Antibiticos

Faculdade de Medicina de Lisboa Farmacologia Manuel Caneira

Aspectos Histricos
Pasteur e Joubert, 1877
Reconheceram a possvel utilidade de microorganismos com fins teraputicos Constataram que crescimento de Bacillus antrax era inibido por bactrias comuns A vida destroi vida entre as espcies inferiores

Aspectos Histricos
Era Moderna
1936: sulfonamidas (sulfanilamida) 1941: penicilina (disponvel para primeiros ensaios)

Actualmente cerca de 30% dos doentes hospitalizados recebem antibiticos Provavelmente a classe de frmacos mais frequentemente utilizada incorrectamente

Aspectos Histricos
Definio
So substncias qumicas produzidas por diversas espcies de microorganismos (bactrias, fungos, actinomicetes) que suprimem o crescimento de outros microorganismos e eventualmente os destroem
Actualmente extensvel a substncias sintticas e semi-sintticas

Sensibilidade e resistncia
Antibitico

Hospedeiro

Infeco

Sensibilidade e resistncia
Defesas de hospedeiro adequadas
Agente becteriosttico

Defesas de hospedeito inadequadas

Agente bactericida

Factores de hospedeiro
Podem determinar tipo de antibitico, via, riscos e eficcia
Mecanismos de defesa
Efeito bacteriosttico (defesas integras) Efeito Bactericida (imunocomprometidos, endocardite) Efeito nas defesas

Factores de hospedeiro
Efeitos locais
Ps: liga aminoglicosdeos e vancomicina Hematomas: dominuem actividade de penicilinas e tetraciclinas pH baixo: diminui actividade de aminoglicosdeos, clindamicina e eritromicina Anaerobiose: diminui actividade de aminoglicosdeos Vascularizao: reduzida em abcessos (drenar) Corpos estranhos: desgranulao de fagocitos, aderncia por glicoclix

Factores de hospedeiro
Idade
Metabolismo e excreo reduzidos
Recm nascido: sndrome de beb cinzento ao cloranfenicol Idoso: toxicidade renal e auditiva aos aminoglicosdeos

Acloridria: em crianas e idosos aumenta a absoro de penicilina e reduz de cetoconazol Metabolismo sseo e dentrio: tetraciclinas podem provocar retardamento de crescimento e descolorao e hipoplasia de esmalte

Factores de hospedeiro
Deficincia de glicose-6-fosfato desidrogenase
Sulfonamidas, cido nalidxico, cloranfenicol

Acetiladores rpidos
Nveis sub-ptimos de isoniazida

Gravidez
Toxicidade fetal: estreptomicina (surdez), tetraciclinas Toxicidade na grvida: necrose heptica, pancreatite, leso renal

Lactao
Dficite de G-6-P-D com hemlise no lactente Kernicterus com sulfonamidas

Factores de hospedeiro
Alergias Sistema nervoso
Convulses (penicilina G) Bloqueio neuromuscular: aminoglicosdeos, polimixina, colistina
Anestesia, mistaenia gravis

Factores farmacocinticos
Local da infeco Ligao a protenas Polaridade do frmaco
Aminoglicosdeos

Metabolismo e excreo
Heptico (eritromicina, cloranfenicol) Renal (amoniglicosdeos)

Forma de administrao
Oral Parentrico (blus/contnuo)
Habitualmente casos mais graves

Seleco de agente antimicrobiano

Teraputica emprica Teste de sensibilidade microbiana
Difuso em disco (Kirby-Bauer)
Semiquantitativo Econmico

Diluies seriadas em agar ou meio lquido

Quantitativo
Concentrao inibitria mnima (MIC) Concentrao bactericida mnima (MBC)

Teraputica definitiva
Agente mais activo e menos txico

Sensibilidade e resistncia
Sensvel
Quando a concentrao para o sucesso teraputico possvel abaixo de nveis txicos

Resistente
Quando a concentrao necessria para matar ou inibir o crescimento superior aquela que pode ser administrada com segurana

Janela teraputica
Larga: penicilina/estreptococo beta hemoltico Estreita: Pseudomonas aeruginosa /gentamicinaa ou tobramicina

