antibiotici beta lattamici

ANTIBIOTICI BETA LATTAMICI
Schematic of the monoderm Gram-positive cell envelope. LTA: lipoteichoic acid
polymers; WTA: wall teichoic acid polymers; M: N-acetyl-muramic acid; G: N-acetyl
glucosamine. Refer to text for further details.
Schematic structure of PG and target sites of different enzymes (pointed by color arrows). The synthetic enzyme (PBP) is
highlighted in red while the lytic enzymes (NagZ, AmpD, and LT) are highlighted in blue. Notably, NagZ and AmpD catalyze the
liberated muropeptides instead of intact PG. Hexagons denote sugars while rectangles denote stem amino acids. The cross-linkage
between the top and bottom glycan strands is D-Ala → meso-A2pm. LT, lytic transglycosylase; PBP, penicillin-binding protein, mA2pm, meso-diaminopimelic acid; AnhMurNAc, 1,6-anhydro-MurNAc; β1 → 4, β-(1,4)-glycosidic bond.
Colorazione di Gram
Distingue gram positivi da gram negativi
Nata per distinguere la polmonite da streptococco
(gram +) e quella da klebsiella (bacillo gram -)
Hans Christian Gram used light microscopy to detect
microbes that were stained with crystal violet/iodine.
Microbes that cannot retain this dye following treatment with
ethanol were counterstained with safranin (or fuchsin),
thereby distinguishing Gram-positive from Gram-negative
bacteria.
The differential staining property is based on the
peptidoglycan layer, which is considerably thicker in Grampositive microbes.
Another difference is that Gram-positive bacteria elaborate a
single membrane, whereas Gram-negative microbes
harbour a plasma membrane and an additional outer
membrane with lipopolysaccharides.
Staphylococcus aureus causes a broad spectrum
of disease.
Humans are colonized by this organism mainly in
the nasopharynx and on the skin.
Staphylococcus aureus has the unique propensity
to infect and destroy normal healthy tissue,
causing skin and wound infections, bloodstream
infection (BSI), pneumonia, osteomyelitis,
endocarditis, lung abscess, and pyomyositis.
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
Amoxicillina, Ampicillina, Azlocillina,
Bacampacillina, Carbenicillina, Cloxacillina,
Dicloxacillina, Flucoxacillina, Piperacillina,
Ticarcillina
1a Cefalessina
2a Cefamandolo
3a Cefotaxima
4a cefepime
5a Ceftobiprolo
3) Monobactami
Aztreonam
4) Carbapenemi
Imipenem, Carbapenem, Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilità batterica
Monobactami
Aztreonam
Carbapenemi
Imipenem
Porzione in comune
Amidasi
6-aminopenicillanico
Penicillinasi
Acido penicilloico
Spettro di azione delle Penicilline:
Staphylococcus,
Streptococcus,
Enterococcus,
Actinobacteria
Nocardia
Polmoniti, Endocarditi, Meningiti
Faringite, Scarlattina, Polmonite
Endocardite, Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
Tazobactam
Sulbactam
Acido Clavulanico
Spettro di azione delle Penicilline:
Bacillus anthracis (G+),
Pseudomonas (G-),
Polmonite
Infezioni Tratto Urinario
Neisseria gonorrhoeae (G-),
Listeria (G+)
Treponema pallidum
Gonorrea
Meningite, Endocardite, Batteriemia
Sifilide
Farmacocinetica
Lo stafilococco aureus può causare intossicazione da
cibo, polmoniti, batteriemia, impetigo (acuta piogenica
che colpisce soprattutto in età pediatrica riguardante gli
strati superficiali della cute, la cui comparsa di solito si
limita al volto e agli arti), follicoliti e osteomieliti
nell’uomo, mastiti artriti e infezioni del tratto urinario
negli animali. Lo stafilococco è la principale causa di
infezioni nosocomiali del sistema nervoso centrale e
l’aureus è il più comune agente della batteriemia.
Acute bacterial meningitis caused by
Streptococcus pneumoniae resistant to the
antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da
parte delle penicilline è dovuta ad una minor
affinità di queste alla parete cellulare di questo
batterio in particolare alle penicillin binding
proteins. C’è una progressiva riduzione della
sensibilità alla penicillina ed altri beta lattamici
che causa il bisogno di aumentare le dosi per
inibire la crescita batterica.
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (P.A.)è un batterio gram
negativo di cui è nota la sua la sua versatilità
ambientale, l’abilità di causare la malattia in particolari
individui suscettibili e di resistere agli antibiotici. La
complicazione più seria in cui è coinvolto è la fibrosi
cistica e porta ad infezione respiratoria diffusa.
