Principi Tp Antibiotica 2014

8/11/2019 Principi Tp Antibiotica 2014

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Principi di Terapia Antibiotica

Corso integrato di Terapia Medica

18 Marzo 2014


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Considerazioni generali1. 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


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Considerazioni generali4. Antibiotico

Meccanismo dazione Attivit Spettro dazione

Effetti collaterali Resistenze (comuni o rare) Azione sinergica

Via di somministrazione


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Modalit della tp antibiotica

A. Terapia profilattica

B. Terapia empirica

C. Terapia specifica


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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


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Terapia empirica Nelle infezioni gravi (ad es: polmonite, pielonefrite,

colecistite) dopo aver prelevato gli esami colturali ed inattesa degli esiti: entro 24 ore dalla diagnosi

in alcuni casi molto gravi e/o ad evoluzione fulminante(meningite, infezioni necrotizzanti dei tessuti molli, sepsigrave/shock settico, neutropenia febbrile, sepsi nelsoggetto splenectomizzato):

entro 1-3 ore dalla diagnosi (o dal sospetto diagnostico)

Nelle infezioni non gravi in cui non si ricerchi unadiagnosi eziologica


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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 tolocate the source of infection.

Consider local epidemiological data Empiric antimicrobial choice depends on local susceptibility

patterns. Knowing the resistance profiles in thecommunity,hospital or unit helps in choosing antimicrobialsappropriately.

PRINCIPLES OF EMPIRICAL

ANTIMICROBIAL THERAPY


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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 susceptibilitypatterns. Knowing the resistance profiles in the community,hospitalor 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 theseverity of organ dysfunction. Others

Pregnancy, drug allergy




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3. Antimicrobial profile

Route of administration The intravenous route should always be used in severe

sepsis as oral absorption is unpredictable even in drugs withgood oral bioavailability.

Dose and interval Antibiotics can be categorised into three different classes

depending on the PK/PD indices associated with theiroptimal killing activity.




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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 ripulituradelle pareti con asportazione delle muffe verdeggianti, il bere quellacqua provocava negli utilizzatori enterocoliti. Alriformarsi delle muffe sulle pareti della cisterna lacqua diveniva nuovamente potabile Per ricercare per quanto tempo illiquido.avesse esercitato questo suo speciale potere iniettai le cavie sopravvissero tutte, eccetto quelle iniettate dopo10 giorni, che fecero notare un ritardo nella morte, rispetto ai controlli..Come tale questo liquido ha unazione preventivae terapica. Ho studiato il potere microbicida dei liquidi, ottenuti nel modo innanzi detto, per i bacteri patogeni pi

importanti Risulta chiaro da queste osservazioni che nella sostanza cellulare delle muffe esaminate sono contenuti deiprincipi solubili in acqua, forniti di azione bactericida bactericida..Per queste propriet le muffe sarebbero di forteostacolo alla vita ed alla propagazione dei bacteri patogeni.


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In the pre-antibiotic era, pneumonia was a dreaded killer of the young and a welcomed friend of the very old. Prior to the specifictherapies and antibiotics of the twentieth century many patients were better off if their disease ran its natural course. Thus doingnothing was often the best therapy. This photograph is common of many similar images of physicians, nurses and the family aboutthe bedside.

Waiting Out the Pneumonia Crisis,1895


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ScenarioIn March 1942, a 33-

year-old woman laydying of streptococcalsepsis in a New

Haven, Connecticut,hospital.

NEJM 2009


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Scenario

Despite the best efforts of contemporary medicalscience, her doctors could not eradicate herbloodstream infection.

Then they managed to obtain a small amount ofa newly discovered substance called penicillin,which they cautiously injected into her.

NEJM 2009


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ScenarioAfter 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


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S il d ffi i d ll h i t i ti i biS il d ffi i d ll h i t i ti i bi


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Sviluppo ed efficacia della chemioterapia antimicrobicaSviluppo ed efficacia della chemioterapia antimicrobica(1935(1935 1993)1993)


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Sixty-six years after her startling recovery, a

report described a 70-year-old man in SanFrancisco with endocarditis caused byvancomycin-resistant Enterococcus faecium

(VRE).

Scenario

NEJM 2009


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Despite the administration, for many days, of the

best antibiotics available for combating VRE,physicians were unable to sterilize the patientsblood.