Defining Resistance
Dose response of clinical outcomes and MIC

In vitro MIC of infecting organism

Resistncia adquirida
Mecanismos variam
Frmaco Bactria Local Tempo

Mutations are central to the growth of antibiotic resistance

http://www.ideacenter.org/contentmgr/showdetails.php/id/1096

Methods of Antibiotic Resistance

a.) pumping out of antibiotic prior to reaching target b.) enzymatic degradation of antibiotics
c.) enzymatic alteration of antibiotics
http://www.paratekpharm.com/i_mechanism.html

Resistncia adquirida
Mutao Transduco Transformao Conjugao

Resistncia adquirida
Mutao
Randomizado Presena de mecanismo de seleco nica fase Vrias fases

p.e. E.coli ou E. aureus com RNA-polimerase DNAdependente na presena de rifampicina P.e. gonococos

Alterao da virulncia

S.aureus resistente rinfampicina produz menos catalase sendo menos resistente no meio ambiente N.gonorrhoeae menos virulenta E.aureus produtor de penicinilasde mais virulento

Resistncia adquirida
Transduco
Bacterifago portador de DNA Bactria infectada resistente e transmite descendncia Importante no E.aureus (plasmdeos codificadores de penicinilase)

Transformao
Envolve incorporao de DNA livre no meio na bactria Desconhece-se a importncia real

Resistncia adquirida
Conjugao
Passagem de material gentico por pilus Importante nas resistncias mltiplas Importante nos Gram negativos Pode ter lugar no tubo digestivo entre bactrias patognicas e no patognicas Consiste na transmisso de duas sequncias de DNA contidas em plasmdeos separados ou num s Transposon: conjunto de genes ladeado por sequncias de insero que lhe permite saltar dentro do material gentico
Determinante R Factor de transferncia

Natural Phenomenon resulting in AR

Quimioterapia combinada

Superinfeco
Evidncia de uma nova infeco durante o tratamento de outra
Supresso do efeito inibitrio da flora endgena (bacteriocinas, competio por nutrientes) Risco aumenta
Alargamento de espectro Durao de tratamento

Classificao Mecanismo de aco

Inibem a sntese ou activam enzimas que interferem com a parede celular causando perde de viabilidade ou lise celular
Penicilinas Cefalosporinas Cicloserina Vancomicina Bacitracina Imidazois

Classificao Mecanismo de aco

Agentes que actuam na membrana celular
Polimixina Colistemetato Nistatina Anfotericina

Classificao Mecanismo de aco

Agentes que actuam sobre a sntese proteica
Cloranfenicol Tetraciclina Eritromicina Clindamicina Aminoglicosdeos Linezolida

Classificao Mecanismo de aco

Agentes que afectam o metabolismo dos cidos nucleicos
Rifamicinas
Inibem RNA-polimerase DNA-dependente

Quinolonas
Inibem sntese e super-enrrolamento de DNA

Antimetabolitos
Sulfonamidas Trimetoprim

-Lactams

-Lactam Characteristics
MOA: All inhibit cell wall synthesis Bactericidal (exception: Enterococcus) Time-dependent killers Short t1/2 Primarily renally eliminated (exceptions: nafcillin, oxacillin, ceftriaxone) Resistance: -lactamase degradation PBP alteration Decreased penetration

Chemical Structure: Allergenicity

Natural Penicillins
Gram-positive

(Penicillin G, Penicillin VK)

Penicillin-susc S. aureus Penicillin-susc S. pneumoniae Group streptococci Viridans streptococci Enterococcus

Gram-negative
Neisseria spp.

Above the diaphragm Clostridium spp. (not difficile)

Anaerobes

Other
Treponema pallidum (syphilis)

Penicillinase-Resistant Penicillins
(Nafcillin, Oxacillin, Dicloxacillin)
Developed to overcome inactivation ability of penicillinase enzyme to S. aureus Gram-positive Methicillin Susceptible S. aureus (MSSA) Group streptococci Viridans streptococci

Aminopenicillins
(Ampicillin, Amoxicillin)
Developed to increase activity against Gram-Negative aerobes
Gram-positive
PCN-Susp S. aureus PCN-Susp S. pneumoniae Group streptococci Viridans streptococci Enterococcus S. pyogenes

Gram-negative
Proteus mirabilis Listeria monocytogenes Salmonella Shigella H. influenzae E. coli

Antipseudomonal Penicillins: Carboxypenicillin

(Ticarcillin) Developed to further increase activity against resistant gram-negative aerobes
Gram-positive marginal Gram-negative Proteus mirabilis Salmonella, Shigella E. coli H. influenzae Enterobacter sp. *Pseudomonas aeruginosa*

Antipseudomonal Penicillins: Ureidopenicillins (Piperacillin)

Developed to further increase activity against resistant gram-negative aerobes
Gram-positive Viridans Strep Group Strep. Enterococcus Gram-negative Proteus mirabilis Salmonella, Shigella E. coli L-H. influenzae Enterobacter spp. *Pseudomonas aeruginosa* Klebsiella spp.

