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Principi di Terapia Antibiotica

Corso integrato di Terapia Medica


18 Marzo 2014
Considerazioni generali
1. Tipo di infezione
agenti eziologici pi frequenti
gravit
2. Particolarit del paziente
Precedenti terapie antibiotiche
Fattori di rischio x MDR (Pneumococco, MRSA, VRSA, P.
Aeruginosa, Enterococco, VRE)
Presenza di allergie
Condizioni particolari: insuff renale, diabete, disfagia
3. Particolarit locali
Pattern di resistenza
Disponibilit del farmaco, costi
Considerazioni generali
4. Antibiotico
Meccanismo dazione
Attivit
Spettro dazione
Effetti collaterali
Resistenze (comuni o rare)
Azione sinergica
Via di somministrazione
Modalit della tp antibiotica
A. Terapia profilattica
B. Terapia empirica
C. Terapia specifica
Terapia profilattica
In alcune classi particolari di pazienti
HIV+: profilassi con Bactrim per Pneumocistosi
Pz con bronchiectasie in fibrosi cistica
Dopo esposizione ad agente infettivo
Meningite da Neisseria
Prima di una procedura chirurgica
Profilassi per endocardite
Interventi chirurgici su tratto GE
Terapia empirica
Nelle infezioni gravi (ad es: polmonite, pielonefrite,
colecistite) dopo aver prelevato gli esami colturali ed in
attesa degli esiti:
entro 24 ore dalla diagnosi
in alcuni casi molto gravi e/o ad evoluzione fulminante
(meningite, infezioni necrotizzanti dei tessuti molli, sepsi
grave/shock settico, neutropenia febbrile, sepsi nel
soggetto splenectomizzato):
entro 1-3 ore dalla diagnosi (o dal sospetto diagnostico)
Nelle infezioni non gravi in cui non si ricerchi una
diagnosi eziologica
1. Likely causative organism
Decide if community or healthcare-acquired infection
Identify the most likely source of infection
Take appropriate specimens for microscopy, culture and
sensitivity testing. Imaging modalities may be necessary to
locate the source of infection.
Consider local epidemiological data
Empiric antimicrobial choice depends on local susceptibility
patterns. Knowing the resistance profiles in the
community,hospital or unit helps in choosing antimicrobials
appropriately.
PRINCIPLES OF EMPIRICAL
ANTIMICROBIAL THERAPY
1. Likely causative organism
Decide if community or healthcare-acquired infection
Identify the most likely source of infection
Take appropriate specimens for microscopy, culture and
sensitivity testing. Imaging modalities may be necessary to locate
the source of infection.
Consider local epidemiological data
Empiric antimicrobial choice depends on local susceptibility
patterns. Knowing the resistance profiles in the community,hospital
or unit helps in choosing antimicrobials appropriately.
Presence of renal or hepatic dysfunction
The risk-benefit of the antimicrobial must be determined on a case-
to-case basis. Maintenance doses are adjusted in line with the
severity of organ dysfunction.
Others
Pregnancy, drug allergy
PRINCIPLES OF EMPIRICAL
ANTIMICROBIAL THERAPY
3. Antimicrobial profile
Route of administration
The intravenous route should always be used in severe
sepsis as oral absorption is unpredictable even in drugs with
good oral bioavailability.
Dose and interval
Antibiotics can be categorised into three different classes
depending on the PK/PD indices associated with their
optimal killing activity.
PRINCIPLES OF EMPIRICAL
ANTIMICROBIAL THERAPY
PRINCIPLES OF EMPIRICAL
ANTIMICROBIAL THERAPY
1928
1892
SirAlexander FLEMING
(Lochfield 1881 1955 Londra)
Premio Nobel per la Medicina nel 1945
Dott. Vincenzo TIBERIO
(Sepino [CB] 1869 1915 Napoli)
Ufficiale Medico della Regia Marina Militare Italiana
Lacqua del pozzo di casa Graniero, in Arzano, era abitualmente potabile, ma, allorquando si provvedeva alla ripulitura
delle pareti con asportazione delle muffe verdeggianti, il bere quellacqua provocava negli utilizzatori enterocoliti. Al
riformarsi delle muffe sulle pareti della cisterna lacqua diveniva nuovamente potabile Per ricercare per quanto tempo il
liquido.avesse esercitato questo suo speciale potere iniettaile cavie sopravvissero tutte, eccetto quelle iniettate dopo
10 giorni, che fecero notare un ritardo nella morte, rispetto ai controlli..Come tale questo liquido ha unazione preventiva
e terapica. Ho studiato il potere microbicida dei liquidi, ottenuti nel modo innanzi detto, per i bacteri patogeni pi
importantiRisulta chiaro da queste osservazioni che nella sostanza cellulare delle muffe esaminate sono contenuti dei
principi solubili in acqua, forniti di azione bactericida bactericida..Per queste propriet le muffe sarebbero di forte
ostacolo alla vita ed alla propagazione dei bacteri patogeni.
In the pre-antibiotic era, pneumonia was a dreaded killer of the young and a welcomed friend of the very old. Prior to the specific
therapies and antibiotics of the twentieth century many patients were better off if their disease ran its natural course. Thus doing
nothing was often the best therapy. This photograph is common of many similar images of physicians, nurses and the family about
the bedside.
Waiting Out the Pneumonia Crisis,
1895
Scenario
In March 1942, a 33-
year-old woman lay
dying of streptococcal
sepsis in a New
Haven, Connecticut,
hospital.
NEJM 2009
Scenario
Despite the best efforts of contemporary medical
science, her doctors could not eradicate her
bloodstream infection.
Then they managed to obtain a small amount of
a newly discovered substance called penicillin,
which they cautiously injected into her.
NEJM 2009
Scenario
After repeated doses, her bloodstream was
cleared of streptococci, she made a full recovery,
and she went on to live to the age of 90.
NEJM 2009
Sviluppo ed efficacia della chemioterapia antimicrobica
Sviluppo ed efficacia della chemioterapia antimicrobica
(1935
(1935

1993)
1993)
Sixty-six years after her startling recovery, a
report described a 70-year-old man in San
Francisco with endocarditis caused by
vancomycin-resistant Enterococcus faecium
(VRE).
Scenario
NEJM 2009
Despite the administration, for many days, of the
best antibiotics available for combating VRE,
physicians were unable to sterilize the patients
blood.
Scenario
NEJM 2009
He died still bacteremic.
Scenario
NEJM 2009
Clatworthy. Nature Biochem Biol 2007; 3: 541 Clatworthy. Nature Biochem Biol 2007; 3: 541- -8 8
Meccanismi di resistenza
Produzione di enzimi che
modificano o distruggono
la molecola di antibiotico
Modificazione del sito di
legame dellantibiotico
Escrezione attiva della
molecola (efflux pump)
Riduzione della
permeabilit della
membrana
Acquisizione della resistenza
Selezione di batteri resistenti
Resistenza intrinseca
Meccanismi di resistenza specifici
Meccanismi di resistenza specifici
Fattori che facilitano la comparsa di
resistenza
Esposizione a livelli di antibiotico
subottimali
Esposizione ad antibiotici ad ampio spettro
Esposizione a microorganismi che
possiedono geni resistenti trasmissibili
Mancata osservazione di regole
igieniche/protocolli di isolamento
Uso indiscriminato nellindustria alimentare
e nellagricoltura
Stime CDC
Conseguenze
Infezioni di difficile readicazione
Incremento della mortalit per infezione
Comparsa di ceppi multi-resistenti (es:
MDR-TB)
Aumento dei costi
Costi per singola dose:
Penicillina $0.24
Linezolid $86.90
(incremento costo di 360 volte)
Resistance: not IF... WHEN
MRSA/VRSA example
1940-1946 first-generation penicillins become widely available for treatment
of staphylococcus and streptococcus infections:
strept throat
pneumonia
scarlet fever
skin infections
wound infections
By the 1950s, S. aureus acquired beta-lactamases (penicillinase) leading to
resistance to first-generation penicillins. Methicillin (not recognized by
penicillinases) deployed to counter lactamase-producing strains
By 1986, S. aureus with mutated PBP-2 prevalent: for treatment of
methicillin-resistant S. aureus (MRSA), vancomycin became the front-line
antibiotic
1996 vancomyin-intermediate S. aureus (VISA) emerged
2002 vancomycin-resistant S. aureus (VRSA) identified
late-1990s quinupristin/dalfopristin (Synercid) combination approved as a
new option
2000 linezolid (Zyvox) approved as a new therapeutic
2003 first cases of resistance to linezolid reported
MRSA
End of antibiotics
End of antibiotics
-
-
the ultimate consequence
the ultimate consequence
Terapia specifica
Basata sullesito di un esame colturale
Solitamente si dispone anche di un test di
sensibilit in vitro
Con esito dellantibiogramma, scegliere il
farmaco in base a:
profilo di tossicit / caratteristiche del pz
spettro ristretto
costi
Le classi di antibiotici
1. Interferenza con la sintesi della parete cellulare
Beta-Lattamici (penicilline, cefalosporine, carbapenemi,
monobattami)
Glicopeptidi
Polipeptidi
Alcuni agenti antimicobatterici
2. Interferenza con la sintesi proteica
Azione su 30S ribosomiale
Aminoglicosidi
Tetracicline
Azione su 50S ribosomiale
Cloramfenicolo
Macrolidi
Clindamicina
Streptogramine
Oxazolidinoni
3. Inibizione della sintesi degli acidi nucleici
Azione sulla replicazione del DNA
Chinoloni / fluorochinoloni
Metronidazolo
Azione sulla sintesi del RNA
Rifampicina
Rifabutina
4. Antimetaboliti
Sulfonamidi
Dapsone
Acido paraminosalicilico (PAS)
Trimetoprim
5. Altri
Daptomicina
Polimixine
FARMACODINAMICA
How antibiotics kill bacteria: from targets to networks. 2010 Nature Reviews
Microbiology 8, 423-435
Farmacocinetica di un
antibiotico
Descrive i processi fondamentali dellorganismo
sul farmaco:
Assorbimento
Distribuzione
Metabolismo
Eliminazione
Farmacodinamica di un
antibiotico
Descrive leffetto fisiologico di una molecola sul
microorganismo allinterno del corpo, nonche il
suo meccanismo di azione
Stretta relazione con la farmacocinetica
Concentrazione plasmatica di un antibiotico
dopo una singola somministrazione
LA PRIMA SOMMINISTRAZIONE DI QUALSIASI ANTIBIOTICO IN
QUALSIASI PAZIENTE E SEMPRE A DOSE PIENA!
Plasmatic concentration of an antibiotic after
a single iv dose
C
o
n
c
e
n
t
r
a
t
i
o
n
Concentrazione plasmatica di un antibiotico
dopo una singola somministrazione
MIC: minimum inhibitory concentration
AUC: area under the curve
Cmax: maximum concentration (tissue
specific)
Pharmacokinetic parameters
Pharmacokinetic parameters
C
O
N
C
E
T
R
A
T
I
O
N

(
m
g
/
d
L
)
TIME (hour)
MIC
Antibiotic Pharmacokinetics
C
O
N
C
E
T
R
A
T
I
O
N

(
m
g
/
d
L
)
TIME (hour)
AUC
Cmax
ANTIMICROBIAL KILLING IS DEPENDENT ON BOTH THE
CONCENTRATION OF DRUG IN RELATION TO THE MIC AND
THE TIME THAT THIS EXPOSURE IS MAINTAINED
When the effect of concentration predominates over that of time, the
antimicrobial is said to be CONCENTRATIONDEPENDENT and
bactericidal effects are associated with an optimal free drug maximum
concentration to MIC ratio
(f fCmax/MIC Cmax/MIC).