Scenario

NEJM 2009


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He died still bacteremic.Scenario

NEJM 2009


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Clatworthy. Nature Biochem Biol 2007; 3: 541Clatworthy. Nature Biochem Biol 2007; 3: 541--88


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Meccanismi di resistenza Produzione di enzimi che

modificano o distruggonola molecola di antibiotico

Modificazione del sito dilegame dellantibiotico

Escrezione attiva dellamolecola (efflux pump)

Riduzione della

permeabilit dellamembrana


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Acquisizione della resistenza


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Selezione di batteri resistenti


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R i t i t i


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Resistenza intrinseca


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Meccanismi di resistenza specifici


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Meccanismi di resistenza specifici

F tt i h f ilit l di


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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


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Stime CDC


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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)

R i IF WHEN


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Resistance: not IF... WHENMRSA/VRSA example

1940-1946 first-generation penicillins become widely available for treatmentof staphylococcus and streptococcus infections: strept throat pneumonia scarlet fever skin infections wound infections

By the 1950s, S. aureus acquired beta-lactamases (penicillinase) leading toresistance 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 ofmethicillin-resistant S. aureus (MRSA), vancomycin became the front-lineantibiotic

1996 vancomyin-intermediate S. aureus (VISA) emerged

2002 vancomycin-resistant S. aureus (VRSA) identified late-1990s quinupristin/dalfopristin (Synercid) combination approved as anew option

2000 linezolid (Zyvox) approved as a new therapeutic 2003 first cases of resistance to linezolid reported


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MRSA


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End of antibioticsEnd of antibiotics -- the ultimate consequencethe ultimate consequence


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Terapia specifica Basata sullesito di un esame colturale

Solitamente si dispone anche di un test disensibilit in vitro

Con esito dellantibiogramma, scegliere ilfarmaco in base a:

profilo di tossicit / caratteristiche del pz spettro ristretto costi


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Le classi di antibiotici1. Interferenza con la sintesi della parete cellulare

Beta-Lattamici (penicilline, cefalosporine, carbapenemi,

monobattami) Glicopeptidi Polipeptidi Alcuni agenti antimicobatterici

2. Interferenza con la sintesi proteicaAzione su 30S ribosomiale Aminoglicosidi Tetracicline

Azione su 50S ribosomiale Cloramfenicolo Macrolidi Clindamicina Streptogramine

Oxazolidinoni


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3. Inibizione della sintesi degli acidi nucleiciAzione 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

FARMACODINAMICAHow antibiotics kill bacteria: from targets to networks. 2010 Nature Reviews


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Microbiology 8, 423-435


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Farmacocinetica di un


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Farmacocinetica di un

antibioticoDescrive i processi fondamentali dellorganismo

sul farmaco:AssorbimentoDistribuzioneMetabolismoEliminazione

Farmacodinamica di un


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Farmacodinamica di un

antibioticoDescrive leffetto fisiologico di una molecola sul

microorganismo allinterno del corpo, nonche ilsuo meccanismo di azione

Stretta relazione con la farmacocinetica

Concentrazione plasmatica di un antibiotico


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dopo una singola somministrazione

LA PRIMA SOMMINISTRAZIONE DI QUALSIASI ANTIBIOTICO INQUALSIASI PAZIENTE E SEMPRE A DOSE PIENA!

Plasmatic concentration of an antibiotic after


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Plasmatic concentration of an antibiotic after

a single iv dose

Conc

entration



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Co ce t a o e p as at ca d u a t b ot co

dopo una singola somministrazione

Pharmacokinetic parameters


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MIC: minimum inhibitory concentration

AUC: area under the curve

Cmax: maximum concentration (tissuespecific)




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CONCETR

ATION

(mg/d

L)

TIME (hour)

MIC

Antibiotic Pharmacokinetics


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CONCETR

ATION

(mg/d

L)

TIME (hour)

AUC

Cmax



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ANTIMICROBIAL KILLING IS DEPENDENT ON BOTH THECONCENTRATION 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, theantimicrobial is said to be CONCENTRATIONDEPENDENT andbactericidal effects are associated with an optimal free drug maximumconcentration to MIC ratio

(ffCmax/MICCmax/MIC).