Anaerobes Fairly good activity including Bacteroides spp.

-Lactamase Inhibitor Combos

Developed to gain or enhance activity against lactamase producing organisms Gram-positive Gram-negative MSSA H. influenzae E. coli Anaerobes Proteus sp. Bacteroides sp. Klebsiella sp. Neisseria gonorrhoeae Moraxella catarrhalis

IV conversion to PO
Penicillin to Penicillin Ampicillin to Amoxicillin Oxacillin to Dicloxacillin
Anti-Staphlococcal penicillin dosed QID

Cephalosporins

Cephalosporins by Generation
1st Generation 2nd Generation
Cefaclor1

3rd Generation
Cefdinir 1

4th Generation
Cefepime2

Cefadroxil 1 Cephalexin1

Cefprozil1
Cefuroxime axetil1 Cefotetan3

Cefixime1
Cefpodoxime1 Ceftibuten1

Cefazolin

Cefoxitin3
Cefuroxime sodium

Ceftazidime2
Cefotaxime

Ceftriaxone

1Oral

dosage form available

3Anaerobe

coverage

2Antipseudomonal

activity notable

1st Generation Cephalosporins

Best activity against gram-positive aerobes, with limited activity against gram-negative aerobes
Gram-positive
MSSA Pen-Susp S. pneumoniae Group Streptococci Viridans Streptococci

Gram-negative
E. coli K. pneumoniae P. mirabilis

2nd Generation Cephalosporins

Slightly less active against gram-positive aerobes, but more active against gram-negative aerobes Several have activity against anaerobes
Gram-positive
MSSA Pen-susp S. pneumoniae Group Streptococci Viridans Streptococci

Gram-negative
E. coli K. pneumoniae P. mirabilis H. influenzae M. catarrhalis Neisseria spp.

3rd Generation Cephalosporins

Spectrum of Activity

Less active against gram-positive aerobes, but have greater activity against gram-negative aerobes Ceftriaxone and cefotaxime have the best activity against gram-positive aerobes, including PCN-resistant S. pneumoniae Strong inducers of ESBL production

3rd Generation Cephalosporins

Spectrum of Activity
Gram-negative aerobes
E. coli P. mirabilis M. catarrhalis N. meningitidis Citrobacter spp. Acinetobacter sp. Serratia marcescens K. pneumoniae H. influenzae N. gonorrhoeae Enterobacter spp. Morganella morganii Providential

Ceftazidime only: Pseudomonas aeruginosa

4th Generation Cephalosporins

Extended spectrum of activity
Gram-positives: similar to ceftriaxone Gram-negatives: similar to ceftazidime (including Pseudomonas aeruginosa), also covers betalactamase producing Enterobacter spp.

Stable against -lactamases Poor inducer of ESBLs

IV to PO - Cephalosporins
Cefazolin to Cephalexin
Cheapest price & good palatability but QID dosing may compromise compliance

Cefoxitin to Cefuroxime axetil + Metronidazole Ceftriaxone or Cefotaxime to Cefdinir or Cefixime

Carbapenems

Carbapenems
(Imipenem, Meropenem, Ertapenem)
Most broad spectrum activity amongst all antimicrobials: gram-positive & gram-negative aerobes & anaerobes Meropenem and Imipenem cover P. aeruginosa Ertapenem does NOT cover P. aeruginosa Bacteria not covered by carbapenems:
MRSA VRE Staph. epidermidis C. difficile

Monobactams

Monobactams
(Aztreonam)
E. coli P. mirabilis H. influenzae Enterobacter Providencia Salmonella Pseudomonas aeruginosa

Gram-negatives

K. pneumoniae S. marcescens M. catarrhalis Citrobacter Morganella Shigella

No activity against gram-positives or anaerobes

-Lactams
ADME
Absorption
Distribution
PO forms have variable absorption Food can delay rate and extent of absorption

