Dolly Mehta 5-0236 dmehta@uic.edu. Methicillin-resistant Staphylococcus aureus (MRSA)...

Dolly Mehta5-0236

dmehta@uic.edu

Methicillin-resistant Staphylococcus aureus (MRSA)

Vancomycin-Resistant Enterococci (VRE) i.e. E. faecium

TB

Superbug: NDM-1 (New Delhi metallo-beta-lactamase bacteria)

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Cell Wall Synthesis inhibitors

Protein Synthesis inhibitors

Beta-Lactum Non Beta-Lactum

PenicillinsCephalosporinsCarbapenamsAzetronam

VancomycinFosfomycinCycloserineBacitracin

AminoglycosidesMacrolides

StreptograminsLincosamides

OxazolidinonesTetracyclines

Chloramphenicol

Rifampin, Isoniazid, Pyrazinamide, Ethambutol/streptomycinAmikacin, linezolid, clindamycin

Dapsone

Anti-tuberculosis and Anti-Leprosy (RNA, Cell wall, cell membrane)(special class of bacteria: Mycobacterium)

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Gram Positive Gram Negative

Cell wall

PG

AG: ArabanioglactanPG: peptidoglycan

Mycolic acid

AG

Cell wall

Cell memb

MycobacteiumCell Wall

Peptidoglycan

N acetylmuramic acid (NAM)

N acetylglucosamine (NAG)

Penta peptide Glycine

NAG

NAM

Overview of cell wall synthesis

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Bactoprenol (C55-carrier or lipid carrier)

NAG UDP

UMP

NAM NAG NAM NAG

NAG NAM NAG NAM

NAM NAM

NAMNAG NAM

NAM

periplasm

Peptidoglycan units

Peptide cross linkGlycosidic bond

autolysin

BP

PNAG PNAM

D-alaD-alaD-alaD-alaL-ala

D-alaD-alaD-alaD-alaD-alaalanine

racemase

D-ala-D-ala-ligase

Mur-A

NAM UDP

M UDP

L-ala

M UDP

D-glu

L-lys

M UDP

D-alaD-alaD-alaD-alaD-ala

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NAM NAG NAM

NAG NAM NAG NAM

NAM NAM

NAMNAG NAM

NAM

periplasm

BP

PP

BP

P

P

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NAM NAG NAM NAG

NAG NAM NAG NAM

NAM NAM

NAMNAG NAM

NAM

periplasm

Glycosidic bond

BP

P

Transglycolase

Peptide cross link

Transpeptidase (penicillin binding proteins)

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Bactoprenol (C55-carrier or lipid carrier)

NAM NAG NAM NAG

NAG NAM NAG NAM

NAM NAM

NAMNAG NAM

NAM

periplasm

BP

P

cycloserine

P

bacitracin

Beta-lactams

Inhibits Transpeptidase

reaction

vancomycinD-alaD-alaD-alaD-alaL-ala

D-alaD-alaD-alaD-alaD-ala

alanineracemase D-ala-D-ala-ligase

Inhibits transglycolasereaction

Cell wall synthesis inhibitors

BP

PNAG PNAMfosfomycin

NAG UDP

MurA

NAM UDP

PBP

Mechanism of resistance for beta-lactums

Production of -lactamase

Increased expression of efflux pumps (i.e P. aeruginosa)

Reduced penetration to site of action (Penn G); P. aeruginosa (lack porins)

Elaboration of normal penicillin binding proteins (PBPs)

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modification of the D-Ala-D-Ala binding site in PG building block. D-Ala is replaced by D-lactate.

Mechanism of Resistance for Vancomycin

PNAM PNAM

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A 55-year-old man is brought to the local hospital emergency department by ambulance. His wife reports that he had been in his normal state of health until 3 days ago when he developed a fever and a productive cough. During the last 24 hours he has complained of a headache and is increasingly confused. His wife reports that his medical history is significant only for hypertension, for which he takes hydrochlorothiazide and lisinopril, and that he is allergic to amoxicillin. She says that he developed a rash many years ago when prescribed amoxicillin for bronchitis. In the emergency department, the man is febrile (38.7°C [101.7°F]), hypotensive (90/54 mm Hg), tachypneic (36/min), and tachycardic (110/min). He has no signs of meningismus but is oriented only to person. A stat chest x-ray shows a left lower lung consolidation consistent with pneumonia. The plan is to start empiric antibiotics and perform a lumbar puncture to rule out bacterial meningitis. What antibiotic regimen should be started to treat both pneumonia and meningitis? Does the history of amoxicillin rash affect the antibiotic choice? Why or why not?