When the effect of time is greater, the antibiotic displays TIME
DEPENDENT antibiotic activity, and bacterial outcomes are associated
with free drug concentrations above the MIC for a defined portion of the
dosing interval, or time above the MIC
(fT>MIC fT>MIC)
Antibiotic Pharmacokinetics
AUC > MIC
Cmax/MIC
Time > MIC
Pharmacokinetic composite
parameters
Pharmacokinetic composite
parameters
C
O
N
C
E
T
R
A
T
I
O
N

(
m
g
/
d
L
)
TIME (hour)
MIC
Time>MIC
E.G.: blactams, vancomycin, some macrolides, tigecycline, clindamycin
Pharmacokinetic composite
parameters
C
O
N
C
E
T
R
A
T
I
O
N

(
m
g
/
d
L
)
TIME (hour)
MIC
Cmax/MIC
E.G.: aminoglycosides, daptomycin, metronidazole, colistin, (fluoroquinolones)
Fluoroquinolones
While fluoroquinolones are concentrationdependent antimicrobials,
the maximum dose that can be given is limited by doserelated
toxicity, thus a Cmax/MIC of 10 to 12 cannot be achieved for many
pathogens and time must be considered to maximize response
Therefore, in many pharmacodynamic studies, the bactericidal effect
has been correlated with the area under the curve (AUC) to MIC
Against Gramnegative bacteria an AUC/MIC 125 is required for
maximal effect
Grampositive bacteria, such as Streptococcus pneumoniae, require
an AUC/MIC 30
Pharmacokinetic composite
parameters
C
O
N
C
E
T
R
A
T
I
O
N

(
m
g
/
d
L
)
TIME (hour)
MIC
AUC>MIC
E.G.: fluoroquinolones
Pharmacokinetics
PENICILLINS PENICILLINS
CEPHALOSPORINS CEPHALOSPORINS
CARBAPENEMS CARBAPENEMS
GLYCOPEPTIDES GLYCOPEPTIDES
ERYTHROMYCIN ERYTHROMYCIN
TIME TIME- -dependent dependent killing + killing +
short or no PAE short or no PAE
PD PD PK PK
correlation correlation: T> MIC : T> MIC
TIME TIME- -dependent dependent killing + killing +
prolonged PAE prolonged PAE
PD PD PK PK
correlation correlation : T> MIC : T> MIC
Prolong Prolong exposure time: exposure time:
maintain maintain serum serum levels levels
> MIC (short > MIC (short intervals intervals
or or continuous continuous
infusion) infusion)
Prolong Prolong exposure time: exposure time:
serum serum levels levels might might be be
< MIC (short < MIC (short intervals) intervals)
AMINOGLYCOSIDES AMINOGLYCOSIDES
FLUOROQUINOLONES FLUOROQUINOLONES
CLARITHROMYCIN CLARITHROMYCIN
AZITHROMYCIN AZITHROMYCIN
CONCENTRATION CONCENTRATION- -
dependent dependent killing + killing +
prolonged PAE prolonged PAE
PD PD PK PK
correlation correlation : :
peak/MIC or AUC/MIC peak/MIC or AUC/MIC
Achieve high Achieve high serum serum and and
tissue tissue concentrations concentrations
(high (high
doses, long doses, long
intervals) intervals)
Antibiotic Pharmacodynamics Dosing reg Antibiotic Pharmacodynamics Dosing regimen imen
Pharmacodynamics and pharmacokinetics Pharmacodynamics and pharmacokinetics
Ccorrelation and clinical significance Ccorrelation and clinical significance
Antibiotic Pharmacokinetics
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
g
/
L
)
0 1 2 3 4 5 6
Time (hours)
t
max
t

Dosing interval Dosing interval


64
8
16
32
4
2
1
C
max
La dose di carico (prima somministrazione) La dose di carico (prima somministrazione)
sempre il 100% sempre il 100%
Parametri farmacocinetici
Key message:
Post-antibiotic effect
Persistence of effect (inhibition of growth
or killing) after drug removed (or level
below MIC)
PAE + pharmacokinetics affects dosing
strategy
Post-antibiotic effect (PAE)
Nutrient broth
*
*
Bacteria
* A
* A
Antibiotics
Post-antibiotic effect (PAE)
Centrifuge Decant
*
*
Resuspend
A A
* *
* *
Post-antibiotic effect (PAE)
Exposed
*
*
*
*
No growth
****
****
*
*
Unexposed Grows
PAE (hours) = T - C
T = is the time required for the count of cfu to increase 1 log10 (10-fold) above the count immediately
seen after drug treatment
C = is the time required for the count to increase 1 log10 in an untreated control culture
PAE measures the time to reach normal logarithmic growth
Post-antibiotic effect (PAE)
1
10
100
1000
10000
0 1 2 3 4 5 6
Time (hours)
Removal of
Antibiotic
Removal of
Antibiotic
V
i
a
b
l
e

C
o
u
n
t

(
c
f
u
/
m
l
)
Control
1.6 hours to increase 1 log
10
1 log
10
increase
3.1 hours to increase 1 log
10
Antibiotic
Induced death
PAE = 3.1 - 1.6 = 1.5 hours
Due to antibiotic effect only
PAE = 3.1 - 1.6 = 1.5 hours
Due to antibiotic effect only
Persistent effect
Bacterial killing
/persistent effect
Drugs Therapy Goal PK/PD
measurement
Concentration
dependent /
prolonged
persistent effect
Aminoglycosides;
daptomycin;
ketolides;
quinolones; metro
High peak serum
concentration
Cmax/MIC
(24-hr AUC/MIC
for quinolones)
Time dependent /
no persistent
effect
Beta-lactams and
monobactams
Long duration of
exposure
Time above MIC
Time dependent /
moderate to long
persistent effect
Clindamycin;
macrolides;
linezolid;
tetracyclines;
vancomycin;
dalfopristin-
quinpristin
Enhanced amount
of drug
24-hr AUC/MIC
Correlazioni PK/PD: beta-lattamici
Exp. Opin. Pharmacother. 2000;1: 1203-1217
Optimizing Antimicrobials in the ICU:
Continuous/Prolonged Infusions of Beta Lactams
Cefotaxime vs Klebsiella in mouse lung model
Farmacodinamica degli
aminoglicosidi in vivo
Moore et al, J Infect Dis 155: 93, 1987
Modelli di attivit battericida
Curve di time-killing per P. aeruginosa
W.A. Craig et al., 1991, modified
0 2 4 6 8
0
2
4
6
8
10
0 2 4 6 8
0
2
4
6
8
10
0 2 4 6 8
0
2
4
6
8
10
64xMIC
16xMIC
4xMIC
MIC
1/4xMIC
Control
Tobramicina Ciprofloxacina Ticarcillina
CONCENTRAZIONE-DIPENDENTE TEMPO-DIPENDENTE
Tempo(hr)
Once-daily vs. Conventional Three-times
Daily AminoglycosideRegimens
NicolauDP et al. AntimicrobAgents Chemother. 1995;39:650655
Vancomycin Outcome vs 24h-
AUC/MIC ratio
24h-AUC/MIC
ratio
Satisfactory Unsatisfactory
< 125 4 (50%) 4
> 125 71 (97%) 2
Hyatt et al, Clin Pharmacokinet 28: 143, 1995
Factors which can influence
therapeutic outcome
Bacterial Human
Inhibitory activity
absorption
Subinhibitory activity
distribution
Concentration-dependent
activity
metabolism
Time-dependent activity
excretion
Bactericidal/bacteriostatic
activity
protein-binding
Post-antibiotic effect
Resistance
Oral Absorption of Antibiotics
Oral Absorption of Antibiotics
Good Good: : sulfonamides
chloramphenicol
clindamycin
trimethoprim
isoniazid, pyrazinamide
quinolones
doxycycline
cycloserine
metronidazole
linezolid
Bad or variable Bad or variable: :
penicillins (some are, many arent)
cephalosporins (few are, most are not)
erythromycin (estolate conjugate)
(clarithromycin is better)
Ugly Ugly: : aminoglycosides:
gentamicin
tobramycin
amikacin
netilmicin
vancomycin
quinupristin/dalfopristin
meropenem
Therapeutic levels in the
Therapeutic levels in the
cerebrospinal fluid?
cerebrospinal fluid?
Good Good: : ciprofloxacin
sulfonamides, trimethoprim
chloramphenicol
some 3rd generation cephalosporins
(e.g. ceftriaxone, ceftizoxime)
meropenem
cycloserine, metronidazole
pyrazinamide, isoniazid
linezolid
OK OK: : (esp. when meninges inflamed)
ampicillin, ticarcillin
vancomycin
rifampin
Poor Poor: :
aminoglycosides aminoglycosides
tetracyclines tetracyclines
clindamycin clindamycin
erythromycin erythromycin
cefaclor cefaclor
quinupristin/dalfopristin quinupristin/dalfopristin
(synercid) (synercid)
INTERRELATIONSHIP OF HYDROPHILICITY AND
LIPOPHILICTY OF ANTIBIOTICS ON THEIR
PHARMACOKINETIC CHARACTERISTICS
Condizioni parafisiologiche
Sepsi
Condizioni parafisiologiche
Ustionati
Condizioni parafisiologiche
Obesi
General concept:
Protein binding
x x x
x x x
x x x
x x x
x x x
x x x
80%
80%
Extensive protein binding
Good: Allows slow, steady release of heavily
bound drug, e.g. ceftriaxone
Bad: since less free drug available for
bacteria, e.g. ceftriaxone
Penicilline
Derivate da Penicillium
chrysogenum.
PNC G e PNC V sono
prodotti non modificati
della fermentazione di
Penicillium.
I derivati semisintetici
sono creati aggiungendo
una catena R alla
struttura base dellanello
betalattamico.
PENICILLINS
bactericidal
interferes with peptide cross-linking required to
produce stable cell walls
development of resistance due to beta
lactamase production and changes in PBPs
may accumulate in renal failure and cause
seizures
good tissue penetration (except prostate and
uninflammed meninges)
Beta Lattamici
B-lattamici inibiscono la
transpeptidasi (PBP).
Effetto su batteri in rapida
crescita che sintetizzano
parete batterica /
peptidoglicano
Le caratteristiche dello spettro
dazione dipendono:
dalle dimensioni
e dalla carica della molecola,
dalla sua affinit per le PBPs,
dalla resistenza di essa alle
beta-lattamasi.
Azione: battericida
A. Gram + B. Gram -
Struttura della parete cellulare
batterica
Penicilline Naturali
Penicillina G (benzipenicillina) EV/IM
Coniugaz con sali insolubili per preparazioni depot per ala via IM
PENICILLINA G PROCAINA
PENICILLINA G BENZATINA
Penicillina V (fenossimetilpenicillina) OS
Attiva nei confronti di: Streptococchi,
peptostr., B anthracis, Actinomyces,
Corynebacterium, Listeria, Neisseria &
Treponema.