When the effect of time is greater, the antibiotic displays TIME

DEPENDENT antibiotic activity, and bacterial outcomes are associatedwith free drug concentrations above the MIC for a defined portion of thedosing interval, or time above the MIC

(fT>MICfT>MIC)


Pharmacokinetic composite


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AUC > MIC

Cmax/MIC

Time > MIC

parameters



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parameters

CONCETR

ATION

(mg/d

L)

TIME (hour)

MIC

Time>MIC

E.G.: blactams, vancomycin, some macrolides, tigecycline, clindamycin



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parameters

CONCETR

ATION

(mg/d

L)

TIME (hour)

MIC

Cmax/MIC

E.G.: aminoglycosides, daptomycin, metronidazole, colistin, (fluoroquinolones)


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parameters

CONCETR

ATION

(mg/d

L)

TIME (hour)

MIC

AUC>MIC

E.G.: fluoroquinolones


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Pharmacodynamics and pharmacokineticsPharmacodynamics and pharmacokinetics


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PENICILLINSPENICILLINSCEPHALOSPORINSCEPHALOSPORINS

CARBAPENEMSCARBAPENEMS

GLYCOPEPTIDESGLYCOPEPTIDESERYTHROMYCINERYTHROMYCIN

TIMETIME--dependentdependent killing +killing +short or no PAEshort or no PAEPDPDPKPK correlationcorrelation: T> MIC: T> MIC

TIMETIME--dependentdependent killing +killing +

prolonged PAEprolonged PAEPDPDPKPK correlationcorrelation : T> MIC: T> MIC

ProlongProlong exposure time:exposure time:maintainmaintain serumserum levelslevels> MIC (short> MIC (short intervalsintervalsoror continuouscontinuous infusion)infusion)

ProlongProlong exposure time:exposure time:

serumserum levelslevels mightmight bebe< MIC (short< MIC (short intervals)intervals)

AMINOGLYCOSIDESAMINOGLYCOSIDES

FLUOROQUINOLONESFLUOROQUINOLONESCLARITHROMYCINCLARITHROMYCINAZITHROMYCINAZITHROMYCIN

CONCENTRATIONCONCENTRATION--

dependentdependent killing +killing +prolonged PAEprolonged PAE

PDPDPKPK correlationcorrelation::peak/MIC or AUC/MICpeak/MIC or AUC/MIC

Achieve highAchieve high serumserum andand

tissuetissue concentrationsconcentrations(high(high doses, longdoses, longintervals)intervals)

Antibiotic Pharmacodynamics Dosing regAntibiotic Pharmacodynamics Dosing regimenimen

y py p

Ccorrelation and clinical significanceCcorrelation and clinical significance


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Parametri farmacocinetici


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Parametri farmacocinetici

Key message:


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Post-antibiotic effect Persistence of effect (inhibition of growth

or killing) after drug removed (or levelbelow MIC)

PAE + pharmacokinetics affects dosingstrategy

Post-antibiotic effect (PAE)


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Post antibiotic effect (PAE)

Nutrient broth

*

*Bacteria

* A

* AAntibiotics



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ost a t b ot c e ect ( )

Centrifuge Decant

*

*Resuspend

A A

* * * *



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( )

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



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( )

1

10

100

1000

10000

0 1 2 3 4 5 6

Time (hours)

Removal ofAntibioticRemoval ofAntibiotic

ViableCo

unt(cfu/ml)

Control

1.6 hours to increase 1 log10

1 log10 increase

3.1 hours to increase 1 log10

AntibioticInduced death

PAE = 3.1 - 1.6 = 1.5 hoursDue to antibiotic effect onlyPAE = 3.1 - 1.6 = 1.5 hoursDue to antibiotic effect only

Persistent effect


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Bacterial killing/persistent effect

Drugs Therapy Goal PK/PDmeasurement

Concentrationdependent /prolongedpersistent effect

Aminoglycosides;daptomycin;ketolides;quinolones; metro

High peak serumconcentration

Cmax/MIC(24-hr AUC/MICfor quinolones)

Time dependent /no persistenteffect

Beta-lactams andmonobactams

Long duration ofexposure

Time above MIC

Time dependent /moderate to longpersistent effect

Clindamycin;macrolides;linezolid;tetracyclines;vancomycin;dalfopristin-

quinpristin

Enhanced amountof drug

24-hr AUC/MIC


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Correlazioni PK/PD: beta-lattamici

Exp. Opin. Pharmacother. 2000;1: 1203-1217

Optimizing Antimicrobials in the ICU:Continuous/Prolonged Infusions of Beta Lactams


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g

Cefotaxime vs Klebsiella in mouse lung model

Farmacodinamica degli


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aminoglicosidi in vivo

Moore et al, J Infect Dis 155: 93, 1987

Modelli di attivit battericida


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Curve di time-killing per P. aeruginosa

W.A. Craig et al., 1991, modified

0 2 4 6 80

2

4

6

8

10

0 2 4 6 80

2

4

6

8

10

0 2 4 6 80

2

4

6

8

10

64xMIC

16xMIC

4xMIC

MIC

1/4xMICControl

Tobramicina Ciprofloxacina Ticarcillina

CONCENTRAZIONE-DIPENDENTE TEMPO-DIPENDENTE

Tempo(hr)

