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 beta-

lactamasi, ma non le metallo beta-

lattamasi.

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 AmpC-overexpressing 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, amp-sensitive), 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 avibactam-

aztreonam combination resulted

inhibitory to MBL-producing 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.