Metabolism & Excretion

Widely to tissues & fluids CSF penetration: Parenteral PCNs limited unless inflamed meninges Parenteral 3rd & 4th gen cephalosporins, meropenem, & aztreonam penetrate well Primarily renal elmination Nafcillin, oxacillin, ceftriaxone, cefoperazone: via liver ALL -lactams have short elimination half-lives

-Lactams
Adverse Effects
Hypersensitivity 0.4% to 10 %
Mild to severe: rash to anaphylaxis & death Cross-reactivity exists among all penicillins and even other -lactams (5 to 10%) Desensitization is possible Aztreonam does not display crossreactivity with penicillins and can be used in penicillin-allergic patients

-Lactams
Adverse Effects Neurologic: notably high dose PCN & carbapenems
Increased incidence w/ high doses &/or renal
insufficiency Irritability, confusion, seizures

Hematologic

Gastrointestinal

Leukopenia, neutropenia, thrombocytopenia with prolonged therapy (> 2 weeks)

Increased LFTs, nausea, vomiting, diarrhea,

pseudomembranous colitis Especially with nafcillin

Interstitial Nephritis (Type IV hypersensitivity reaction)

Gram positive Bacteria

Gram negative Bacteria

Fluoroquinolones

Fluoroquinolones
(Ciprofloxacin, Levofloxacin, Moxifloxacin)

Novel synthetic antibiotics developed in response to growing resistance

Concentration-dependent bactericidal activity Broad spectrum of activity Improved PK properties excellent bioavailability, tissue penetration, prolonged half-lives

Disadvantages: emergence of resistance

Fluoroquinolones
Mechanism of Action

Inhibit bacterial topoisomerases which are

necessary for DNA synthesis DNA gyrase Primary target for gram-negatives Topoisomerase IV Primary target for grampositives

Resistance

Altered target sites: Most important and most

common Altered cell wall permeability Efflux pumps Cross-resistance occurs between FQs

Fluoroquinolones
Spectrum of Activity
Gram-positive: moxi>levo>>cipro
MSSA Streptococcus pneumoniae

Gram-Negative: cipro=levo>moxi
Enterobacteriaceae H. influenzae, M. catarrhalis, Neisseria sp. Pseudomonas aeruginosa ciprofloxacin &

levofloxacin

Atypical bacteria: all have excellent activity

Fluoroquinolones
ADME

Absorption: good bioavailability

Food delays peak concentration Distribution: extensive tissue distribution Lung, skin/soft tissue, bone, urinary tract (not
moxifloxacin) Minimal CSF penetration

Metabolism & Elimination renal and hepatic

Exception: Moxifloxacin is NOT reanally eliminated

Fluoroquinolones
Adverse Effects

Gastrointestinal: nausea, vomiting, diarrhea

CNS: headache, agitation, insomnia, dizziness, rarely, hallucinations Cardiac: prolongation QTc interval
Assumed to be class effect Led to withdrawal of grepafloxacin, sparfloxacin

Articular Damage: cartilage damage, arthralgia Dysglycemias

Led to withdrawal of gatifloxacin

Hepatotoxicity
Led to withdrawal of trovafloxacin

Fluoroquinolones
Drug Interactions

Divalent and trivalent cations

Zinc, Iron, Calcium, Aluminum, Magnesium Antacids, Sucralfate, enteral feeds Administer doses 2 to 4 hours apart; FQ first

Macrolides

Macrolides
Mechanism of Action

Inhibits protein synthesis by reversibly

binding to the 50S ribosomal subunit
Bacteriostatic Time-dependent activity
Resistance
Efflux pumps Altered target sites Cross-resistance occurs between all macrolides

Macrolides
(Erythromycin, Azithromycin, Clarithromycin)
Erythromycin: narrow spectrum of activity, short t1/2, not acid labile, GI intolerance Clarithromycin & azithromycin:

Broader spectrum of activity Improved PK properties:

Better bioavailability Better tissue penetration Prolonged half-lives

Improved tolerability

Macrolides

Spectrum of Activity
Gram-Positive Aerobes: Clarithr>Erythr>Azithr
MSSA S. pneumoniae: resistance is emerging Group and viridans streptococci

Gram-Negative Aerobes: Azithr>Clarithr>Erythr

H. influenzae, M. catarrhalis, Neisseria sp. NO activity against any Enterobacteriaceae

Anaerobes: upper airway anaerobes Atypical Bacteria Other Bacteria: Mycobacterium avium complex