Once-daily vs. Conventional Three-times


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Daily AminoglycosideRegimens

NicolauDP et al. AntimicrobAgents Chemother. 1995;39:650655

Vancomycin Outcome vs 24h-


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AUC/MIC ratio

24h-AUC/MICratio

Satisfactory Unsatisfactory

< 125 4 (50%) 4

> 125 71 (97%) 2

Hyatt et al, Clin Pharmacokinet 28: 143, 1995


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Factors which can influence


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therapeutic outcomeBacterial HumanInhibitory activity

absorptionSubinhibitory activity distributionConcentration-dependent

activity

metabolism

Time-dependent activity excretionBactericidal/bacteriostatic

activityprotein-binding

Post-antibiotic effect

Resistance

Oral Absorption of AntibioticsOral Absorption of Antibiotics

GoodGood:: sulfonamides


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chloramphenicol

clindamycin

trimethoprim

isoniazid, pyrazinamide

quinolonesdoxycycline

cycloserine

metronidazole

linezolid

Bad or variableBad or variable::

penicillins (some are, many arent)

cephalosporins (few are, most are not)

erythromycin (estolate conjugate)(clarithromycin is better)

UglyUgly:: aminoglycosides:

gentamicin

tobramycin

amikacin

netilmicinvancomycin

quinupristin/dalfopristin

meropenem

Therapeutic levels in theTherapeutic levels in the

b i l fl id?b i l fl id?


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cerebrospinal fluid?cerebrospinal fluid?GoodGood::ciprofloxacin

sulfonamides, trimethoprim

chloramphenicol

some 3rd generation cephalosporins

(e.g. ceftriaxone, ceftizoxime)

meropenem

cycloserine, metronidazole

pyrazinamide, isoniazidlinezolid

OKOK::(esp. when meninges inflamed)

ampicillin, ticarcillin

vancomycinrifampin

PoorPoor::

aminoglycosidesaminoglycosides

tetracyclinestetracyclinesclindamycinclindamycin

erythromycinerythromycin

cefaclorcefaclor

quinupristin/dalfopristinquinupristin/dalfopristin

(synercid)(synercid)

INTERRELATIONSHIP OF HYDROPHILICITY ANDLIPOPHILICTY OF ANTIBIOTICS ON THEIR

CO C C C S CS


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PHARMACOKINETIC CHARACTERISTICS

Condizioni parafisiologiche


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Sepsi



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Ustionati



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Obesi

General concept:

P i bi di


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Protein bindingx x x

x x xx x x

x x x

x x x

x x x

80%80%

Extensive protein binding


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Good: Allows slow, steady release of heavilybound drug, e.g. ceftriaxone

Bad: since less free drug available forbacteria, e.g. ceftriaxone


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Penicilline


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Derivate da Penicilliumchrysogenum.

PNC G e PNC V sonoprodotti non modificatidella fermentazione diPenicillium.

I derivati semisinteticisono creati aggiungendouna catena R alla

struttura base dellanellobetalattamico.

PENICILLINS


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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 anduninflammed meninges)

Beta Lattamici


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B-lattamici inibiscono latranspeptidasi (PBP).

Effetto su batteri in rapida

crescita che sintetizzanoparete 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

Struttura della parete cellulare

batterica


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A.Gram + B. Gram -

batterica


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Penicilline Naturali


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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


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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 duenot due

to betato beta--lactamaselactamase

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 betanot 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 inflammation

Neisseria gonorrhoeae however is now resistant due to beta-lactamases Enterobacteriaceae, Pseudomonas, H. influenzae: resistant


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Will we ever find a cure for penicillin?


THE ANTIBIOTIC TIMELINE


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Clatworthy. Nature Biochem Biol 2007; 3: 541C at o t y atu e oc e o 00 ; 3 5 88


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-lattamasi


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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, GRAMSTAFILOCOCCHI, GRAM--NEG e ANAEROBINEG e ANAEROBI

-lattamasi


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Penicilline Anti-Stafilococciche Meticillina nafcillina oxacillina cloxacillina e


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Meticillina, nafcillina, oxacillina, cloxacillina edicloxacillina.

Resistenti alla degradazione ad opera dellepenicillinasi stafilococciche.

Mirate nei confronti di S. aureus, non efficaciverso gli streptococchi (Streptococco NONPRODUCE BETA-LATTAMASI!).

Meticillina non pi usata (tossicit). Oxacillina farmaco di scelta Breve emivita NOT FOR: MRSA, Methicillin-resistant

Staphylococcus epidermidis (MRSE) orENTEROCOCCI (Enterococchi NONPRODUCONO BETA-LATTAMASI!).

