b-lattamasi Penicillinasi-cefalosporinasi-carbapenemasi
b-lactamase Clinically isolated distinct b-lactamase now number > 1400. The simplest classification is by protein sequence, four classes, A, B, C, and D, Classes A, C, and D include enzymes that hydrolyze their substrates by forming an acyl enzyme through an active site serine, whereas class B b-lactamases are metalloenzymes that utilize at least one active-site zinc ion to facilitate b-lactam hydrolysis.
Inibitori delle β-lattamasi Alcuni β-lattamici, derivati dalla ricerca di nuovi antimicrobici, sono stati inizialmente scartati a causa della loro modesta potenza antibatterica nei confronti dei vari patogeni. Un numero ristretto di queste molecole è stato in seguito identificato come capace di legarsi in modo covalente alle β- lattamasi. Attraverso tale meccanismo l enzima viene catturato e reso indisponibile per inattivare l altro eventuale farmaco presente.
Inibitori delle β-lattamasi Gli inibitori suicidi oggi in uso sono: acido clavulanico, trovato in colture di Streptomyces clavurigerus, tazobactam che è un sulfone dell acido penicillanico e sulbactam che è un 6- desaminopenicillino sulfone. Questi composti sono abbinati a penicilline o cefalosporine garantendo loro immunità dalle più diffuse β-lattamasi.
Inibitori delle β-lattamasi Ac. clavulanico, inibisce le più diffuse β- lattamasi incluse le ESBL che derivano da Tem-1. Sulbactam, è un inibitore a spettro più ampio del clavulanato, ma meno potente, non è induttore Tazobactam, simile a sulbactam ma potente come il clavulanato, non è induttore.
Currently available b-lactamase inhibitors are effectively limited to many class A b-lactamases, excluding the KPC carbapenemases.
Ceftolozane--tazobactam CXA-101 (oxyimino-aminothiazolyl cephalosporin) + tazobactam (beta-lactamase inhibitor) (2:1 ratio) Microbiology Coverage P. aeruginosa (MIC90 = 1-8 μg/ml) CXA-101 is not a substrate of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY efflux pumps nor the carbapenem-specific porin OprD in P. aeruginosa Spectrum Gaps Bacteria producing metallo-lactamases and certain ESBLs (OXA-15 and OXA- 11, -14 and 16) confer losses of CXA-201 activity (MIC >32 μg/ml); derepression of ampc in P. aeruginosa can increase MIC up to 8-fold; MIC90 vs. MDR P. aeruginosa of >64 μg/ml Ceftazidime-R E. coli, K. pneumoniae ceftazidime-r or KPC producers, Enterobacter, Citrobacter, ESBL+ Proteus spp. (MIC90= 16/>16/>16/>16/>16 μg/ml) No activity against MRSA and other key gram-positives IV only The addition of tazobactam at 8 μg/ml resulted in restoring the susceptibility of 93% of the ESBL producers and 95% of the AmpC overproducers. Tazobactam was unable to lower MICs, however, for Enterobacteriaceae producing KPC carbapenemases
Molecole in evoluzione Tra gli inibitori suicidi che non includono i beta-lattamici vi sono acido boronico, fosfonati (poco stabili e sensibili alle fosfodiesterasi) e diazabiciclo octanoni Avibactam inibisce B, C e D betalactamasi, ma non le metallo betalattamasi. E in fase di sperimentazione clinica
Avibactam DBO diazabiciclo octanoni Avibactam has an extremely broad spectrum of activity against classes A and C serine b-lactamases, including ESBLs and class A carbapenemases This molecule inhibits selected class D b-lactamases including OXA-48, but apparently not other class D carbapenemases, as judged by the absence of synergy with imipenem against resistant strains of A. baumannii producing OXA-51 and OXA-58 and does not inhibit class B MBLs.