PENICILLINE NATURALI
Penicillin G Spectrum: mostly Gram+
Gram+ cocci
S. pyogenes: minimal resistance observed, does not produce beta-lactamases
S. pneumoniae: modified PBP in 30-40% gave rise to PRSP (penicillin resistant S. pneumo), not due not due
to beta to beta- -lactamase lactamase
most common cause of CAP (community-aquired pneumonia) 50-80%
very common cause of otitis media ~35%
S. viridans: usually still sensitive
Endocarditis (heart valve infection)
Enterococcus faecalis: PenG generally effective (not due to beta not due to beta- -lactamase) lactamase)
But note, E. faecium: highly resistant to PenG (92%) and vancomycin
Gram+ rods
Clostridium tetani (tetanus), C. perfringens (gangrene, food poisoning) sensitive
C. difficile resistant
Helical and spirochetes:
Treponema pallidum (syphilis): sensitive to Pen G
Relatively little Gram- coverage (scarce penetration of outer membrane!)
Use against sensitive Neisseria meningitidis: and PenG can penetrate meninges ONLY IF
ongoing inammation
Neisseria gonorrhoeae however is now resistant due to beta-lactamases
Enterobacteriaceae, Pseudomonas, H. inuenzae: resistant
Will we ever find a cure for penicillin?
Clatworthy. Nature Biochem Biol 2007; 3: 541 Clatworthy. Nature Biochem Biol 2007; 3: 541- -8 8
THE ANTIBIOTIC TIMELINE
-lattamasi
Insieme molto ampio ed eterogeneo di anzimi
Spettro di azione molto ampio
-lattamasi AmpC
ESBLs
Carbapenemasi
Ampiamente distriubite in GRAM-POS e GRAM-NEG
Rappresentano il principale meccanismo di resistenza per
STAFILOCOCCHI, GRAM STAFILOCOCCHI, GRAM- -NEG e ANAEROBI NEG e ANAEROBI
-lattamasi
Penicilline Anti-Stafilococciche
Meticillina, nafcillina, oxacillina, cloxacillina e
dicloxacillina.
Resistenti alla degradazione ad opera delle
penicillinasi stafilococciche.
Mirate nei confronti di S. aureus, non efficaci
verso gli streptococchi (Streptococco NON
PRODUCE BETA-LATTAMASI!).
Meticillina non pi usata (tossicit).
Oxacillina farmaco di scelta
Breve emivita
NOT FOR: MRSA, Methicillin-resistant
Staphylococcus epidermidis (MRSE) or
ENTEROCOCCI (Enterococchi NON
PRODUCONO BETA-LATTAMASI!).
Attualmente in forte aumento ceppi MRSA!!
Anti-staph penicillinase resistant
penicillins
resistant to staphylococcal beta-lactamase but not to other beta-
lactamases produced by gram-negative microbes.
very narrow spectrum because the effect against gram-positive
bacteria other than staphylococci is weaker comparing to penicillin
G.
methicillin (only parenteral forms), nafcillin, oxacillin, cloxacillin,
dicloxacillin
Oxacillin is the most widely used
Methicillin-resistant strains of Staphylococcus aureus (MRSA) or
Staphylococcus epidermidis (MRSE) have changed their PBP
receptor resistant to all beta-lactam antibiotics (except for V gen
cephalosporins).
These microbes are also simultaneously resistant to macrolides and
lincosamides (clindamycin). Drugs of choice in this situation are
glycopeptides.
Anti-staph penicillinase resistant
penicillins: clinical uses
1) Staphylococcal Infections
Spectrum similar to Pen G, but includes Staph. aureus & Staph.
epidermidis.
Community-acquired Methicillin-resistant forms of Staph aureus
(MRSA) are increasing.
50-80% of S. epidermidis in hospitals is methicillin-resistant (but
Staph. epi . is not a invasive or virulent).
Staphylococci cause skin infections (impetigo), abcesses in many
organs, pneumonias, prosthetic joint, catheter, and artificial valve
infections, endocarditis, meningitis (rare), bone infections
(osteomyelitis: may require months of therapy).
2) Streptococcal infections, when Staph. is also a
possibility (although anti-staph penicillins are less
effective than natura penicillins againsta streptococci)
Aminopenicilline
(penicilline a spettro esteso)
Ampicillina EV
Amoxicillina (Velamox; OS).
Facile Spettro antimicrobico pi esteso.
Gram negativi: E. coli, Proteus, Salmonella, Shigella,
Haemophilus, M. catarrhalis, Klebsiella, Neisseria,
Enterobacter, Bactoroides.
NOT FOR: MRSA, Methicillin-resistant Staphylococcus
epidermidis (MRSE) or ENTEROCOCCI
DO NOT USE if beta-lactamase (penicillinase)
producing Gram-neg strains
NB: Aminopenicillins should not be prescribed for patients suffering from tonsillitis
until infectious mononucleosis has been excluded. Patients with mononucleosis
readily develop severe maculopapular exanthema even after a few tablets of
aminopenicillin. This effect is caused by production of heterophile antibodies and
should not be interpreted as true and lasting allergy
Aminopenicillins
Aminopenicillins have spectra similar to natural penicillins with one exception: an
additional aminogroup in their side chain increases their idrophylicity and allow them
to pass through the porins in the outer memnbrane of some Gram-negative bacteria
(E. Coli, P. mirabilis, S. Enterica, Shigella)
Even though they can penetrate the outer Gram-negative bacterial membrane, many
Gram-neg bugs produce beta-lactamases that can degrade ampicillin.
For example:
E. coli (80-90% of UTIs), 50% resistant to ampicillin due to beta-lactamase production
Proteus mirabilis (UTIs), 30% resistant
N. meningitidis generally sensitive, but some produce penicillinase
N. gonorrhoeae signicant penicillinase production now, resistant
H. inuenzae ~30% produce beta-lactamases
Most nosocomial pathogens are resistant either due to innate impermeability or
several resistance mechanisms including beta-lactamase production
Sometimes used in combination with aminoglycoside for E. faecalis (synergy)
Signicant enterohepatic recycling : unmodied amp re-secreted into bile many
cycles, leading to high intestinal levels of the drug. Potentially useful for Shigella,
Salmonella, enteric infections. Greater risk of adverse effects such as diarrhea and C.
difcile overgrowth.
Note: Amoxicillin is the number one antibiotic sold in U.S.
1. Otitis Media - still drug of choice.
Strep. pneumoniae resistance is increasing. Vaccine should reduce incidence of invasive
infections but may not be effective vs. all otitis media strains.
Haemophilus type b infections are rapidly decreasing due to vaccination, but vaccine is
directed against capsular antigens. Haemophilus sp. that cause otitis media are not
encapsulated, vaccine is not effective. 40-50% are penicillinase +
Moraxella catarrhalis strains are b-lactamase positive and are resistant.
2. Bronchitis/Pneumonia may be used, but resistance is a problem.
3. Enterococcal endocarditis (ampicillin or PenG + aminoglycoside)
4. Meningitis Ampicillin - alternative choice to 2nd gen. cephalosporins (+
chloramphenicol).
Infant meningitis Ampicillin covers Strep. pneumoniae, N. meningitidis, H. influenzae
Neonatal meningitis - group B Strep., Listeria, & E. coli. (the most common causative
organisms)
Some strains of Strep. pneumoniae, H. influenzae & E. coli are resistant. Drug of choice for
Listeria (in combo with gentamicin). Note: cephalosporins are not active vs. Listeria
5. Urinary Tract Infections - Covers three most common organisms
E. coli, Proteus mirabilis, & Staph. Saprophyticus but resistance is common in E. coli
6. Prophylaxis for bacterial endocarditis
7. Lyme Disease (Borrelia burgdorferi) and Erlichiosis (Erlichia chaffeinsis) - alternate
to doxycycline
8. Alternate for susceptible strains of N. gonorrheae
Aminopenicillins: clinical uses
-lattamasi
Bush, Jacoby, Madeiros Classification
of -Lactamases
Combinations with beta-
lactamase inhibitors
Two combinations are available, both for oral and parenteral administration:
ampicillin + sulbactam
amoxicillin + clavulanic acid
The combinations are effective against many gram-negative and anaerobic bacteria
expressing beta-lactamase, and also against Staphylococcus aureus.
Thus beta-lactamase inhibitors drmatically broaden the antimicrobial spectrum of the
aminopenicillins
NB: These antibiotics are needless and should not be prescribed against
streptococci, enterococci or other bacteria that do not produce beta-lactamase.
Aminopenicillins with or without beta-lactamase inhibitor are widely used in clinical
practice. They are given in bacterial sinusitis, mesotitis and lower respiratory tract
infections, urinary and hepatobiliary tract infections, purulent gynecological infections,
and other community-acquired infections.
Remember:
1) Bacteria have developed many beta-lactamases, and only some of them can be destroyed
with inhibitors. Many bacteria causing community acquired infection use to dispose
plasmide-transmitted lactamases that can be inhibited with sulbactam, clavulanic acid or
tazobactam. However these inhibitors do not work against lactamases produced by majority
of nosocomial pathogens.
2) Beta-lactamase inhibitors possess weak, if any, natural antibacterial activity. From general
point of view, minimal clinically important difference exists between these three drugs.
Combinations with beta-
lactamase inhibitors
Inclusion of beta-lactamase inhibitor increases
coverage of Gram- to also include:
M. catarrhalis (otitis media, pneumo, sinusitis)
H. inuenzae (otitis media, pneumo, sinusitis)
S. pneumoniae (otitis media, pneumo, sinusitis)
MSSA
Klebsiella
Enterobacter
E. coli
N. gonorrhoeae
Good activity against anaerobes
Aminopenicillins +
beta-lactamase inhibitors:
clinical uses
Otitis media, sinusitis, and respiratory tract infections
(acute exacerbations of bronchitis or
chronic obstructive pulmonary disease (COPD) due to b-
lactamase producing H. influenzae & Moraxella
catarrhalis.
High doses recently approved for otitis media due to
Strep. pneumoniae
Skin and Skin-structure infections caused by b-
lactamase-producing strains of Staph. aureus, E. coli,
and Klebsiella sp.
UTIs due to b-lactamase-producing strains of E. coli,
Enterobacter sp., and Klebsiella sp
BROAD-SPECTRUM (anti-
Pseudomonal) PENICILLINS
karbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin
Polar side chain which allow even greater penetration into Gram-
neg bacteria (increased ability to pass through the outer membrane
porins)
More resistant to cleavage by Gram-neg beta-lactamases than
aminopenicillins
More active against Gram-neg bacilli, including many strains of P.
Aeruginosa
Maintain Gram-pos activity of natural penicillins but (like natural
penicillins) are susceptible to beta-lactamases of staphylococci
Usually, the third generation cephalosporins are preferred to these
drugs because of lower costs.
USES OF BROAD-SPECTRUM
(ANTIPSEUDOMONAL) PENICILLINS
1. Pseudomonas aeruginosa infections
(often with aminoglycosides)
2. Mixed infections - good gram negative
activity, covers most B. fragilis
3. Complicated urinary tract infections &
prostatitis - Carbenicillin indanyl OK orally.