Attualmente in forte aumento ceppi MRSA!!


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Anti-staph penicillinase resistant

penicillins: clinical uses 1) Staphylococcal Infections


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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 (butStaph. epi . is not a invasive or virulent).

Staphylococci cause skin infections (impetigo), abcesses in many

organs, pneumonias, prosthetic joint, catheter, and artificial valveinfections, 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 lesseffective than natura penicillins againsta streptococci)

Aminopenicilline

(penicilline a spettro esteso)


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(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 Staphylococcusepidermidis(MRSE) or ENTEROCOCCI

DO NOT USE if beta-lactamase (penicillinase)producing Gram-neg strains

NB: Aminopenicillins should not be prescribed for patients suffering from tonsillitisuntil infectious mononucleosis has been excluded. Patients with mononucleosisreadily develop severe maculopapular exanthema even after a few tablets ofaminopenicillin. 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

ddi i l i i h i id h i i h i id h li i d ll h


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additional aminogroup in their side chain increases their idrophylicity and allow themto 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, manyGram-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 significant penicillinase production now, resistant

H. influenzae ~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) Significant enterohepatic recycling : unmodified 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.difficile overgrowth.


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-lattamasi


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Bush, Jacoby, Madeiros Classificationof -Lactamases


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Combinations with beta-

lactamase inhibitors Two combinations are available, both for oral and parenteral administration:i illi lb


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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 theaminopenicillins

NB: These antibiotics are needless and should not be prescribed againststreptococci, 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 tractinfections, 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 disposeplasmide-transmitted lactamases that can be inhibited with sulbactam, clavulanic acid or

tazobactam. However these inhibitors do not work against lactamases produced by majorityof nosocomial pathogens.

2) Beta-lactamase inhibitors possess weak, if any, natural antibacterial activity. From generalpoint of view, minimal clinically important difference exists between these three drugs.

Combinations with beta-

lactamase inhibitors Inclusion of beta-lactamase inhibitor increases


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c us o o beta acta ase b to c easescoverage of Gram- to also include:

M. catarrhalis (otitis media, pneumo, sinusitis) H. influenzae (otitis media, pneumo, sinusitis) S. pneumoniae (otitis media, pneumo, sinusitis) MSSA

Klebsiella Enterobacter E. coli N. gonorrhoeae

Good activity against anaerobes


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Aminopenicillins +beta-lactamase inhibitors:

clinical uses


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Otitis media, sinusitis, and respiratory tract infections(acute exacerbations of bronchitis or

chronic obstructive pulmonary disease (COPD) due to b-lactamase producing H. influenzae & Moraxellacatarrhalis.

High doses recently approved for otitis media due toStrep. 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, piperacillinP l id h i hi h ll t t ti i t G


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Polar side chain which allow even greater penetration into Gram-neg bacteria (increased ability to pass through the outer membraneporins)

More resistant to cleavage by Gram-neg beta-lactamases thanaminopenicillins

More active against Gram-neg bacilli, including many strains of P.Aeruginosa

Maintain Gram-pos activity of natural penicillins but (like naturalpenicillins) 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


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1. Pseudomonas aeruginosa infections(often with aminoglycosides)

2. Mixed infections - good gram negativeactivity, 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


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piperacillin + tazobactam The fullest antimicrobial potential of the penicillins has

been achieved by combining extended-spectrumpenicillins 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


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ANTIPSEUDOMONAL PENICILLINS+ BETA LACTAMSE INHIBITORS: Clinical uses

Extends spectrum towards b-lactamase-producing Enterobacteriaciae &Pseudomonas. For Pseudomonas infections, often combined with aminoglycosides.


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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 Klebsiellapneumoniae, 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 thecausative 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 elevatoindice terapeutico


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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): evitaretutte le altre penicilline. Raramente crisi comiziali

accumulo in pz con insuffrenale

Infusione ev troppo rapida Soggetti predisposti


THE ANTIBIOTIC TIMELINE


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Cefalosporine

Derivati B-lattamici semisintetici ottenuti


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aggiungendo diverse catene laterali allacido

aminocefalosporanico

pi resistenti alle beta-lattamasi rispetto apenicilline naturali.

Cefalosporine


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Ceftazidime

La catena laterale conferisceprotezione sterica dallazionedelle beta-lattamasi

Cefalosporine

Reazioni avverse


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5-10% cross-reattivit

negli allergici allepenicilline 1-2% reazione da

ipersensibilit neipazienti non allergicialle penicilline(soprattutto per I e II

generazione). Spettro dazione

ampio infezioniopportunistiche!