Ceftazidime-avibactam Microbiology Covers ESBL-producing Enterobacteriaceae and P. aeruginosa isolates producing class A and C β-lactamases, including KPC producers as well as AmpCoverexpressing strains Spectrum Gaps Not active against bacteria producing metallo-lactamases, OXA or VEB ESBLs, OXA carbapenemases in A. baumannii, NDM-1 producers, and efflux-mediated ceftazidime resistance in P. aeruginosa IV only
Ceftaroline - avibactam Gram-positives: MRSA, VRSA, MRSE, VRE ( E. faecalis, ampsensitive), S. pneumoniae, S. pyogenes Gram-negatives: H. influenzae, M. catarrhalis, ESBL-producing Enterobacteriaceae, wild type Acinetobacter, KPC-producers Atypicals: No coverage Anaerobes: No, requires combination with metronidazole Spectrum Gaps: Acinetobacter producing OXA β-lactamases, Enterobacteriaceae producing metallo-β-lactamases, P. aeruginosa producing AmpC or with reduced outer membrane permeability, amp-resistant E. faecalis Mutant Selection: Frequencies for stable mutants from 25 enterobacteria with ESBL, AmpC or KPC β-lactamases were mostly < 10-9 IV only
Aztreonam-Avibactam Monobactams are hydrolyzed by ESBLs but are inherently stable to hydrolysis by MBLs, an avibactamaztreonam combination resulted inhibitory to MBLproducing pathogens.
MK 7655 MK-7655, a new member of the DBO series. A combination of imipenem and MK-7655 has excellent activity against a KPC- 2-producing isolate of K. pneumoniae and displays moderate improvements in the imipenem efficacy against most AmpC-overexpressing isolates of P. aeruginosa.
Imipenem-MK7655 Spectrum with Imipenem Gram-positives: streptococci, MSSA, MSSE, non-vre Gram-negatives: At 4-8 μg/ml MK-7655, imipenem MICs of all strains were below the resistant breakpoint of IPM for Pseudomonas and Klebsiella containing KPCs Atypicals: No coverage Anaerobes: Coverage of B. fragilis and others Spectrum Gaps: VRE, MRSA, Stenotrophomonas spp., Burkholderia spp. strains containing class D metalloproteases; high levels of AmpC or KPC; certain class A β- lactamases Mutant Selection: 10-8 - 10-9 for 2 isolates of P. aeruginosa; 2 x10-7 to <3 x 10-8 for KPC+ K. pneumoniae for imipenem + MK-7655 IV only Preclinical Findings Restored activity of imipenem to kill rapidly Low protein binding (20%)
RPX7009 RPX7009, a boronic acid-containing - lactamase inactivator with inhibitory activity against class A and class C serine -lactamases, particularly highlighting both in vitro and in vivo activity against KPC-producing K. pneumoniae. Boronic acid inhibitors of PBPs and of classes A, C, and D - lactamases had previously been identified, but none has achieved success as a clinical candidate. Preclinical testing of RPX7009 indicated that the inhibitor had no off-target effects, and it was well tolerated at high doses, with no safety signals that would preclude future development
Biapenem-RPX7009 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. Although carbapenem resistance is increasing, 75% of recent Japanese pseudomonal isolates were susceptible to biapenem and meropenem. Pharmacologically, biapenem is notable for its low proconvulsive activity compared to that of imipenem
Carbapenem + carbapenem A combination of ertapenem and doripenem in both an in vitro chemostat and an in vivo murine thigh infection model. Overall, the combination of doripenem plus ertapenem demonstrated enhanced efficacy over either agent alone (2011) Double-Carbapenem Therapy Not Proven To Be More Active than Carbapenem Monotherapy against KPC-Positive Klebsiella pneumoniae (2012) Ertapenem plus doripenem or meropenem were given in three patients suffering from pandrug-resistant, KPC-2-positive Klebsiella pneumoniae bacteremia (2 patients) and urinary tract infection (1 patient), respectively. All responded successfully, without relapse at follow-up. The results obtained should probably be attributed to ertapenem s increased affinity for the carbapenemases hindering doripenem/meropenem degradation in the environment of the microorganism (2013)
Enzimi autolitici La lisi cellulare ottenuta con le penicilline non è dovuta alla semplice inibizione della sintesi del peptidoglicano ma all induzione di enzimi: un amilasi che scinde i legami tra i tetrapeptidi e, una glucosilasi che scinde il glucano. Quando questi enzimi sono inattivati o per mutazione o per crescita dei batteri a basso ph, la penicillina ha effetti batteriostatici.