4. Surgical prophylaxis - intra-abdominal,
gynecologic surgery
ANTIPSEUDOMONAL PENICILLINS
+ BETA LACTAMSE INHIBITORS
ticarcillin + clavulanic acid
piperacillin + tazobactam
The fullest antimicrobial potential of the penicillins has
been achieved by combining extended-spectrum
penicillins with beta-lactamase ihibitors
Calvulanate and tazobactam neutralize many beta-
lactamases resulted in a marked enhancement of their
activity
Highly active against:
Gram- neg:
Pseudomonas, E. coli, klebsiella, enterobacter, serratia and
B. fragilis, H. Influenzae
Gram-pos (NOT FOR MRSA)
Nearly all anaerobic bacteria except for C. Difficile
ANTIPSEUDOMONAL PENICILLINS
+ BETA LACTAMSE INHIBITORS: Clinical uses
Extends spectrum towards b-lactamase-producing Enterobacteriaciae &
Pseudomonas. For Pseudomonas infections, often combined with aminoglycosides.
Indications are as follows:
Septicemia due to b-lactamase-producing strains of Klebsiella sp., E. coli, Staph. aureus, &
Ps. aeruginosa
Lower respiratory tract infections due to b-lactamase-producing strains of Klebsiella
pneumoniae, S. aureus, H. influenzae, & Moraxella catarrhalis
Bone & joint infections due to b-lactamase-producing Staph. aureus.
UTIs (complicated & uncomplicated) due to b-lactamase-producing strains of E. coli,
Klebsiella, Ps aeruginosa, Citrobacter sp., Enterobacter sp., Serratia marcescens, & Staph.
Gynecologic infections: endometritis due to b-lactamase-producing strains of Prevotella
(formerly Bacteroides) melaninogenica, Enterobacter sp., E. coli, Klebsiella pneumoniae, S.
aureus, and Staph. epidermidis.
Treatment of mixed infections and for presumptive therapy prior to identification of the
causative organisms.
Appendicitis or peritonitis caused by b-lactamase-producing E. coli or Bacteroides fragilis
Uncomplicated & complicated skin and skin structure infections caused by piperacillin-
resistant b-lactamase-producing Staph. Aureus
Post-partum endometritis or pelvic inflammatory disease caused by piperacillin-resistant b-
lactamase-producing strains of E. coli
Community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant b-
lactamase-producing strains of H. influenzae & Ps. aeruginosa
Effetti collaterali delle penicilline
Farmaci molto sicuri con elevato
indice terapeutico
Reazioni da ipersensibilit: 5%
Rash reazione pi comune.
Ampicillina: rash nel 50-100%
dai pz con mononucleosi.
Orticaria, angioedema, schock
anafilattico (1/10000): evitare
tutte le altre penicilline.
Raramente crisi comiziali
accumulo in pz con insuff
renale
Infusione ev troppo rapida
Soggetti predisposti
Clatworthy. Nature Biochem Biol 2007; 3: 541 Clatworthy. Nature Biochem Biol 2007; 3: 541- -8 8
THE ANTIBIOTIC TIMELINE
Cefalosporine
Derivati B-lattamici semisintetici ottenuti
aggiungendo diverse catene laterali allacido
aminocefalosporanico
pi resistenti alle beta-lattamasi rispetto a
penicilline naturali.
Cefalosporine
Ceftazidime
La catena laterale conferisce
protezione sterica dallazione
delle beta-lattamasi
Cefalosporine
Reazioni avverse
5-10% cross-reattivit
negli allergici alle
penicilline
1-2% reazione da
ipersensibilit nei
pazienti non allergici
alle penicilline
(soprattutto per I e II
generazione).
Spettro dazione
ampio infezioni
opportunistiche!
CEPHALOSPORINS
Cephalosporin generations: generally get broader, more Gm- coverage
with later generations
Generation 1: Generally had better Gram+ than Gram- activity; susceptible to
many Gram- beta-lactamases
Examples: Cephalexin, Cefazolin
Generation 2: Better resilience to Gram- beta-lactamases, Gram- coverage
(Cefotetan less active against Gram+)
Examples: Cefuroxime
Generation 3: More potent, better Gram- beta-lactamase stability, better
penetration; pick up some anti-Pseudomonal activity (Ceftazidime), give up some
Gram+ coverage (Ceftazidime: limited activitv against S. Aureus)
Examples: Cefpodoxime, Cefdinir, Cexime, Cefotaxime, Ceftriaxone, Ceftazidime,
Generation 4: Very broad spectrum (Gm- and Gm+)
Example: Cefepime
Generation 5: MRSA and PRSP (penicillin-resistant Streptococcus pneumoniae)
coverage; Gm- activity similar to ceftriaxone (not for Pseudomonas!)
Example: Ceftaroline
DO NOT USE IN: ENTEROCOCCI, LISTERIA MONOCYTOGENES,
(MRSA, except 5th generation)
Cefalosporine
Cefalosporine
Classificazione per generazioni
Classificazione per generazioni
Generazione Generazione Attivit Attivit relativa su specie relativa su specie
batteriche batteriche
Gram Gram- -positive positive Gram Gram- -negative negative
Prima Prima ++++ ++++ + +
Seconda Seconda +++ +++ ++ ++
Terza Terza + + +++* +++*
Quarta Quarta ++ ++ ++++** ++++**
* In parte attive anche su * In parte attive anche su P. aeruginosa; P. aeruginosa; ** molto attive su ** molto attive su P. aeruginosa P. aeruginosa
Cefalosporine
III
a
Generazione
Spettro: gram negativi > gram
positivi.
Ceftriaxone (Rocefin; IM/EV)
Molto efficace sia contro
pneumococchi (penicillino-
sensibili) che contro gram-neg
respiratori.
Ottimo profilo farmacocinetico.
Ceftazidime (Glazidim) attivit
specifica contro Pseudomonas
(ma ridotta verso Gram +!!).
CEPH: 1st Gen
used predominantly against gram-positive cocci (streptococci and
staphylococci).
Their spectrum further includes corynabacteria, meningococci, and
some community-acquired stems of gram-negative rods like
Escherichia coli or Proteus mirabilis.
The drugs are active against anaerobes in the extent similar to
penicillin.
cefalotin, cefazolin (for parenteral administration)
cefalexin, cefadroxil, cefaclor (for oral administration)
(cefaclor has moderate effect against Haemophilus, so it belongs to
one-and-half generation)
The drugs are predominantly used for treatment skin and soft tissue
infections, and for prophylaxis in surgical procedures (except
colorectal surgery and situations when methicillin-resistant
staphylococci are spread in the surgery department).
CEPH: 2nd Gen
contain antibacterial activities of the 1st generation and extend to further
community-acquired gram-negative bacteria like Haemophilus influenzae,
Moraxella catarrhalis, or less susceptible strains of E.coli or similar
patogens.
cefuroxime, cefamandol (for parenteral administration)
cefuroxim-axetil (for oral administration)
prescribed for treatment respiratory tract infections (bacterial sinusitis or
mesotitis, pneumonia), and urinary and hepatobiliary tract infections.
They can be used for prophylaxis in surgery as well.
cefoxitin (only parenteral administration)
It is a representative of cefamycines. These antibiotics are closely related to
true cephalosporins differing in one substituent on cephem nucleus.
Their common feature is a very good activity against relatively resistant anaerobe
Bacteroides fragilis.
With its antibacterial activity against other gram-neg bacteria, cefoxitin has been
joined to the 2nd generation cephalosporins but shows limited activity against
Gram-pos cocci.
Its typical disposal is intra-abdominal, pelvic, and gynecological infections, foot
infections in diabetics, infected decubitus ulcers and other mixed aerobic-
anaerobic infections. Unfortunately, resistance to cefoxitin raises quickly in
departments where this drug used to be given frequently.
CEPH: 3rd Gen
can be divided in two subgroups according to their activity against Ps.aeruginosa:
The subgroup A consists of antibiotics of similar spectrum as 2nd generation but with enhanced
activity against gram-negative bacteria and weaker effect against staphylococci.
cefotaxim, ceftriaxone (for parenteral administration)
These drugs are used for treatment of severe and life-threatening infections caused by community
gram-negative patogens like E.coli, H.influenzae, meningococci, salmonellae etc. The relevant
clinical diagnoses are purulent meningitis, epiglotitis, sepsis of urinary or hepatobiliary tract origin
etc.
Ceftriaxone is an antibiotic of extreme long half-time (8 hrs) in addition that allows once-daily
administration. This feature makes the treatment easier but is of particular importance in treatment
of outpatients or in home treatment.
cefetamet-pivoxil, cefpodoxim-proxetil, cefixim, ceftibuten (for oral administration)
The position of these antibiotics is rather problematic. They can be used for treatment of mild or
moderate community acquired infections but cephalosporines of 2nd generation suffice in these
situations usually. The only rational indication remains infection caused by pathogens of
microbiologically verified intermediate sensitivity where 2nd generation cephalosporins perform
only a weak effect.
The subgroup B included antibiotics effective against Ps. aeruginosa and other problematic gram-
negative pathogens. However, the stronger is the anti-pseudomonadal effect, the weaker is the
activity against staphylococci and other gram-positive microbes.
ceftazidime, cefoperazon (for parenteral administration)
These antibiotics are used in nosocomial infections/sepsis caused by gram-negative bacteria.
Ceftazidime is strongest anti-pseudomonal cephalosporin. Cefoperazons unique feature is
predominant excretion via the bile: this advocates for its usage in hepatobiliary tract infections and
in renal insufficiency. Cefaperazon is available in a mixture with beta-lactamase inhibitor as well:
cefoperazon/sulbactam that can be worthy against Acinetobacter sp. and some problematic
pathogens owing beta-lactamase activity.
CEPH: 4th Gen
Antibiotics of this group have a broad spectrum
summarizing the 1st, 2nd and 3rd generation.
They can resist some potent beta-lactamases.
Nevertheless, their activity against staphylococci is not
better than with cephalotin and activity against
Ps.aeruginosa is not better than with 1Gen agents .
cefpirome, cefepime (only parenteral administration)
used in nosocomial infections of special resistance
pattern (stable induction of ampC gene) or in nosocomial
sepsis of unknown origin where covering the broad
spectrum of pathogens is necessary (i.e. febrile
neutropenia).
Ceftobiprole
Carbapenemi
Imipenem-Cilastina (Imipem EV), meropenem (Merrem EV)
Cilastina: inibitore della deidropeptidasipreviene la formazione
di un metabolita nefrotossico.
Antibiotici betalattamici con spettro pi ampio.
Staph (no MRSA), Strep (highly resistant), Neisseria, Haemophilus, Proteus,
Pseudomonas, Klebsiella, Bacteroides, anaerobes (escluso C. difficile)
Nelle infezioni da Pseudomonas raccomandata associazione
(AMINOGLICOSIDE, CHINOLONICO).
NO ACTIVITY AGAINST: MRSA, MRSE,
Stenotrophomonas maltophilia, Pseudomonas cepacia
Tossicit:
Allergia crociata con penicillina: < 5 %.
Imipenem epilettogeno
Imipenem
Slightly more activity versus gram positive and a little less
activity with gram negative compared to meropenem
Risk of seizures more common in renal failure
Meropenem
Similar spectrum of activity as imipenem
Little or no risk of seizures
Carbapenems
Molecular properties:
Quite small molecules and have charge characterustics that allow them to utilize
special porins in the outer membrane of Gm-neg bacteria
Structure resistant to cleavage by most beta-lactamases
Affinity for a broad range of PBPs from many different species of bacteria.
very potent antibiotics of extremely broad spectrum including majority of
gram-positive and gram-negative patogenes and anaerobes.