Lo P. A. può produrre un numero considerevole di
proteine tossiche le quali non solo causano un esteso
danno tissutale ma anche interferiscono con il sistema
immunitario. Queste proteine possono uccidere le
cellule entrandovici o portare danni al tessuto
connettivo.
Penicilline antipseudomonas
MIC (microgrammi/ml)
Antibiotico
Carbenicillina
Piperacillina
Ticarcillina
Mezlocillina
Pseudomonas
E.Coli
32
8
4
2
32
8
32
2
Sintomi della Gonorrea
La gonorrea è causata dal batterio Neisseria gonorrhoeae.Il
periodo di incubazione è di 10/20 giorni con comparsa dei
sintomi tra il 15 e il 20 giorno dopo l’infezione. Un piccolo
numero di persone sono asintomatici per tutta la vita. Tra il 30
e il 60% delle persone con gonorrea hanno la malattia in uno
stato subclinico. Nelle donne questa malattia si può
manifestare con perdite uterine, difficoltà di urinare,
alterazione del ciclo mestruale o sanguinamento dopo
rapporto sessuale. La cervice pu; apparire in varie forme; da
normale ad stremamente infiammata con pus. Infezioni
dell’uretra e della cervice sono frequenti. L’infezione si
trasmette per via vaginale, orale e anale. Gli uomini hanno
solo un 20% di probabilità di infettarsi per via sessuale mentre
le donne per il 50%. Una madre affetta da gonorrea può
trasferirla al nascituro durante il parto producendogli oftalmia
neonatale.
Antibiotici che possono essere usati in caso di
gonorrea
Penicilline
Amoxicillina 2 g più probenecid 1 g orale
Ampicillina 2 to 3 g più probenecid 1 g orale
Macrolidi
Azitromicina 2 g orale
Cefixime 400 mg orale
Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare , plus probenecid 1 g orale
Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Cefalosporine
Chinolonici
Aminociclitolo
Ciprofloxacina 500 mg orale
Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Indicazioni Terapeutiche
per le Penicilline:
Endocarditi batteriche
Gonorrea
Meningite
Polmoniti
Ascessi polmonari
Sifilide
Setticemia
Antibiotic-induced liver toxicity: mechanisms, clinical features and causality
assessment.
Robles M, Toscano E, Cotta J, Lucena MI, Andrade RJ.
Source
Liver Unit, Gastroenterology Service and Department of Medicine, Vírgen de
Victoria University Hospital, University of Málaga, Spain.
Abstract
Antibiotics are the therapeutic agents most often associated with hepatotoxicity.
However, this is mainly due to the widespread prescription of these drugs. The
relative risk of antibiotic-related hepatotoxicity is low. Causality assessment of
suspected drug-induced liver injury (DILI) related to antibiotics can be difficult,
particularly because some cases occur long after the drug has been stopped.
Among the penicillins, amoxicillin clavulanate is the most associated with
hepatotoxicity and is the most frequent cause of DILI-related
hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many
countries. The severity of antibiotic-induced DILI varies widely, with the hepatitislike (hepatocellular) damage tending to be more severe that than cholestatic/mixed
type. The pattern is strongly influenced by age. Recently telithromycin (a new
generation macrolide) has been linked with DILI, with a typical pattern, which
includes abrupt commencement of fever, abdominal pain, jaundice and, in some
cases, ascites. Antibiotic-induced DILI appears, in most instances, to be
idiosyncratic. Genetic-association studies have recently identified genotypes
related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.
Carbapenemi
Imipenem
Porzione in comune
Carbapenemi
A questa classe appartengono: l’imipenem, il meropenem,
l’ertapenem, e il doripenem.
Questi agenti hanno il più vasto spettro antibatterico rispetto agli altri
beta lattamici. Sono resistenti alle beta lattamasi.
Sono attivi contro i gram positivi e negativi con l’eccezione di quelli
intracellulari come le clamidie.
Essi provvedono ad una maggiore copertura nei confronti
dei batteri gram negativi rispetto agli altri beta lattamici e
sono stabili nei confronti delle beta lattamasi e nei
confronti di batteri multiresistenti.
Carbapenems versus other beta-lactams in treating severe infections in
intensive care: a systematic review of randomised controlled trials.
Edwards SJ, Clarke MJ, Wordsworth S, Emmas CE.
Carbapenems have not been comprehensively compared in clinical trials with
fourth-generation cephalosporins (4GC) and antipseudomonal penicillins
(APP) in the treatment of severe infections (SI) and febrile neutropenia (FN).