CEPHALOSPORINS Cephalosporin generations: generally get broader, more Gm- coverage

with later generationsG ti 1 G ll h d b tt G th G ti it tibl t


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Generation 1: Generally had better Gram+ than Gram- activity; susceptible tomany 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, betterpenetration; pick up some anti-Pseudomonal activity (Ceftazidime), give up someGram+ coverage (Ceftazidime: limited activitv against S. Aureus)

Examples: Cefpodoxime, Cefdinir, Cefixime, 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)

CefalosporineCefalosporine

Classificazione per generazioniClassificazione per generazioniGenerazioneGenerazione AttivitAttivit relativa su specierelativa su specie


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ppbatterichebatteriche

GramGram--positivepositive GramGram--negativenegative

PrimaPrima ++++++++ ++

SecondaSeconda ++++++ ++++

TerzaTerza ++ +++*+++*

QuartaQuarta ++++ ++++**++++**

* In parte attive anche su* In parte attive anche su P. aeruginosa;P. aeruginosa; ** molto attive su** molto attive su P. aeruginosaP. aeruginosa

Cefalosporine


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IIIa Generazione

Spettro: gram negativi > grampositivi


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positivi.

Ceftriaxone (Rocefin; IM/EV) Molto efficace sia contropneumococchi (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).Th i t f th i l d b t i i i d


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Their spectrum further includes corynabacteria, meningococci, andsome community-acquired stems of gram-negative rods likeEscherichia coli or Proteus mirabilis.

The drugs are active against anaerobes in the extent similar topenicillin. 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 (exceptcolorectal 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 similarpatogens


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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 totrue 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, footinfections in diabetics, infected decubitus ulcers and other mixed aerobic-anaerobic infections. Unfortunately, resistance to cefoxitin raises quickly indepartments 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)


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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 relevantclinical diagnoses are purulent meningitis, epiglotitis, sepsis of urinary or hepatobiliary tract originetc.

Ceftriaxone is an antibiotic of extreme long half-time (8 hrs) in addition that allows once-dailyadministration. This feature makes the treatment easier but is of particular importance in treatmentof 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 ormoderate community acquired infections but cephalosporines of 2nd generation suffice in thesesituations usually. The only rational indication remains infection caused by pathogens ofmicrobiologically verified intermediate sensitivity where 2nd generation cephalosporins performonly 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 theactivity 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 ispredominant excretion via the bile: this advocates for its usage in hepatobiliary tract infections andin 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 problematicpathogens owing beta-lactamase activity.

CEPH: 4th Gen

Antibiotics of this group have a broad spectrumsummarizing the 1st, 2nd and 3rd generation.


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They can resist some potent beta-lactamases.Nevertheless, their activity against staphylococci is notbetter than with cephalotin and activity againstPs.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 nosocomialsepsis of unknown origin where covering the broad

spectrum of pathogens is necessary (i.e. febrileneutropenia).


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Ceftobiprole


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Carbapenemi Imipenem-Cilastina (Imipem EV), meropenem (Merrem EV) Cilastina: inibitore della deidropeptidasi previene la formazione

di un metabolita nefrotossico. Antibiotici betalattamici con spettro pi ampio


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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 Pseudomonasraccomandata 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 utilizespecial porins in the outer membrane of Gm-neg bacteria

Structure resistant to cleavage by most beta-lactamases


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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 ofgram-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 nosocomialinfections/sepsis.


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Monobattamici

Aztreonam (Azactam; IM/EV;) Resistente alle beta-lattamasi.


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Spettro antibatterico ristretto. H. influenzae, N. gonorrhea(produttori di penicillinasi), E.coli, Klebsiella, Proteus,

Pseudomonas. Inattivo verso I Gram + e gliInattivo verso I Gram + e glianaerobi.anaerobi.

Non cross-reazione nei pz

allergici alle penicilline!


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Vancomicina

Glicopeptide triciclico Streptomycesorientalis.


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Inibisce la sintesi della parete battericalegandosi alle catene di peptidoglicanoin allungamento e prevenendo il cross-linking.

Attivo verso i Gram +, compresiMRSA, MDRSP, enterococchi, Staph.epidermidise clostridi.

Sinergico con AG. Azione: battericida

Vancomicina


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Vancomicina

Resistenza: Ridotta permeabilit. Cambiamento negli aminoacidi del peptidoglicano


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(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 livelliplasmatici

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-


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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 betweenvancomycin 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 offurther intravenous administration etc. Because of its long half-time, teicoplanin is useful for the outpatient

therapy.