The group of resistant bacteria microbes includes:
methicillin-resistant staphylococci,
Clostridium difficile,
Stenotrophomonas maltophilia,
Pseudomonas cepacia
Enterococcus faecium
Some exceptionally resistant strains of Acinetobacter or Pseudomonas.
imipenem, meropenem (only parenteral administration)
These antibiotics are reserved for extreme resistant nosocomial
infections/sepsis.
Monobattamici
Aztreonam (Azactam; IM/EV;)
Resistente alle beta-lattamasi.
Spettro antibatterico ristretto.
H. influenzae, N. gonorrhea
(produttori di penicillinasi), E.
coli, Klebsiella, Proteus,
Pseudomonas.
Inattivo verso I Gram + e gli Inattivo verso I Gram + e gli
anaerobi. anaerobi.
Non cross-reazione nei pz
allergici alle penicilline!
Vancomicina
Glicopeptide triciclico Streptomyces
orientalis.
Inibisce la sintesi della parete batterica
legandosi alle catene di peptidoglicano
in allungamento e prevenendo il cross-
linking.
Attivo verso i Gram +, compresi
MRSA, MDRSP, enterococchi, Staph.
epidermidis e clostridi.
Sinergico con AG.
Azione: battericida
Vancomicina
Vancomicina
Resistenza:
Ridotta permeabilit.
Cambiamento negli aminoacidi del peptidoglicano
(da ala-ala a ala-lattato). Enterococchi vanA
Reazioni avverse
Febbre e brivido, ipotensione, red man syndrome.
Somministrazione lenta!
Ototossicit. Nefrotossicit (exp se usata con AG)
Eliminazione renale (90-100%).
Emivita normale 6-10 h.
Emivita fino > 200 h in pz con IR grave.
Possibilit di misurazione dei livelli
plasmatici
Teicoplanin
penetrates better in tissues except brain.
very long half-time (33-70 hours) and can accumulate in organism.
The first three doses should be given in 12-hour period for
saturation, then the drug can be given once daily or in every-other-
day regime.
well tolerated and can be administered in a rapid infusion, slow
intravenous injection, or intramuscular injection.
adverse effects are much less frequent.
allergy (and also resistance) is only partially crossed between
vancomycin and teicoplanin.
the main limiting factor of teicoplanin prescription is its relatively high
cost.
teicoplanin is usually administered when vancomycin treatment can
not be continued because of allergy, renal failure, impossibility of
further intravenous administration etc.
Because of its long half-time, teicoplanin is useful for the outpatient
therapy.
Effetti collaterali dei glicopeptidi
Effetti collaterali dei glicopeptidi
Frequenza Frequenza
Tipo Tipo Vancomicina Vancomicina Teicoplanina Teicoplanina
Tromboflebite Tromboflebite +++ +++ ++ ++
Nefrotossicit Nefrotossicit +++ +++ - -
Rash cutaneo Rash cutaneo ++ ++ ++ ++
Neutropenia Neutropenia ++ ++ ++ ++
Ototossicit Ototossicit + + - -
Sindrome Sindrome red man red man +++ +++ - -
Disturbi gastrointestinali Disturbi gastrointestinali - - ++ ++
Epatotossicit Epatotossicit - - ++ ++
+++ = 5 +++ = 5 - - 10%; ++ = 2 10%; ++ = 2 - - 4,9%; + = < 2; 4,9%; + = < 2; - - = assente = assente
Vancomicina
Aminoglicosidi
Aminoglicosidi
Streptomycin
Isolated in 1943 by Selman Waksman from Streptomyces griseus
Breakthrough drug for treatment of tuberculosis (Mycobacterium
tuberculosis)
Gentamicin
Isolated in 1963 from Micromonospora purpurea (mycin only if from
Strep.)
Significant use in treatment of Gram- infections including
Pseudomonas
Kanamycin
isolated in 1957 and was the
Drug of choice until Gentamicin in 1963.
Amikacin
Semi-synthetic, derived from Kanamycin
Designed to overcome resistance due to modifying enzymes
Aminoglicosidi
Binds to 30s ribosomal subunit and:
Interferes with initiation, ribosome locked at AUG start codon of mRNA (at higher
concentrations)
Premature termination of translation
Incorporation of incorrect amino acid leading to nonsense proteins.
Highly positively charged Interacts with Gram- outer membrane and makes it leaky
increased penetration of the drug.
role in increasing penetration of other drugs.
Scarce penetration into Gram+ envelope (do not bind Gram+ membrane)
Bactericidal unlike most protein synthesis inhibitors
This is probably due to the activity against the membrane.
Access from periplasmic space to cytosol accomplished by energy-dependentactive
bacterial ytransport mechanism requiring oxygen
Non activity against anaerobic bacteria
Work poorly un anaerobic and acidic environments (such as abscesses)
Widely used for for treatment of Gram+ infection
???
Combined with cell-wall inhibitor (synergy) Cell-wall disruptors increase permeability of
aminoglycoside into Gram+ cell
But beta-lactams and aminoglycosides in vitro at high concentrations can interact, undergo
chemical reaction, and inactivate each other
Do not mix in the same solution
This effect varies based on pairing of beta-lactam and aminoglycoside
Aminoglicosidi
Spectrum and usage:
Gram- aerobes:
Pseudomonas aeruginosa Tobramycin is more potent against Pseudomonas than gentamicin
Acinetobacter spp.
Enterobacteriaceae:
Klebsiella, Proteus, Enterobacter, Serratia, Providencia...
Haemophilus influenzae
Etc.
Gram+ aerobes: used in combination with a beta-lactam or vancomycin (synergy)
Streptococcus
Staphylococcus
Mycobacteria
M. tuberculosis
MAC
No activity against anaerobes
anaerobes lack the ability to actively take up AG into their cytosol
synergism is expressed against
BOTH some gram-positive (streptococci, enterococci)
AND gram-negative (E.coli, Pseudomonas) bacteria
Examples:
Often Pseudomonas (Gram-): high intrinsic resistance to mono-therapies
Infective endocarditis (Gram+): Staph, Strep viridans, Enterococci
Aminoglicosidi
Aminoglycosides are associated with significant nephrotoxicity or ototoxicity.
Excreted primarily by glomerular filtration
serum half-life will be prolonged and significant accumulation will occur in patients with impaired renal
function.
Toxicity may develop even with conventional doses, particularly in patients with prerenal azotemia
or impaired renal function.
Nephrotoxicity
Usually reversible
More common than ototoxicity, 5-20% of patients
Aminoglycoside accumulates in proximal tubules of renal cortex, kills the cells
Tubular cell degeneration can lead to sloughing of cells and fine sediment in urine
Ototoxicity
Irreversible
Less common than nephrotoxicity; toxicities do not appear to be correlated
Aminoglycoside accumulates in inner ear and leads to destruction of cochlear hair cells
Produces reactive radicals that kill the hair cells
Vestibular toxicity: imbalance, vertigo, tinnitus, nystagmus (involuntary eye movement)
More frequently seen with gentamicin
Auditory toxicity: high frequency hearing loss
More common with amikacin, kanamycin (particularly damaging)
Emergence unpredictable, could be after a single dose; can appear weeks after therapy is completed (continue monitoring)
AG accumulate in inner ear fluids and are cleared slowly, hence latency
Possibly a genetic factor: mutation on ribosomal RNA in mitochondria that enables AG to bind to human ribosomes; leading
to disruption of mitochondrial protein synthesis
Neuromuscular blockage
Rare
Myasthenia gravis
Drug induces auto-immune response that leads to blockage of neuromuscularcommunication
Antibodies block acetylcholine receptors at neuromuscular junctions
Fatigue, weakness
Aminoglicosidi
PEAK LEVEL (see optimal values above)
efficacy
measured one hour after an infusion begins;
TROUGH LEVEL (optimal: <1g/ml)
Toxicity
measured immediately prior to the next dose (all
done at steady state)
Aminoglicosidi
In order to minimize the toxic effects, it
is recommended:
to be careful of good water supply
(daily diuresis 2 liters)
to prefer higher doses for few days at
the onset of therapy
to respect a maximal treating period of
2-3 weeks, than a pause should follow
of minimum 4-6 weeks
to prefer once-daily administration
(except infective endocarditis where
multiple daily doses are preferred)
while intravenous infusion, the time of
administration should be 30-45 minutes
(the period more then 1 hour enhances
nephotoxicity, the period less then 20
minutes enhances the risk of
neuromuscular blocade)
to monitor renal (CREATININE) and
auditive functions three times weekly
to measure serum levels of
aminoglykosides (especially the
THROUG serum level)
*advanced age, persistently high trough serum
levels, duration of therapy, hypotension, concomitant
liver disease, use of other nephrotoxins (e.g.
vancomycin, furosemide)
Aminoglicosidi
Gentamycin (IV/IM, opthalmic, topical)
The go-to aminoglycoside for Gram- aerobic infections
Associated with ototoxicity, especially affecting vestibular system
Tobramycin (IV/IM, opthalmic, topical)
Greater potency compared to Gentamycin against Pseudomonas
Less ototoxicity than Gentamycin, but auditory loss possible
Kanamycin (IV/IM, PO)
Can be used for intestinal infections or as sterilizing prophylaxis of the gut, often
combined with cell-wall disruptor (beta-lactam, vanco)
Can be profoundly ototoxic, less impact on vestibular system
Amikacin (IV/IM)
Less susceptible to enzymatic inactivation by resistance factors (side chain
modification made Amikacin more resistant to enzyme modification)
Powerful agent, reserved for cases that are resistant to Gentamycin/Tobramycin,
so as not to foster resistance
Somewhat less toxic to vestibular system than gentamycin
If a bacteria is resistant to Amikacin, it is likely to be resistant to all the other
aminoglycosides as well
Potency against P. Aeruginosa:
AMIKA > TOBRA > GENTA
Aminoglicosidi
Reserved for serious infections only Reserved for serious infections only
Elimination is renal (excreted unchanged by glomerular filtration):
REQUIRE DOSE ADJUSTEMENT IN RENAL FAILURE!
Does not cross blood-brain barrier into CNS
Aminoglycosides work excellent in blood, in extracellular fluid, and in urine. Their effect in the
inner area of inflammation may be poor due to limited penetrance and acidic condition.
Due to serious toxicity concerns: ototoxicity, nephrotoxicity
Concentrations require monitoring
IV only for severe systemic infections; majority passed unmodified in urine
If the patient is predisposed to renal dysfunction, important to monitor closely
Active against broad spectrum of Gram- aerobes and facultative anaerobes
Weak coverage of Gram+ if used alone, but active if combined with another inhibitor of wall-
syntesis such as beta-lactams or glycopeptides.
Poor coverage of obligate anaerobes
Aminoglycosides are preferably used in combination with other antibiotics.
Typical indications for usage aminoglycosides include:
a) severe infections or sepsis caused by gram-negative microbes and staphylococci:
Amonoglycosides are given especially at the onset of therapy, for rapid lowering of the
massive bacterial load.
b) severe infections caused by semi-resistant microbes when monotherapy is not
bactericidal: In these situations, synergistic effect of aminoglycosides and wall-affecting
antibiotics is often utilized.
Examples:
nosocomial infections caused by resistant gram-negative bacteria
infective endocarditis caused by streptococci or enterococci
infections in immunocompromised patients in whom bactericidal activity of antibiotics is
necessary.
Single vs multiple daily doses for
aminoglycosides
Concentration-dependent killing: Want to hit a certain optimal peak concentration,
which can be hard to achieve with traditional multi-dosing.