Of the 265 papers identified, 12 were appropriate for meta-analysis (four 4GC
and eight APP). The results showed that carbapenems are associated with
a significant reduction in all-cause mortality compared to APP in the
treatment of SI, and withdrawals due to adverse events (RR 0.65, 95% CI: 0.45
to 0.96; p=0.03) are also less common. When compared in the treatment of FN,
carbapenems are associated with a significant increase in clinical response
during the initial 72 h of treatment (RR 1.37, 95% CI: 1.09 to 1.74; p=0.008) and
bacteriologic response (RR 1.73, 95% CI: 1.03 to 2.89; p=0.04). For all other
outcomes, including all comparisons with 4GC, there were no significant
differences between treatments. The use of carbapenems rather than APP
could reduce mortality and, by simplifying treatment decisions, reduce
the time before patients receive appropriate antibiotic treatment.
Un esempio:
Nella esacerbazione acuta della bronchite cronica
First-Line : Amoxicillin, ampicillin,
pivampicillin, TMP/SMX, and doxycycline were considered to
be first-line antibiotics for the management of patients with
AECB (acute exacerbations of chronic bronchitis).
and Second-Line Antibiotics:
Amoxicillin/clavulanic acid, macrolides (ie,
roxithromycin, clarithromycin, and azithromycin), secondgeneration or third-generation cephalosporins (ie, cefaclor),
and quinolones were considered to be advanced or secondline antibiotics for this indication according to published
guidelines.
Monobactami
Aztreonam possiede una forte attività nei confronti dei batteri
gram-negativi compreso lo Pseudomonas aeruginosa.
Non è attivo nei confronti dei gram positivi o gli anaerobi.
E’ efficace nei confronti di un gran numero di batteri tra I
quali: IlCitrobacter, l’Enterobacter, l’E coli, l’Haemophilus, la
Klebsiella, il Proteus, e le specie di Serratia.
Attualmente si sta studianto la somministrazione di
aztreonam per via inalatoria come lisinato nel trattamento
della fibrosi cistica polmonare.
Klebsiella
Polmoniti
Infezioni del tratto urinario
Setticemia
Spondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S. marcescens)
Proteus
E’ un batterio a forma di bastoncino ed ha alte capacità di
produrre ureasi che rappresenta il modo di riconoscerlo.
L’ureasi idrolizza l’urea in ammoniaca e perciò alcalinizza
maggiormente le urine.
L’alcalinizzazione può portare a formazione di cristalli che
possono precipitare nei tubuli.
Questo batterio può essere trovato nei calcoli renali e questi
possono ricominciare l’infezione se non eliminati. Questi calcoli
possono portare anche a morte renale.
Il proteus può anche causare infezioni nelle ferite, setticemia e
polmoniti sopratutto nei pazienti ospedalizzati.
Cephalosporin use in treatment of patients with penicillin allergies.
DePestel DD, Benninger MS, Danziger L, LaPlante KL, May C, Luskin A,
Pichichero M, Hadley JA.
Department of Clinical Sciences, College of Pharmacy, University of Michigan
Hospitals and Health Centers, University of Michigan, Ann Arbor 48109, USA.
OBJECTIVE: To review the evidence that supports the use of certain
cephalosporins in penicillin-allergic patients. DATA SYNTHESIS: Physicians
may now prescribe certain cephalosporins in patients with a history of a
nonserious, non-life-threatening penicillin reaction. Exclusions include
type I anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis,
angioedema, and other potentially life-threatening responses to medication.
Recent reports demonstrate that a considerable body of literature
describing the cross-reactivity between cephalosporins and penicillin
was established based on nonallergic adverse reactions or in vitro
studies rather than on clinically relevant immune-mediated reactions.
Oral rechallenge and skin testing data support the relationship of the betalactam side-chain structures of these drugs as a predictor of cross-reactivity.
CONCLUSION: Recent data suggest that the incidence of cross-reactivity
among penicillins and cephalosporins is lower than historically reported.
Pharmacists should be aware that cephalosporin cross-reactivity in a
penicillin-allergic patient is not necessarily a class effect. Dispensing
should be evaluated based on the type of allergic manifestations and the drug
prescribed.
Tossicità da beta lattamici
Tossicità da beta lattamici
Acc Chem Res. 2008 Jan;41(1):11-20.
Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway.
Lu H, Tonge PJ.
Source
Department of Chemistry and Institute for Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook,
New York 11794-3400, USA.