Effetti collaterali dei glicopeptidiEffetti collaterali dei glicopeptidi

FrequenzaFrequenzaTipoTipo VancomicinaVancomicina TeicoplaninaTeicoplanina

TromboflebiteTromboflebite ++++++ ++++


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NefrotossicitNefrotossicit ++++++ --Rash cutaneoRash cutaneo ++++ ++++

NeutropeniaNeutropenia ++++ ++++

OtotossicitOtotossicit ++ --SindromeSindrome red manred man ++++++ --

Disturbi gastrointestinaliDisturbi gastrointestinali -- ++++

EpatotossicitEpatotossicit -- +++++++ = 5+++ = 5 -- 10%; ++ = 210%; ++ = 2 -- 4,9%; + = < 2;4,9%; + = < 2; -- = assente= assente

Vancomicina


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Aminoglicosidi


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Aminoglicosidi Streptomycin

Isolated in 1943 by Selman Waksman from Streptomyces griseus Breakthrough drug for treatment of tuberculosis (Mycobacterium

tuberculosis)


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Gentamicin Isolated in 1963 from Micromonospora purpurea (mycin only if fromStrep.)

Significant use in treatment of Gram- infections includingPseudomonas

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 higherconcentrations)

Premature termination of translation Incorporation of incorrect amino acid leading to nonsense proteins.


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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-dependentactivebacterial 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 ofaminoglycoside 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.


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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 renalfunction.

Toxicity may develop even with conventional doses, particularly in patients with prerenal azotemiaor impaired renal function.

Nephrotoxicity


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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; leadingto 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


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PEAK LEVEL (see optimal values above) efficacy measured one hour after an infusion begins; TROUGH LEVEL (optimal:


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to respect a maximal treating period of2-3 weeks, than a pause should followof minimum 4-6 weeks

to prefer once-daily administration(except infective endocarditis wheremultiple daily doses are preferred)

while intravenous infusion, the time of

administration should be 30-45 minutes(the period more then 1 hour enhancesnephotoxicity, the period less then 20minutes enhances the risk ofneuromuscular blocade)

to monitor renal (CREATININE) andauditive functions three times weekly

to measure serum levels ofaminoglykosides (especially theTHROUG serum level)

*advanced age, persistently high trough serumlevels, duration of therapy, hypotension, concomitantliver 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)


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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, oftencombined 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 onlyReserved 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


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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 themassive bacterial load.

b) severe infections caused by semi-resistant microbes when monotherapy is notbactericidal: 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.


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Aminoglicosidi Compared to other antibiotics, resistance to aminoglycosides is rare Primarily mediated by enzymatic modification of the OH and NH2

groups Phosphorylation Acetylation


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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


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Tetracicline


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Tetracicline First tetracycline isolated 1945 from Streptomyces aureofaciens, chlortetracycline

(though apparently the Egyptians 1600 years ago may have benefitted fromtetracyclines in their beer and bread).

Tetracycline is derived from Streptomyces Minocycline and doxycycline are newer sintetic molecules (longer half-life, better oral

absorption)Ri b i i i i d h h ki i i b


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absorption) Ring substitutions to positions 5, 6, and 7 change pharmacokinetic properties, but notspectra 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.


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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)


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g (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, andureaplasmata. 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, inclusionconjuctivitis 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

TETRACYCLINES:CLINICAL USE


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3) Rickettsial infections: Q fever, ehrlichiosis, typhus fever etc. (Alternative drug ischloramphenicol)

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 drugsare fluoroquinolones.)

6) Mild to moderate infections caused by anaerobes: acne, actinomycosis, some pelvicinflammatory diseases. (Alternative drugs are lincosamides and other antibiotics effective againstanaerobes.)

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 ofsuccessful treatment with various antibiotics) is not known.

DUE TO RELATIVELY FREQUENT RESISTANT ISOLATES (G+ and G-),THEY ARE NOT INDICATED FOR EMPIRIC TREATMENT OF SEVEREINFECTIONS

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 notreabsorbed


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Fanconi syndrome: numerous small molecule nutrients are notreabsorbed 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


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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 microbeStreptomyces 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-)


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g, y g ( , , )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 aconsequence 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


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pa as tes suc as C a yd a) penetrates poorly into CNS, synovial fluid and fetal tissues Oral bioavailability: variable

Erythromycin (not acid stable) ~25%, should be taken on emptystomach

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 serumconcentration is extremely low.

Macrolides: spectrumand 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)


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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 otherantibiotics) etc.