More likely to hit those optimal concentrations w/ consolidated dose.
Possible benefits:
Reduced toxicity (nephro only; does not reduce ototoxicity):
Assume aminoglycoside renal and inner ear uptake can be saturated
Do not want to have the trough concentrations stay elevated due to increased chance of nephrotoxicity
Lower cost
Not necessarily effective for treatment of all bacteria (e.g. Gram+ dont show PAE)
Aminoglicosidi
Compared to other antibiotics, resistance to aminoglycosides is rare
Primarily mediated by enzymatic modification of the OH and NH2
groups
Phosphorylation
Acetylation
Adenylation
Encoded on plasmids, transposons
Amikacyn is the most resistant AG to enzyme modification
Pseudomonas
Efflux pump removal of drug from cytosol
Modified ribosomal binding site
Methylation of 16s ribosomal RNA
Single mod can knock out streptomycin binding since it has a single
binding site;
other AG have more than one, harder to evolve resistance
Tetracicline
Tetracicline
First tetracycline isolated 1945 from Streptomyces aureofaciens, chlortetracycline
(though apparently the Egyptians 1600 years ago may have benefitted from
tetracyclines in their beer and bread).
Tetracycline is derived from Streptomyces
Minocycline and doxycycline are newer sintetic molecules (longer half-life, better oral
absorption)
Ring substitutions to positions 5, 6, and 7 change pharmacokinetic properties, but not
spectra complete cross resistance
Originally, their antimicrobial spectrum was broad:
Gm+ and Gm-, plus many unusual pathogens.
But significant resistance developing (except tigecycline new related molecule with
extremely broad spectrum)
Dramatic overuse in animals
Chelates, forms an insoluble complex with, calcium
Tooth discoloration of child if administered to pregnant mother, or to children < 8 y.o.
Incorporates into bone, may affect bone growth in fetus
Possibly antagonistic with amino-penicillins; they diminish each others activities.
Bacteriostatic: shuts down protein synthesis, but doesnt lead to nonsense proteins
(like aminoglycosides). As a result damage to cells is less severe
BACTERIOSTATIC
TETRACYCLINES:
SPECTRUM OF ACTIVITY
Mostly the same for all tetracyclines (except tigecycline)
Aerobic Gram+:
S. pyogenes
S. pneumoniae
S. aureus: MSSA, CA-MRSA
Aerobic Gram-: many are becoming resistant
N. gonorrheae (significant resistance)
H. influenzae
Enterobacteriacea: Klebsiella, Shigella, E. coli, Salmonella
Atypicals:
Chlamydia trachomatis (STD) and Chlamydia (aka Chlamydophilia) pneumoniae (but
now azithromycin is preferred)
Rickettsia rickettsii: Rocky Mountain spotted fever
Borellia burgdoferi: Lyme disease
Pasturella multocida: from animal bites
Mycoplasma pneumoniae: walking pneumonia
Brucella spp.
Vibrio cholerae
Bacillus anthracis: anthrax; 2 months treatment (spores)
Treponema pallidum: syphilis (but Penicillin is the drug of choice)
Plasmodia spp.: malaria prophylaxis
Entamoeba histolytica
1) Respiratory, genitourinary or ocular infections caused by chlamydiae, mycoplasmata, and
ureaplasmata.
These infections include walking pneumonia cause dy M Pneumoniae, COPD , acute and chronic urethritis
and/or urethral syndrome, epididymitis, cervicitis, some of pelvic inflammatory diseases, inclusion
conjuctivitis and trachoma. (Alternative drugs are macrolides.)
2) Mild COPD exacerbation (some activity against: Gram+, H. Influenzae, Serratia)
3) Rickettsial infections: Q fever, ehrlichiosis, typhus fever etc. (Alternative drug is
chloramphenicol)
4) Spirochetal infections: Lyme borreliosis, relapsing fever (Borrelia recurrentis), leptospirosis,
syphilis and other treponemal infections. (Alternative drugs are penicillins, cephalosporines,
macrolodes.)
5) Some other anthropozoonoses caused by non-pyogenic bacteria: brucellosis,
campylobacteriosis, malleus, pasteurellosis, plague, rat-bite fever, or tularemia. (Alternative drugs
are fluoroquinolones.)
6) Mild to moderate infections caused by anaerobes: acne, actinomycosis, some pelvic
inflammatory diseases. (Alternative drugs are lincosamides and other antibiotics effective against
anaerobes.)
7) Mild specific skin infections (Acne)
Remember: In majority of above-mentioned pathogens, no systematic monitoring of resistance
exists due to problems with cultivation. The percentage of resistance (and probability of
successful treatment with various antibiotics) is not known.
DUE TO RELATIVELY FREQUENT RESISTANT ISOLATES (G+ and G-),
THEY ARE NOT INDICATED FOR EMPIRIC TREATMENT OF SEVERE
INFECTIONS
TETRACYCLINES:
CLINICAL USE
TETRACYCLINES:
ADVERSE EFFECTS
Do not use outdated products due to higher chance of renal toxicity
(tetracycline)
Drug breaks down into antimicrobially inactive compounds that may
increase renal toxicity; use full course and do not store
Fanconi syndrome: numerous small molecule nutrients are not
reabsorbed
Less of a problem with newer formulations (doxycycline,
minocycline) wich are genearrly safe even in renal failure
Clearance is mostly hepatic/fecal
Accumulates in growing bone and teeth in fetuses and children.
Permanently discolors the teeth and can affect bone growth.
Not recommended for children < 12 y.o. or pregnant women
(Pregnancy category D)
Chelates cations: avoid dairy, iron, antacid products for 2 hours
Esophagitis: drink a lot of water and remain upright for 30 minutes
Photosensitivity
MACROLIDES
Originally, exhibited a broad-spectrum antibacterial activity involving gram-positive and gram-
negative bacteria, anaerobes, spirochetes, and obligatory intracellular pathogens (chlamydiae,
mycoplasmata).
most important drug of that time was erythromycine, isolated 1952 from a soil microbe
Streptomyces erythreus.
Its usage was limited because of frequent disagreeable side effects like diarrhea, nausea and
vomiting.
In 80ties, modern macrolides were introduced widely. Later drugs (azithro-, clarithro-, telithro-)
have
broader spectra, especially Gm-.
better acid stability and oral bioavailability
They became very popular because of low frequency of side effects and comfortable usage.
Frequent resistance has been developed mainly in gram-positive cocci (staphylococci,
streptococci, and pneumococci) and in gram-negative (enterobacteria, H.influenzae) as a
consequence of their massive prescription.
The number of resistant isolates exceeds 50% in many countries and their further destiny become
problematic.
Frequently used for community-acquired respiratory infections; also for skin, otitis media (ear)
Alternative drug for Strep., Staph., H. flu infections for pen-allergic
Excellent tissue penetration, especially azithromycin and clarithromycin, but not to CNS
Target the 50s large ribosomal subunit in bacteria, inhibit protein synthesis
Similar MOA to clindamycin and chloramphenicol (shared binding site)
Bacteriostatic, except at very high concentration can be bactericidal
Macrolides
Excellent tissue penetration
But low serum levels
Tissue:blood ratio 10-100:1
highly concentrated in tissue, especially in the lung and in tonsils
Extremely high penetration into host cells (good for intracellular
parasites such as Chlamydia)
penetrates poorly into CNS, synovial fluid and fetal tissues
Oral bioavailability: variable
Erythromycin (not acid stable) ~25%, should be taken on empty
stomach
Clarithromycin and azithromycin ~50% (not influeced by food)
T
Erythro: ~1.5-2h (administered x3 in die)
Clarithro: ~3-7h (administered x2 in die)
Azithro: 2-4 days (administered once in die, short courses: 5-7 days)
a 3-day administration can make therapeutical levels in tissues for 7-14 days
transported to a locus of inflammation in leukocytes. Consequently, drug
concentration in the site of inflammation is high, whereas serum
concentration is extremely low.
Macrolides: spectrum
and clinical use
Good Gm+ and reasonable Gm- activity
Clarithromycin and azithromycin more potent than erythromycin for Gram-neg coverage
Staph. Aureus (some isolates), but not MRSA
S. pneumoniae resistance is rapidly on the rise (telitro is active against clarithro and azitro- resistant isolates)
S. pyogenes
M. cattarhalis
N. menengitidis
Mycoplasma (walking pneumonia)
Chlamydia
Not Enterobacteriacae, cannot penetrate outer cell membrane (except for Campylobacter and some Shigella)
Not Pseudomonas
H. influenzae (not erythromycin),
Atypicals (not easily categorized by Gram stain technique)
Mycoplasma pneumoniae (walking pneumonia)
Legionella pneumophilia (Legionares disease)
Helicobacter pylori
Chlamydia trachomatis (STD) and Chlamydia (aka Chlamydophila) pneumoniae
Mycobacterium avian complex (MAC): Clarithro- and azithro-
Uses:
respiratory infections (bronchitis and mild community-acquired pneumonia), mainly in atypical pneumonia and in legionellosis.
urogenital infections caused by chlamydiae, mycoplasmata, and ureaplasmata.
may be used for treatment tonsillitis or lyme borreliosis (erythema migrans) in patients with allergy to beta-lactam antibiotics.
special indications include campylobacteriosis (travelers diarrhea), tularemia in children, mycobacteriosis (in association with other
antibiotics) etc.
NB: Except legionellosis, macrolides should not be used for treatment severe infections. Their prescription
must be correlated to the frequency of resistance in pathogenic microbes in every country or district.
Generally, macrolides are not appropriate for treatment staphylococcal infections as well.
Macrolides
Clarithromycin
2-4x more potent than erythromycin
Broader spectrum of coverage compared to erythromycin, more Gram-
Somewhat more potent against Gram+ than azithro
Macrolide of choice for treatment of:
Mycobacterium avium complex (MAC); common opportunist in AIDS
H. pylori
Azithromycin
More potent than erythromycin; higher tissue conc (e.g. lungs) than clarithro-
Better Gm- coverage than clarithromycin, but less Gm+ than clarithromycin
Macrolide of choice for: Chlamydia trachomatis, M. catarrhalis, H. influenzae, N.
gonorrhea (if patient is beta-lactam allergic), Legionella
Used for some tougher infections: COPD exacernations, pneumonia (CAP),
Legionella, mild skin infections
Telithromycin
Binds more tightly to bacterial ribosome, and in more than one site
Bugs that are erythromycin resistant (and clarith-, azith- too) may be still
susceptible to telithromycin
Does not induce expression of erm (erythromycin ribosome methylase) that
methylate parts of ribosomal RNA to reduce binding of other macrolides
Similar spectrum to azithromycin, also covers Penicillin-resistant S. Pneumo (but
not MRSA)
Macrolides
Resistance is on the rise for S. pneumo (and much more rarely, for
S. pyogenes)
Often associated with resistance to penicillin (and clindamycin)
Common mechanisms:
Methylation of ribosome binding site via erm (erythromycin ribosomal
methylation) enzymes
S pneumo
Affects erythro-, clarithro-, azithro-, but NOT telithromycin
Erm expression is inducible
Active macrolide efflux pumps
mef gene (macrolide efflux)
S pneumo, S aureus, S epidermidis
Rare: esterases cleave the lactone ring
Intrinsic
Enterobacteriacea resistance due to outer membrane permeability
http://www.ecdc.europa.eu/en/publications/Publications/antimicro http://www.ecdc.europa.eu/en/publications/Publications/antimicrobial bial- -resistance resistance- -surveillance surveillance- -europe europe- -2012.pdf 2012.pdf
Resistenza dello pneumococco
Macrolides: adverse effects
Erythromycin
GI discomfort, diarrhea (13-32%) sometimes used as a prokinetic
QT prolongation risk of ventricular arrhythmias. Careful with other drugs that can have QT prolongation
Drug interactions:
P-glycoprotein inhibitor: e.g. interacts with digoxin
CPY3A4 inhibitor: e.g. interacts with carbamazepine, cyclosporin
CYP1A2 inhibitor: e.g. interacts with theophyline and caffeine
Clarithromycin
Drug interactions.