Abstract
The modern age of drug discovery, which had been slowly gathering momentum during the early part of the twentieth
century, exploded into life in the 1940s with the isolation ofpenicillin and streptomycin. The immense success of these
early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled
and even eradicated. However this initial optimism was misplaced, and pathogens such as multidrug-resistant
Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human
health. Drug resistance arises through the unrelenting pressure of natural selection, and there is thus a continuing need
to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms. In
this Account, we summarize current progress in developing inhibitors of FabI, the NADH-dependent enoyl reductase
from the type II bacterial fatty acid biosynthesis pathway (FAS-II), a validated but currently underexploited target for drug
discovery. The FabI inhibitors have been divided into two groups, based on whether they form a covalent adduct
with the NAD (+) cofactor. Inhibitors that form a covalent adduct include the diazaborines, as well as the frontline tuberculosis drug isoniazid. The NAD adducts formed with these compounds are formally bisubstrate
enzyme inhibitors, and we summarize progress in developing novel leads based on these pharmacophores.
Inhibitors that do not form covalent adducts form a much larger group, although generally these compounds
also require the cofactor to be bound to the enzyme. Using structure-based approaches, we have developed a
series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA, the FabI from M. tuberculosis, and that are active
against INH-resistant strains of M. tuberculosis. This rational approach to inhibitor development is based on the proposal
that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active
site. Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the
enzyme. The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors
of the FabI enzymes from other pathogens such as Escherichia coli, S. aureus, and Plasmodium falciparum. Meanwhile
chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of
several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo. Finally, screening of natural
product libraries may provide useful chemical entities for the development of novel agents with low toxicity. While the
discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a
broad spectrumtarget, there is substantial optimism that FabI inhibitors can be developed for disease-specific
applications. In addition, the availability of genome sequencing data, improved methods for target identification and
validation, and the development of novel approaches for determining the mode of action of current drugs will all play
critical roles in the road ahead and in exploiting other components of the FAS-II pathway.
Recent Pat Antiinfect Drug Discov. 2007 Jan;2(1):73-7.
Linezolid in children: recent patents and advances.
Velissariou IM.
Source
Research Fellow in Pediatric Infectious Diseases and Pulmonology, P and A Kyriakou Children's
Hospital, Athens, Greece. [email protected]
Abstract
Linezolid is the first approved member of a new generation of antibiotics, the
synthetic oxazolidinones, to become available, with a broad spectrum of in vitro
activity against Gram-positive organisms, including methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis
and vancomycin-resistant Enterococcus faecium. It has an excellent bioavailability
both intravenously and orally and a very good safety profile both in adults and in children. With
regards to its antimicrobial action, linezolid has a predominantly bacteriostatic action, rather
than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to
other antibiotics. Linezolid is currently showing great promise for the treatment of multi-resistant
Gram-positive infections, both in the community and in a hospital setting. Clinical indications so
far include skin and soft tissue infections, community-acquired or nosocomial pneumonia
due to MRSA, VRE bacteremia and community-acquired pneumonia due to penicillinresistant Streptococcus pneumoniae. We anticipate that this new generation of antimicrobial
agents will provide adequate cover in the future for infections that cause significant treatment
failures so far, such as VRE- associated endocarditis, bone and joint multi-drug resistant infections
and possibly central nervous system infections, both in adult and children populations. Some
patents on linezolid are also discussed in this review.
Pharmacotherapy. 2008 Apr;28(4):458-68.
Telavancin: an antimicrobial with a multifunctional mechanism of action for the treatment
of serious gram-positive infections.
Leonard SN, Rybak MJ.
Source
Anti-Infective Research Laboratory, Pharmacy Practice 4148, Eugene Applebaum College of
Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Abstract
Telavancin is a once-daily lipoglycopeptide antibiotic structurally derived from
vancomycin. It has broad-spectrum activity against gram-positive bacteria, including
strains with reduced susceptibility to vancomycin. Telavancin's multifunctional mechanism
of action, including inhibition of peptidoglycan synthesis and disruption of membrane potential,
account for this enhanced activity as well as rapid bactericidal properties. In vitro activity has
been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant
Streptococcus pneumoniae, as well as methicillin-resistant, glycopeptide-intermediate, and
vancomycin-resistant Staphylococcus aureus. The agent also displays activity against many
gram-positive anaerobic organisms. Predictable linear pharmacokinetics have been
demonstrated over a wide range of doses, with the most common adverse effects being taste
disturbance and nausea. Clinical experience with telavancin in phase II and III studies for
complicated skin and skin structure infections has shown it to have similar efficacy and
tolerability compared with vancomycin and antistaphylococcal penicillins, and recently telavancin
received an approvable letter from the United States Food and Drug Administration for this
indication. Telavancin appears to be a promising agent for the treatment of serious infections
caused by gram-positive pathogens, including drug-resistant pathogens. Further clinical
experience will clarify its role in therapy.