Macrolides
ADME

Absorption
Erythromycin: variable absorption of 15% - 45% Clarithromycin: 55% Azithromycin: 38%

Distribution
Clarithromycin & azithromycin extensive tissue penetration with minimal CSF penetration

Metabolism & Elimination

Clarithromycin partially eliminated by the kidney ALL hepatic elimination t1/2: erythro 1.4 hr, clarithro 3-7 hr, azithr 68 hr

Macrolides
Adverse Effects

Gastrointestinal: up to 33 %
Nausea, vomiting, diarrhea, dyspepsia Erythro > > clarithro, azithro

Thrombophlebitis: IV Erythro & Azithro QTc prolongation, ventricular arrhythmias Other: ototoxicity (high dose erythro in patients with RI)

Macrolides
Drug Interactions Erythromycin and Clarithromycin are STRONG INHIBITORS of cytochrome p450 system (3A4):
Digoxin Carbamazepine Benzodiazepines Phenytoin Ergot alkaloids Tacrolimus Sirolimus SSRIs Valproic acid Methylprednisolone Warfarin Azole antifungals Cyclosporine Calcium ChannelBlockers

Aminoglycosides

Aminoglycosides
Mechanism of Action

Inhibition of protein synthesis by irreversibly bind to 30S ribosomes resulting in a defective bacterial cell membrane
Bactericidal Concentration-dependent killer

Resistance
Alteration of ribosomal binding site Decreased intracellular penetration

Aminoglycosides
Spectrum of Activity

Gram-Negative Aerobes
E. coli, K. pneumoniae, Proteus sp. Acinetobacter, Citrobacter, Enterobacter sp. Morganella, Providencia, Serratia, Salmonella, Shigella Pseudomonas aeruginosa (amik>tobra>gent)

Gram-Positive Aerobes (in combination w/ cell

wall inhibitor)
S. aureus and coagulase-negative staph viridans streptococci Enterococcus sp. (gentamicin)

Aminoglycosides
Pharmacology
Absorption: negligible Distribution
Hydrophilic: widely distributes into body fluids but NOT the CSF Distribute poorly into adipose tissue

Elimination
85-95% eliminated unchanged via kidney t1/2 dependent on renal function

Aminoglycosides
Adverse Effects
Nephrotoxicity
Direct proximal tubular damage - reversible if caught early Risk factors: High troughs, prolonged duration of therapy, underlying renal dysfunction, concomitant nephrotoxins

Ototoxicity
8th cranial nerve damage irreversible vestibular and auditory toxicity
Vestibular: dizziness, vertigo, ataxia Auditory: tinnitus, decreased hearing

Risk factors: same as for nephrotoxicity

Vancomycin

Vancomycin
Mechanism of Action
Inhibits bacterial cell wall synthesis at final stage of peptidoglycan polymers
Bactericidal (except for Enterococcus) Time dependent killer

Resistance
Modification of D-alanyl-D-alanine binding site of peptidoglycan

Vancomycin
Spectrum of Activity

Gram-positive bacteria

Anaerobes

MSSA, MRSA and S. epidermidis Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus Enterococcus Corynebacterium, Bacillus, Listeria, Actinomyces

Clostridium sp. (including C. difficile), Peptostreptococcus, Peptococcus

No activity against gram-negative aerobes

Vancomycin
ADME
Absorption
oral is negligible IV required therapy for systemic infections

Distribution
Distributes widely into body tissues and fluids, including adipose tissue Variable penetration into CSF, even with inflamed meninges

Elimination
Primarily eliminated unchanged by the kidney

Vancomycin
Adverse Effects
Red-Man Syndrome
Erythema multiforme-like reaction with intense pruritus, tachycardia, hypotension, rash involving face, neck, upper trunk, back and upper arms
Related to infusion rate Resolves spontaneously after discontinuation Lengthen infusion (over 2 - 3 hr) and/or pretreat with antihistamines

Hematologic: neutropenia, eosinophilia

Vancomycin
Clinical Uses

Serious gram-positive infections (MRSA) in -lactam allergic patients Colite pseudomembranosa per os

Oxazolidinone

Linezolid
Mechanism of Action
Inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit
Time dependent killer Bacteriostatic against enterococci & staphylococcus Bacteriocidal against streptococci