E.g. many anti-retroviral drugs interact (not to be used with HIV patients)
Colchicine
QT prolongation risk of ventricular arrhythmias. Careful with other drugs that can have QT prolongation
Teratogenic effects observed in animal models (Pregnancy category C)
Dizziness
Azithromycin
Few drug interactions
Do not take with antacids, impairs absorption
Rare hepatotoxicity
QT prolongation risk of ventricular arrhythmias. Careful with other drugs that can have QT prolongation
Pregnancy category B
Telithromycin
Potentially fatal liver toxicity found after it was on the market (FDA Boxed warning)
Aggravates myasthenia gravis
Due to potentially severe adverse effects, telithromycin not to be used for mild cases or to treat bronchitis,
sinusitis. Removed indications for those.
NOW, only indicated use is CAP (and as an alternative option)
SULFA DRUGS
Folic Acid Pathway Inhibitors
SULFA DRUGS
Folic Acid Pathway Inhibitors
SULFONAMIDES, TRIMETHOPRIM
SULFONAMIDES, TRIMETHOPRIM

selective toxicity:
selective toxicity:
sulfonamides: animal cells do not make folate, we sulfonamides: animal cells do not make folate, we
absorb it from the environment absorb it from the environment
trimethoprim: has much higher affinity for the trimethoprim: has much higher affinity for the
bacterial DHFR than the mammalian DHFR bacterial DHFR than the mammalian DHFR
(1:50.000 (1:50.000 100.000) 100.000)
co-trimoxazole = trimethoprim + sulfamethoxazole TMP/SMX (ratio 1:5)
TMP-SMX
SMX is a PABA analog that
binds to dihydropteroate
synthase (synthatase) and
prevents it from using PABA
TMP binds to and inhibits
dihydrofolate reductase
Depleting folic acid hinders the
eventual production of DNA so
bacteria are unable to
reproduce
SMX given with TMP
synergistic effect
Alone, each is bacteriostatic,
together bactericidal
85% bioavailable, not affected by food
Broad distribution in tissues (penetrate
excellently into tissues and cells).
TMP is more lipophilic, so it gets concentrated to
higher levels in tissue than SMX, so 1:5
(SMX:TMP) ends up ~1:20, which is optimal for
synergy
Both penetrate to CSF and across and placental
barrier
SMX gets acetylated in the liver, TMP is
excreted in urine unchanged
Synergistic combinations of
Trimethoprim & Sulfamethoxazole
(Bactrim)
Staph sensitivity
Sulfamethoxazole MIC = 3 ug/ml
Trimethoprim MIC = 1 ug/ml
combo MIC = 0.3 Sulf & 0.015 Trim
20:1 ratio most effective 20:1 ratio most effective
Advantages
more likely to be cidal
broader spectrum
decreased resistance
lower doses = lower toxicity
TMP-SMX: spectrum of activity
Active against many Gm+ and Gm- aerobes, for example:
S. aureus including some use against CA-MRSA
H. influenzae
Salmonella
E. coli: UTI
Proteus mirabilis: UTI
However, significant differences in local resistance do occur!!!
Nosocomial pathogens:
Burkholderia cepacia: e.g. pneumonia in immunocompromised patients, CF
Stenotrophomonas maltophilia: respiratory tract infections, UTI, from device
insertions (tubes, cath)
Serratia marcescens: UTI, bacteremia from catheter insertions
Protozoal and fungal parasites:
Toxoplasma gondii: toxoplasmosis
Pneumocystis jiroveci: pneumonia, esp in HIV patients
Not effective against: most anaerobes, enterococci, streptococci,
Pseudomonas sp.
NB: in vitro effectiveness of against enterococci is completely false: in vivo,
enterococci can use folic acid from the host tissues
TMP-SMX: clinical uses
severe diarrheal diseases with fever (especially if
salmonella is expected to be the cause)
urinary tract infections (if local E. Coli resistant rates
<20%)
Mild respiratory infections
However, co-trimoxazol is rather a drug of second choice for
most of these infections because safer and/or more effective
alternatives do exist.
Special indications include
therapy or prophylaxis in HIV/AIDS patients (pneumocystosis,
toxoplasmosis)
Nocardiosis
Brucellosis
long-term treatment of staphylococcal osteomyelitis
etc.
TMP-SMX adverse reactions
Crystallurea
Metabolized sulfonamides are insoluble and form crystals in urea
Maintain hydration
Sulfonamides compete for bilirubin-binding sites on plasma albumin and
may increase blood levels of unconjugated bilirubin Kernicterus (can not
be given to pregnant women or to newborns and sucklings up to the age of
2 months)
In G6PD-deficient patients, risk of hemolytic anemia
Clearance is throug hepatic acetylation Slow acetylators have a higher
risk of developing toxicity
Many drug-interactions, for example: warfarin, cyclosporin, rifampin,
dapsone, phenytoin, etc
Hypersensitivity allergic reaction (6-8%):
Rash
Urticaria
Erythema multiforme
Steven-Johnson Syndrome
Toxic epidermal necrolysis
HIV-patients show more frequent and more severe hypersensivity reactions
(25-50%)
Fluorochinoloni
Ciprofloxacina (Ciproxin; OS/EV)
Levofloxacina (Tavanic; OS/EV)
Moxifloxacina (Avalox; OS).
Derivati sintetici dellacido nalidixico.
Azione: battericida.
Agiscono sia su microorganismi in fase di
crescita che in fase stazionaria
Alta concentrazione nelle urine e ottima
penetrazione nei tessuti
Inibiscono le DNA girasi e
topoisomerasi IV: blocco del processo
di duplicazione e trascrizione del DNA
Resistenza ai fluoroquinoloni
Mutazione della DNA Girasi (comune)
Efflux-pump
Riduzione del numero di porine ridotto
ingresso intracellulare.
Spettro antibiotico
Efficace vs. gram +, gram (incl Pseudomonas), atipici.
Fluorochinoloni respiratori (levofloxacina e moxifloxacina).
Attivi verso Strep (incluse forme penicillino resistenti), S.
aureus (not MRSA), H. influ, M. cat (including penicillin-
resistant strains), e atipici.
Utilizzati in AOM, sinusite, faringite
Fluorochinoloni antipseudomonas (ciprofloxacin/ofloxacin)
Attivi contro Pseudomonas, H. flu, M. cat.
Strep pyogenes, Strep pneumoniae, e MRSA sono resistenti.
In profilassi nei pz con fibrosi cistica.
Formulazione topica.
Levofloxacina e Moxifloxacina hanno attivit anche
verso ceppi di Staph cipro-resistenti.
Ottimi farmaci anti TB (oflo, levo, moxi)
Fluorochinoloni
Ciprofloxacin
Osteomyelitis, peritonitis, pneumonia, sepsis, UTI,
infectious diarrhea, gonorrhea, otitis, soft tissue
infections (good penetration into lungs, tissue, bone,
and peritoneum)
Active against gram negative organisms, no anaerobe
coverage, little to no strep coverage
Pseudomonas activity notable (better than other FQ)
Levofloxacin
Better gram positive activity including staph, strep and
Enterococcus faecalis
Fluorochinoloni
Effetti collaterali.
Cefalea, nausea/vomito, vertigini.
Tendinopatie e rotture tendinee, artralgie.
Abbassano la soglia epilettogena (CIPRO>LEVO)
Ipoglicemia (gatifloxacina ritirata dal mercato)
Allungamento QT
(Sparfloxacin, Grepafloxacin) > Moxifloxacin, Levofloxacin >
Ciprofloxacin
Riacutizzazione di miastenia gravis
Da evitare nei bambini (possibile accumulo nelle
cartilagini in accrescimento)
Ottimo assorbimento enterico, ma non assumere con
cationi.
Linezolid
Unico rappresentante della classe oxazolinidoni
Meccanismo di azione: legame con la subunita
23S del ribosoma batterico batteriostatico
Zyvoxid (OS/EV) 300mg die fino a 600mg BID
Ottimo assorbimento per OS (biodisponibilita
circa 100%).
Spettro dazione: batteri G+ inclusi MRSA,
VISA, VRSA, VRE. Mycobacterium
tuberculosis
Non attivo contro batteri G-!
Linezolid
Precauzioni: uso concomitante di MAOi, SSRIs,
amitriptilina
Effetti collaterali:
Neuropatia ottica
Mielosoppressione
Acidosi lattica
Neuropatia periferica
Ottima diffusione nei tessuti
Metronidazole
Anaerobic organisms
contain ferredoxins that
can activate
metronidazole to form a
reactive nitro radical
anion that kills by
targeting DNA/other
biomolecules
Treatment examples:
Giardiasis (protozoal
infection)
also used to treat
Clostridium difficile
Giardia lamblia
Metronidazole
Bactericidal, cytotoxic to obligate anaerobes and some
facultative anaerobes
Concentration-dependent killing
Diffuses across bacterial membranes
Essentially 100% bioavailable after oral administration
Reaches very high serum concentrations
Excellent tissue penetration
Penetrates blood-brain barrier to CSF (~45%/100% for -
/+ meningitis)
Good penetration into brain abscesses
Metabolized in the liver
If there is liver impairment, serum concentrations remain high for
extended time
Spectrum of activity: Protozoa and
Anaerobic bacteria
Trichomonas vaginalis (Trich)
Entamoeba histolytica
Giardia lamblia
Clostridium difficile (resistance observed:
alternative is vancomycin (oral))
Gardnerella vaginalis
Helicobacter pylorii
Metronidazole: Adverse reactions
Metallic taste: lasts the duration of therapy
Disulfram-like reaction
Avoid alcohol for at least 3 days after last dose
Rare peripheral neuropathy
Seizures
Urine darkens
Drug interactions: in the liver, inhibits
metabolism of phenytoin, warfarin,
carbamazepine, numerous others
Nuovi antibiotici
Gia in uso in Italia:
Tigeciclina
Daptomicina
Quinupristin/Dalfopristin
Gia in fase di sperimentazione
avanzata/commercializzazione:
Ceftobiprole - Ceftaroline
Iclaprim
Dalbavancina, Telavancina, Oritavancina
GLICILGLICINE: Tigeciclina
meccanismo dazione: analogo alle tetracicline; la sua struttura chimica le
permette de superare i principali meccanismi di resistenza che limitano le
tetracicline; attivit batterostatica.
Spettro dazionesimile a quello delle tetracicline ma ulteriormente
allargato. Gram+: attiva sulla maggior parte di questi patogeni, inclusi
MRSA , VRSA, S. epidermidis multiresistente, VRE, pneumococchi
penicillino-resistenti; Gram-: sensibili la maggior parte degli enterobatteri,
compresi ESBL+, Acinetobacter spp., S. maltophilia
abitualmente resistenti P. aeruginosa, Proteus mirabilis e Providencia
spp., difficolt nelleradicazione di Legionella pneumophila.