NB: Except legionellosis, macrolides should not be used for treatment severe infections. Their prescriptionmust 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

A ith i


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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


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Methylation of ribosome binding site via erm (erythromycin ribosomalmethylation) 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


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http://www.ecdc.europa.eu/en/publications/Publications/antimicrohttp://www.ecdc.europa.eu/en/publications/Publications/antimicro bialbial--resistanceresistance--surveillancesurveillance--europeeurope--2012.pdf2012.pdf


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Resistenza dello pneumococco


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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)


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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)


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SULFA DRUGSFolic Acid Pathway Inhibitors


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SULFA DRUGSFolic Acid Pathway Inhibitors

SULFONAMIDES, TRIMETHOPRIMSULFONAMIDES, TRIMETHOPRIM

selective toxicity:selective toxicity:

sulfonamides: animal cells do not make folate, wesulfonamides: animal cells do not make folate, weabsorb it from the environmentabsorb it from the environment


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trimethoprim: has much higher affinity for thetrimethoprim: has much higher affinity for thebacterial DHFR than the mammalian DHFRbacterial DHFR than the mammalian DHFR

(1:50.000(1:50.000100.000)100.000)

co-trimoxazole = trimethoprim + sulfamethoxazole TMP/SMX (ratio 1:5)

TMP-SMX

SMX is a PABA analog thatbinds to dihydropteroatesynthase (synthatase) andprevents it from using PABA

TMP binds to and inhibitsdihydrofolate reductase


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Depleting folic acid hinders theeventual production of DNA sobacteria are unable toreproduce

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 tohigher levels in tissue than SMX, so 1:5


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higher levels in tissue than SMX, so 1:5(SMX:TMP) ends up ~1:20, which is optimal forsynergy

Both penetrate to CSF and across and placentalbarrier

SMX gets acetylated in the liver, TMP is

excreted in urine unchanged

Synergistic combinations ofTrimethoprim & Sulfamethoxazole

(Bactrim) Staph sensitivity Sulfamethoxazole MIC = 3 ug/ml Trimethoprim MIC = 1 ug/ml combo MIC = 0.3 Sulf & 0.015 Trim


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20:1 ratio most effective20:1 ratio most effective

Advantages more likely to be cidal broader spectrum decreased resistance lower doses = lower toxicity


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TMP-SMX: clinical uses

severe diarrheal diseases with fever (especially ifsalmonella is expected to be the cause) urinary tract infections (if local E. Coli resistant rates


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However, co trimoxazol is rather a drug of second choice formost of these infections because safer and/or more effectivealternatives 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 andmay increase blood levels of unconjugated bilirubin Kernicterus (can notbe 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


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Clearance is throug hepatic acetylation Slow acetylators have a higherrisk 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%)


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Fluorochinoloni

Ciprofloxacina (Ciproxin; OS/EV) Levofloxacina (Tavanic; OS/EV) Moxifloxacina (Avalox; OS).

Derivati sintetici dellacido nalidixico


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Derivati sintetici dell acido nalidixico.

Azione: battericida. Agiscono sia su microorganismi in fase di

crescita che in fase stazionaria

Alta concentrazione nelle urine e ottimapenetrazione nei tessuti


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Inibiscono le DNA girasi etopoisomerasi IV: blocco del processodi duplicazione e trascrizione del DNA

Resistenza ai fluoroquinoloni

Mutazione della DNA Girasi (comune) Efflux-pump

Riduzione del numero di porine ridottoingresso intracellulare.


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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


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a , s s , a g

Fluorochinoloni antipseudomonas (ciprofloxacin/ofloxacin)

Attivi contro Pseudomonas, H. flu, M. cat. Strep pyogenes, Strep pneumoniae, eMRSA sono resistenti. In profilassi nei pz con fibrosi cistica. Formulazione topica.

Levofloxacina e Moxifloxacina hanno attivit anche

verso ceppi di Staphcipro-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


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Active against gram negative organisms, no anaerobecoverage, little to no strep coverage

Pseudomonas activity notable (better than other FQ) Levofloxacin

Better gram positive activity including staph, strep and

Enterococcus faecalis


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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


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(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 concationi.

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

Otti bi t OS (bi di ibilit


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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


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Mielosoppressione Acidosi lattica Neuropatia periferica

Ottima diffusione nei tessuti


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Metronidazole

Bactericidal, cytotoxic to obligate anaerobes and somefacultative anaerobes

Concentration-dependent killing Diffuses across bacterial membranes Essentially 100% bioavailable after oral administration Reaches very high serum concentrations

E ll t ti t ti


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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

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Principi Tp Antibiotica 2014