Resistance: RARE
Alterations in ribosomal binding sites

Linezolid
Spectrum of Activity

Gram-Positive Bacteria

MSSA, MRSA and S. epidermidis Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus Enterococcus faecium & faecalis (including VRE) Bacillus, Listeria, Clostridium sp. (NOT C. difficile), Peptostreptococcus, P. acnes

Linezolid
ADME
Absorption: 100% bioavailable Distribution: readily distributes into wellperfused tissue; CSF 30% Metabolism & Elimination: primarily metabolized via liver; 30% parent drug excreted via kidney

Linezolid
Adverse Effects
Gastrointestinal: nausea, vomiting, diarrhea (11%) Headache: 10% Thrombocytopenia: 3 to 10%

Overall myelosuppression often with treatment durations of >2 weeks Therapy should be discontinued and hematologic counts will return to normal

Linezolid
(Drug-Drug & Drug-Food Interactions)
Linezolid is a reversible, nonselective monoamine oxidase inhibitor Serotonin syndrome possible with concomitant use of:
Tyramine rich foods Serotonergic medications (SSRIs, MAOIs)

Foods high in tyramine:

Aged, fermented, pickled, smoked
Cheese, pepperoni, soy sauce, red wines, beer, sauerkraut

Serotonin Syndrome
Presence of three or more of the following: Agitation (34%) Abdominal pain (4%) Ataxia/incoordination (40%) Diaphoresis (45%) Diarrhea (8%) Hyperpyrexia (45%) Hypertension/hypotension (35%) Hyperthermia Hyper-reflexia (52%) Mental status change

Daptomycin

Daptomycin
Mechanism of Action
Binds to bacterial membranes and causes rapid depolarization of the membrane potential, inhibiting synthesis of protein, DNA, RNA and protein
Concentration-dependent Bactericidal activity

Mechanism of Resistance
Currently, no mechanisms of resistance have been identified

Daptomycin
Spectrum of Activity
Gram-Positive Bacteria
MSSA, MRSA and Staph. epidermidis Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus Enterococcus faecium AND faecalis (including VRE)

Gram-Negative Aerobes: inactive

Daptomycin
ADME
Absorption: minimal Distribution: protein binding = 95%, small volume of distribution
NOT indicated for TREATMENT of PNEUMONIA

Metabolism & Elimination: possible renal metabolism and 80% parent drug excreted via the kidneys

Daptomycin
Adverse Effects
Gastrointestinal: nausea, diarrhea, constipation Headache, insomnia Injection site reactions Rash Myopathy and CPK elevations

Drug Interactions
HMG-CoA reductase Inhibitors (statins)

Tigecycline

Mechanism of Action Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis.

Tigecycline Spectrum of Activity

Broad spectrum of activity
Treatment of complicated skin and skin structure infections caused by susceptible organisms, including methicillin-resistant Staphylococcus aureus and vancomycinsensitive Enterococcus faecalis; treatment of complicated intra-abdominal infections

Tigecycline
Pharmacokinetics
Metabolism: Hepatic, via glucuronidation, Nacetylation, and epimerization to several metabolites, each <10% of the dose Half-life elimination: Single dose: 27 hours; following multiple doses: 42 hours Excretion: Urine (33%; with 22% as unchanged drug); feces (59%; primarily as unchanged drug) No dose adjustment required in renal dysfunction

Tigecycline
Adverse Effects
>10%: Gastrointestinal: Nausea (25% to 30%), diarrhea (13%) 2% to 10%: Cardiovascular: Hypertension (5%), peripheral edema (3%), hypotension (2%) Central nervous system: Fever (7%), headache (6%), dizziness (4%), pain (4%), insomnia (2%) Dermatologic: Pruritus (3%), rash (2%) Endocrine: Hypoproteinemia (5%), hyperglycemia (2%), hypokalemia (2%) Hematologic: Thrombocythemia (6%), anemia (4%), leukocytosis (4%) Hepatic: SGPT increased (6%), SGOT increased (4%), alkaline phosphatase increased (4%), amylase increased (3%), bili increased (2%), LDH increased (4%) Neuromuscular & skeletal: Weakness (3%) Renal: BUN increased (2%) Respiratory: Cough increased (4%), dyspnea (3%)

Clindamycin

Clindamycin
Mechanism of Action

Reversibly binds to 50S ribosomal subunits

inhibiting bacterial protein synthesis Bacteriostatic or bactericidal depending on drug
concentration, infection site, and organism Binds in close proximity to macrolides competitive inhibition

