistant Gram-positive organisms including MRSA, and it retained the typical carbapenem-like spectrum against Gram-negative bacteria including Pseudomonas spp. Razupenem included (1) wild type ESBL producers (K. pneumoniae and E. coli isolates which were known by PCR/sequencing to harbor genes coding for ESBL but which do not posses currently known mechanisms of carbapenem resistance. hey posses various combinations of CTX-M, SHV and TEM type ESBLs), (2) carbapenem-resistant ESBL producers (K. pneumoniae and E. coli isolates that were ESBL pro-ducers as well as carbapenem resistant) and, (3) ESBL producing E. cloacae. he MIC50 and MIC90 for PZ-601 were found to be 1 mg/L and 4 mg/L, respectively, while carbapenem resistant-ESBL producers showed elevated MICs (ranging from 4 mg/L to > 32 mg/L). 24

Razupenem wild type ESBL producers (K. pneumoniae and E. coli isolates harboring genes coding for ESBL including strains coding various combinations of CTX-M, SHV and TEM type ESBLs) carbapenem-resistant ESBL producers (K. pneumoniae and E. coli isolates that were ESBL producers as well as carbapenem resistant) ESBL producing E. cloacae Razupenem (SMP-601 (PZ-601) is a novel broad-spectrum carbapenem. High affinity for PBPs enhances its activity against multidrug-resistant Gram-positive organisms including MRSA, and it retained the typical carbapenem-like spectrum against Gram-negative bacteria including Pseudomonas spp. Razupenem included (1) wild type ESBL producers (K. pneumoniae and E. coli isolates which were known by PCR/sequencing to harbor genes coding for ESBL but which do not posses currently known mechanisms of carbapenem resistance. hey posses various combinations of CTX-M, SHV and TEM type ESBLs), (2) carbapenem-resistant ESBL producers (K. pneumoniae and E. coli isolates that were ESBL pro-ducers as well as carbapenem resistant) and, (3) ESBL producing E. cloacae. he MIC50 and MIC90 for PZ-601 were found to be 1 mg/L and 4 mg/L, respectively, while carbapenem resistant-ESBL producers showed elevated MICs (ranging from 4 mg/L to > 32 mg/L). 25

ME1036 ME1036 is a novel investigational parenteral carbapenem with potent in vitro activity against many Gram-positive and Gram-negative pathogens, and improved activity over existing carbapenems against Haemophilus influenzae, Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus pneumoniae. ME1036 is active against isolates of many species, including extended spectrum b-lactamase (ESBL)-producing Enterobacteriaceae, b-lactamase-producing H. influenzae, methicillin- resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae.

Tebipenem Tebipenem/pivoxil Tebipenem-pivoxil (TBM-PI) is a new oral carbapenem agent whose active metabolite, tebipenem (TBM), shows broad-spectrum activity against Gram-positive and – negative bacteria, except for Pseudomonas aeruginosa Unlike other available oral b-lactam antibiotics, TBM displays excellent activity against penicillin-resistant Streptococcus pneumoniae TBM-PI is indicated for treatment of community-acquired pediatric infections such as pneumonia, acute otitis media (AOM), and sinusitis. Faropenem medoxil (formerly faropenem daloxate) is an oral prodrug that is rapidly cleaved, releasing the microbiologically active faropenem following absorption in plasma. Faropenem is active against the primary respiratory pathogens, including non–penicillin susceptible S. pneumoniae and M. catarrhalis (Critchley et al. 2002). Faropenem is most active -lactam agains S. pneumoniae with MIC90 of 0. 5 mg/L and is four fold active than amoxicillin clavulanate (MIC90 , 2 mg/L) eight-fold more active than cefdinir and cefuroxime (MIC90 , 4 mg/L). Activity of faropenem was affected by penicillin susceptibility status of isolates, with faro penem MIC90 increasing from 0. 015 mg/L for penicillin susceptible isolates to 1 mg/L for penicillin resistan strains (Stone et al. 2007). Although faropenem exhib- ited higher MIC against penicillin resistant S. pneumo- niae it had activity equivalent to that of telithromycin and levoloxacin (MIC90, 1mg/L) and was more active than all other -lactam tested, including amoxicillin- clavulanate, cefdinir and cefuroxime, with MIC90 of 2, 4 and 8 mg/L. 29

Trinems Trinems (previously tribactams) have a Carbapenem related structure but with a Cyclohexane ring attached across carbon 1 and 2. Sanfetrinem (GV104326), which is a trinem b-lactam, can be administered orally as a hexatil ester. Like imipenem, sanfetrinem was found to be stable to TEM-1 and TEM-10 enzyme, and like imipenem and cefixime but unlike cefpodoxime also retained activity against P. vulgaris and K. oxytoca that hyperproduced potent chromosomal class A b- lactamase Sme1, NMC-A and an unnamed enzyme from Acinetobacter spp. increased the Sanfetrinem MICs by up to 64- fold.