Effetti collateralidisturbi GE (ridotti dallassunzione a stomaco pieno),
segnalati inoltre cefalea e aumento transitorio delle transaminasi sieriche.
Controindicazionigravidanza, uso nei bambini, IVU.
SINERGISTINE: Quinopristina-dalfopristina
meccanismo dazione: inibizione della sintesi proteica mediante legame con
la sub unit ribosomiale 50S che provoca interruzione dellallungamento
della catena polipeptidica; battericida sulla maggior parte dei cocchi Gram+,
batteriostatico sugli enterococchi.
Spettro dazione Gram+: tutti i ceppi di pneumococco (anche quelli
penicillino-resistenti), molti ceppi di MRSA, la maggior parte dei ceppi di
Enterococcus faecium multiresistenti (insensibili invece E. faecalis e gli altri
Enterococchi), Listeria monocytogenes, Leuconostoc spp., Lactobacillus
spp., Pediococcus spp., Corinebatteri; Gram-: Moraxella catarrhalis e in
minor grado H. influenzae; Micoplasmi, Legionelle.
Effetti collateralifenomeni irritativi in sede di infusione, disturbi GE,
artralgie e mialgie, eruzioni cutanee, eosinofilia piastrinopenia, aumento
transitorio di bilirubina transaminasi sieriche.
Controindicazioninon ne esistono; possibili interazioni farmacologiche
per inibizione del CYP 3A4 (ridotto metabolismo di ciclosporina, midazolam,
inibitori delle proteasi, statine, nifedipina, terfenadina).
LIPOPEPTIDI: Daptomicina
meccanismo dazione: azione a livello della membrana citoplasmatica
batterica cui si lega tramite linserzione calcio-dipendente della sua
componente lipidica; ci determina la depolarizzazione della membrana e la
formazione di canali che facilitano lefflusso di potassio; attivit battericida
dipendente dalla concentrazione.
Disattivata da surfattante: non efficace nelle infez polmonari
Spettro dazione limitato ai Gram+: stafilococchi, streptococchi,
enterococchi (compresi ceppi meticillino- e vancomicino-resistenti); nei
confronti di MRSA attivit battericida pi marcata di quinopristina-
dalfopristina e linezolid; sensibili anche Corynebacterium jeikeium e molti
anaerobi Gram+ (Clostridum spp., Peptostreptococcus spp.,
Propionibacterium acnes); contro enterococchi sinergismo con ampicillina,
gentamicina, rifampicina.
Effetti collateralitossicit muscolare, disturbi GE.
Controindicazionicautela nellutilizzo associato ad altri farmaci che
possono causare miopatia.
Glossario della terapia antibiotica
Spettro dazione: numero di specie batteriche
contro cui un antibiotico attivo
Batteriostatico: antibiotico che inibisce la
crescita batterica
Battericida: antibiotico che uccide i batteri
MIC: minima concentrazione di un antibiotico in
grado di inibire la crescita batterica
MBC: minima concentrazione con effetto
battericida
Glossario della terapia antibiotica (2)
Breakpoint: concentrazione al di sopra della quale
lisolato definito resistente e sotto la quale
considerato sensibile (CONSIDERA EFFETTO IN
VIVO!)
e.g. S < 8mg/L R 8mg/L Breakpoint = 8mg/L
Azione sinergica: combinazione di due antibiotici che
mostra attivit maggiore rispetto alla somma dei singoli
antibiotici
Azione additiva: combinazione di due antibiotici che
somma lattivit dei singoli antibiotici
Azione antagonistica: combinazione di due antibiotici
meno efficace dei singoli antibiotici
M.I.C.
(Minimum Inhibitory Concentration)
La MIC e un parametro generato in vitro
La MIC e specifica per il singolo
antibiotico / classe di antibiotici
La MIC piu bassa non sempre indica
lantibiotico piu efficace!
LA MIC BISOGNA SAPERLA INTERPRETARE!!
M.I.C.
Glossario della terapia antibiotica
Spettro dazione: numero di specie batteriche
contro cui un antibiotico attivo
Batteriostatico: antibiotico che inibisce la
crescita batterica
Battericida: antibiotico che uccide i batteri
MIC: minima concentrazione di un antibiotico in
grado di inibire la crescita batterica
MBC: minima concentrazione con effetto
battericida
Glossario della terapia antibiotica (2)
Breakpoint: concentrazione al di sopra della quale
lisolato definito resistente e sotto la quale
considerato sensibile (CONSIDERA EFFETTO IN
VIVO!)
e.g. S < 8mg/L R 8mg/L Breakpoint = 8mg/L
Azione sinergica: combinazione di due antibiotici che
mostra attivit maggiore rispetto alla somma dei singoli
antibiotici
Azione additiva: combinazione di due antibiotici che
somma lattivit dei singoli antibiotici
Azione antagonistica: combinazione di due antibiotici
meno efficace dei singoli antibiotici
SINERGIA ANTAGONISMO INDIFFERENZA
SENSIBILIT: MIC e
BREAKPOINT
Per definire la sensibilit di uno specifico microrganismo ad uno
specifico antibiotico la MIC di per s non utile, ma deve essere
comparata per esempio alla concentrazione che il farmaco pu
raggiungere nel sito di infezione
Tale parametro considerato nella definizione dei breakpoints
Valori di MIC pi bassi del breakpoint sono da interpretare come
espressioni di sensibilit del ceppo microbico, mentre valori pi alti
come espressioni di resistenza
La farmacocinetica specifica per ogni singolo farmaco, per ogni sito di
infezione, per ogni schema posologico utilizzato, questo comporta che anche
i breakpoints possano essere significativamente diversi. In altre parole, i
medesimi valori di MIC per due farmaci diversi per uno stesso patogeno possono
essere interpretati clinicamente in modo diverso dato che possiedono
breakpoints completamente diversi. In pi, un valore di MIC pi basso di un
antibiotico potrebbe rappresentare un valore di resistenza, mentre un valore pi
alto di MIC di un altro antibiotico potrebbe indicare un valore di sensibilit,
semplicemente a causa dei differenti breakpoints.
Glossario della terapia antibiotica (3)
Batterio resistente: ha MIC maggiore di quella che possibile raggiungere
nei tessuti
Resistenza intermedia vs resistenza completa
Resistenza intrinseca vs resistenza acquisita
Batterio sensibile: lantibiotico raggiunge concentrazioni pari alla MIC nei
tessuti e tale MIC minore del breakpoint
Esempi:
BATT1 (otite), AB1: MIC 0.8mg/L, BP 1mg/L
SENS
BATT1 (otite), AB2: MIC 0.5mg/L, BP 0.4mg/L
RES
BATT1 (meningite), AB1: MIC 60mg/L, BP 50mg/L
RES
BATT1 (meningite), AB1 ad alta dose: MIC 60mg/L, BP 80mg/L
SENS
Breakpoint MIC 0.05 mg/L
http://www.eucast.org/clinical_breakpoints/ http://www.eucast.org/clinical_breakpoints/
Staph aureus
(MRSA)
Pneumococci
(PRSP)
Enterococci
Gonococci
Clostridium
difficile
Corynebactera
E. Coli (ESBL)
Klebsiella (ESBL+CPE)
Salmonella
Pseudomonas
Acinetobacter
Stenotrophomonas
Helicobacter
plus many others
Multi
Multi
-
-
drug resistant bacteria: a rough
drug resistant bacteria: a rough
overview
overview
Principali batteri MDR
Staphylococcus aureus
MRSA modificaz PBPs
VISA altered peptidoglycan
VRSA altered peptidoglycan
Strep
Streptococcus pneumoniae
PRSP PBPs mofification
Enterococcus
VRE PBPs modification (RES to beta-lactam), peptidoglycan
modification (RES to glycopeptides), lytic enzymes (RES to
aminoglycosides), modification of the ribosomal RNA target (RES
to linezolid)
SPACE (Serratia, Pseudomonas, Proteus,
Acinetobacter, Citrobacter, Enterobacter) ESBL,
carbapenemases
MRSA
il pi comune patogeno nosocomiale MDR
Resistenza acquisita mediante gene MecA
Codifica per PBP2a
Proteina inducibile che conferisce resistenza a TUTTI I -LATTAMICI
(scarsa affinit per meticillina e tutti i -lattamici: penicillina,
amoxicillina, oxacillina, cefalosporine, carbapenemi)
Inlcusa entro un elemento cromosomiale che spesso riunisce altri geni
che conferiscono resistenza mediante altri meccanismi: staphylococcal
cassette chromosome (SCCmec)
SCCmec types I, II, and III
Multidrug resistant
Large cassettes
Healthcare associated
SCCmec type IV and type V
Not multidrug resistant
Community associated
Mechanisms of S. Aureus
resistance to antimicrobials
Mechanisms of S. aureus resistance to
vancomycin: VISA vs VRSA strains
VISA VISA
MIC 4-8 mcg/ml
VRSA VRSA
MIC 16 mcg/ml
Hospital-associated MRSA (HA-MRSA) vs
Community-associated MRSA (CA-MRSA)
two genetically distinct variants:
HA-MRSA (~86% of invasive MRSA cases)
Resistant to: beta-lactams, macrolides, aminoglycosides, quinolones, clindamycin
Not as readily spread person-to-person
Recent trends suggest a decline in prevalence (30-50% from 2005 to 2008)
CA-MRSA: (~14% of invasive MRSA cases); probably a genetic hybrid of HA-
MRSA and other
Resistant to beta-lactams, macrolides (somewhat more sensitive to treatment)
More readily spread person-to-person
PVL toxin more common; can cause tissue damage and recurrent disease/infection
Virulence factors (depends on strain):
Exotoxins: e.g. Panton-Valentine Leukocidin (PVL) cytotoxin; necrotic lesions;
PVL gene carried by a bacteriophage hosted by S. Aureus
Protein A: binds host immune proteins to its surface, stealth
Toxin superantigens: lipotheichoic acid (cytokine storm)
Enterotoxins
Alpha-hemolysin toxin
Alters collagen tissues
HA-MRSA
Multiresistant to
Clindamycin
Aminoglycosides
Tetracyclines
Fluoroquinolones
CA-MRSA
Often remains
susceptible to
Clindamycin
Aminoglycosides
Tetracyclines
Fluoroquinolones
Higher association
with skin/soft tissue
infections and severe
necrotizing
pneumonia
Hospital-associated MRSA (HA-MRSA) vs
Community-associated MRSA (CA-MRSA)
Bad Bugs, No Drugs
Gram-positive bacteria
MRSA and VRE
Emergence of vancomycin-resistant S. aureus and
linezolid-resistant Enterococcus
Decreased S. aureus susceptibility to vancomycin
associated with decreased susceptibility to daptomycin
Gram-negative bacteria
Pan-resistant Acinetobacter and Pseudomonas
Colistin/Polymixin E
nephrotoxicity 20-30%
neurotoxicity 7%
Extended-spectrum -lactamase organisms
Clin Infect Dis 2006;42:657-68
http://www.ecdc.europa.eu/en/publications/Publications/antimicro http://www.ecdc.europa.eu/en/publications/Publications/antimicrobial bial- -resistance resistance- -surveillance surveillance- -europe europe- -2012.pdf 2012.pdf
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