Resistance
Altered binding site: confers resistance to
clindamycin & macrolides

Clindamycin
Spectrum of Activity Gram-Positive Aerobes
MSSA CA MRSA Streptococcus pneumoniae (only PSSP) resistance is developing Group and viridans streptococci Bacteroides sp Peptostreptococcus Actinomyces Propionibacterium Clostridium sp. (not C. difficile)

Anaerobes

Clindamycin
ADME

Absorption: Rapidly & completely absorbed (90%); food with minimal effect on absorption Distribution
High concentrations in bone and urine NO significant levels in CSF Metabolism & Elimination
Clindamycin primarily metabolized by the liver 10% of an oral dose excreted in urine

Clindamycin
Adverse Effects

Gastrointestinal: >10%
Nausea, vomiting, diarrhea, dyspepsia Esophagitis Pseudomembranous colitis
Mild to severe diarrhea Requires treatment with metronidazole

Hepatotoxicity: rare
Elevated transaminases

Allergy: rare

Metronidazole

Metronidazole
Mechanism of Action

After complex reduction reactions,

causes DNA to lose helical structure and results in inhibition of protein synthesis Concentration-dependent killer Bactericidal activity Resistance: relatively uncommon
Impaired oxygen scavenging ability Altered ferredoxin levels

Metronidazole
Spectrum of Activity Gram positive and negative anaerobes
Bacteroides sp. Fusobacterium Prevotella sp. Helicobacter pylori Clostridium sp. (Drug of choice: C. difficile pseudomembranous colitis)

Anaerobic Protozoa
Trichomonas vaginalis Giardia lamblia
Gardnerella vaginalis

Metronidazole
ADME

Absorption: Rapidly and completely (90%) Distribution

Saliva, bile, seminal fluid, bone, liver, abscesses, lung and vaginal secretions Penetrates CSF

Metabolism & Elimination

30% - 60% metabolized by the liver Kidney excretes up to 77% as unchanged drug
Urine may be dark or reddish-brown

Metronidazole
Adverse Effects

Gastrointestinal: Nausea, vomiting, stomatitis,

metallic taste CNS: seizures, encephalopathy, confusion, headache
Requires discontinuation of metronidazole

Neuromuscular & skeletal: Peripheral neuropathy

Metronidazole
Drug Interactions
Drug
Warfarin Alcohol Phenytoin Lithium Phenobarbital Rifampin

Interaction
anticoagulant effect Disulfiram-like reaction phenytoin concentrations lithium concentrations metronidazole concentrations metronidazole concentrations

TrimethoprimSulfamethoxazole (Bactrim)

Bactrim
(Mechanism of Action) Provide sequential inhibition of folinic acid synthesis; necessary for microbial DNA production
SMX: Inhibits dihydropteroate synthase inhibits incorporation of p-aminobenzoic acid (PABA) into dihydrofolic acid TMP: Inhibits dihydrofolate reductase prevents reduction of dihydrofolate to tetrahydrofolate Each agent is bacteriostatic, however, combination displays bactericidal activity

Resistance
Mediated by point mutations in dihydro-pteroate synthase and/or altered production or sensitivity of dihydrofolate reductase

Bactrim
(Spectrum of Activity)
Gram-Positives:
Some S. pneumoniae CA MRSA Staph aureus S. pyogenes Nocardia

Gram-Negatives:

E. coli Pneumocystis jiroveci (carinii) K. pneumoniae Salmonella, Shigella M. catarrhalis Haemophilus sp. N. gonorrhoeae Stenotrophomonas maltophilia

Other:

Bactrim
ADME

Absorption: Rapidly & completely absorbed (> 90%)

Peaks are higher and more predictable with IV administration

Distribution: urine, joints, sputum, middle ear fluid, bile and CSF Metabolism & Elimination:
SMX- extensive metabolized in liver and 10%-30% parent drug excreted in urine TMP- metabolized by liver and up to 75% parent drug excreted in urine

Bactrim
Adverse Effects

Gastrointestinal: Nausea, vomiting, diarrhea

Hematologic
Leukopenia, thrombocytopenia, eosinophilia Hemolysis (with G-6-PD deficiency)

Dermatologic: Rash, urticaria, epidermal necrolysis, Stevens-Johnson, drug fever CNS: Headache, seizures, KENICTERUS in neonates Other: phlebitis