Faropenem medoxil (formerly faropenem daloxate) is an oral prodrug. Faropenem is active against the major respiratory pathogens, including penicillin-resistent S. pneumoniae and M. catarrhalis. Faropenem is four fold more active than amoxicillin clavulanate) eight-fold more active than cefdinir and cefuroxime. Against penicillin resistant S. pneumoniae its activity is equivalent to that of telithromycin and levofloxacin and is more active than all other -lactam tested, including amoxicillin- clavulanate, cefdinir and cefuroxime Faropenem medoxil (formerly faropenem daloxate) is an oral prodrug that is rapidly cleaved, releasing the microbiologically active faropenem following absorption in plasma. Faropenem is active against the primary respiratory pathogens, including non–penicillin susceptible S. pneumoniae and M. catarrhalis (Critchley et al. 2002). Faropenem is most active -lactam agains S. pneumoniae with MIC90 of 0. 5 mg/L and is four fold active than amoxicillin clavulanate (MIC90 , 2 mg/L) eight-fold more active than cefdinir and cefuroxime (MIC90 , 4 mg/L). Activity of faropenem was affected by penicillin susceptibility status of isolates, with faro penem MIC90 increasing from 0. 015 mg/L for penicillin susceptible isolates to 1 mg/L for penicillin resistan strains (Stone et al. 2007). Although faropenem exhib- ited higher MIC against penicillin resistant S. pneumo- niae it had activity equivalent to that of telithromycin and levoloxacin (MIC90, 1mg/L) and was more active than all other -lactam tested, including amoxicillin- clavulanate, cefdinir and cefuroxime, with MIC90 of 2, 4 and 8 mg/L. 33

La differenza con i carbapenemici è dovuta all’atomo di S 34

Monobattamici L’aztreonam è il solo agente attualmente in uso di questa classe di antibiotici. Il composto è attivo nei confronti di microorganismi aerobi gram-negativi, ed è estremamente resistente a molte delle lattamasi prodotte da queste specie. Non riesce a superare l’involucro dei gram- positivi e quindi non è utilizzato nella terapia di infezioni sostenute da questi microorganismi. 35

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Molecole in evoluzione BAL30072 è un sideroforo legato ad un monobattamico che risulta stabile all’idrolisi delle metallo-beta-lactamasi e si comporta come un cavallo di Troia. E’ assunto dai gram-negativi attraverso il trasporto del ferro. Dimostra attività antibatterica nei confronti di non- fermentanti multiresistenti incluso Acinetobacter, Burkholderia, P. aeruginosa e Stenotrophomonas maltophilia. tam) thathasactivityagainstmultiresistantGram-negativebacilli [27]. Ithasexcellentactivityagainstmultidrug-resistant(MDR) strains of P. aeruginosa and Acinetobacter spp. andisactiveagainst many speciesofMDRisolatesofEnterobacteriaceae,includingiso- lates containingaclassAcarbapenemaseorametallo- -lactamase (MBL). Thiscompoundutilisesa‘Trojanhorse’strategythathas been triedunsuccessfullyinthepast.Itisknownthatbacteria require ironforgrowthand,underiron- limitedconditions(suchas infections inmammalsduringwhichironisboundbyacute-phase reactants suchasferritin,transferrinandotheriron-bindingpro- teins), bacteriausesiderophorestoscavengeforiron.Amongstthe siderophores utilisedbyGram- negativebacteriaarecarbamates and catechols.Inthe1980s,Glaxoproducedanumberofcatechol- cephalosporins inwhichthecatecholmoietywasattachedtothe 3-position ofthemolecule [28]. Thesecatechol-cephalosporins had outstandingactivityagainstresistantGram- negativebacte- ria, including P. aeruginosa, butunfortunatelythesidechainat the 3- positionofthecephalosporinmoleculeischemicallya‘leav- ing group’thatisreleasedwhenthe -lactam ringishydrolysed. Since thereleasedcatecholshadpotentialpressoreffects,thedrugs could notbedevelopedforclinicaluse,althoughGlaxodidsyn- thesise compoundsinwhichthecatecholswereattachedtothe side chainatthe7- position(whichwasnotaleavinggroup)before abandoning theproject [29]. BasileaPharmaceuticahasrenewed interest inthisapproach.BAL30072utilisesadihydropyridone iron-chelating groupattachedtothe3- positionofamonobactam. As noted,thisgivesitenhancedactivityagainstmultiresistantnon- fermenters including Acinetobacter, Burkholderia, P. aeruginosa and Stenotrophomonas maltophilia [27].

BAL30072