Case Study

Penicillin

Penicillin G, NaturalPenicillin VRepository forms of Penn G:WycillinBicillin

Penicillinase resistant Penicillin (anti-staphyloccal penicillins)(strains not resistant to methacillin: nafcillin, oxacillindicloxacilin)

Ampicillin, AmoxicllinTicarcillin : Anti-pesudomonal (i.v) Piperacillin

Cephalosporins

CephalothinCefazolin

Cefoxitin, Cefotetancefmetazole

Ceftazidime, cefoperazone

Cefepime

VancomycinCarbapenams

Imepenam (combined with cilastatin; Primaxin)MeropenamEtrapenam

ImepenamFosfomycin

Monurol

-lactamase Inhibitors

Clavulanic acid(“suicide inhibitor”)SulbactumTazobactum

Clavulanic acid

MonobactumAzteronam (does not exhibit cross-allergy with Penn and Cef Excluding ceftazidime)

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Amoxicillin + clavulanate: Augementin (oral)Ampicillin + Sulbactam: UnasynPiperacillin +Tazobactam: Zosyn Ticarcillin and Clavulanate: Timentin

15Penicillin Cephalosporins Carbapenams VancomycinPenicillin G/V

Pneumococcal Infections (S. pneumoniae)Pneumococcal Peumonia/meningitis (only penicillin sensitive)Streptococcal InfectionsEnterococcal endocarditis (+ ampilcillin)Meningococcal infectionsSyphilisActinomycosisClostridia InfectionsListeria infections (along with Ampicillin)Prophylactic: Streptococcal and rheumatoid fever

AminopenicillinOtitis mediaDental infection and endocarditis prophylaxisUpper respiratory tract infectionsUrinary tract infections (UTI)Listeria monocytogenesEnterococcal infections

Carboxypenicillin and Ureidiopenicillin(Tricarcillin, Pipericillin)

In Neutropenic patients, Bacteremia, pneumonia, burns infections, UTI (resistant to Penn G and Ampicillin caused by Pseudomonas or indole + proteus Infections and enterobacter strains), Hospital-acquired and ventilator-associated pneumonia

Ist generation i.e. CefazolinSkin and soft tissue infections caused by S aureus, S pyogens;Surgical prophylaxisCelluulitis, endocarditis

IIIrd generation

All forms of GonorrheaSevere form of Lyme diseasePneumococcal Meningitis (+ vancomycin)(non-immunocompromised)Pneumococcal PeumoniaTyphoid

Noscomal infectionsNeutrpenia with feverVentilator-associated pneumonia

IVth generation

Imepenam (Primaxin)

Meropenam

Etrapenam

Azteronam

lower respiratory tract infectionsUrinary tract infections (UTI)Intra-abdominal, gynecological, skin and soft tissues infections

Therapeutic equivalent to Prixamin

Abdominal and pelvic infections by Gram +

Resembles aminoglycosidesUse for gram – infections in patients with B-lactum allegenicity

Amoxicillin + clavulanate: Augementin (oral): low risk febrile patients with neutropenia from cancer therapy, acute otitis in childerns, bite wounds, cellulitis and diabetic foot infections Ampicillin + Sulbactam: Unasyn: good for Gram+ cocci, Intra-abdominal and pelvic infectionsPiperacillin +Tazobactam: Zosyn: Appendicitis (complicated by rupture or abscess) and peritonotis, community and hospital acquired pneumonia, Postpartum endometritis, cellulitisTicarcillin and Clavulanate: Timentin: Septicemia, Lower Respiratory Infections, UTI, Intra-abdominal, bone-joint, gynecological, skin and soft tissues infections

Methicillin-resistent staph infections:Peumonia, empyema, endocarditis,OsteolmyelitisSoft-tissues abscessesEnterococcal endocardiatis (+ aminoglycosides in patients with serious penn allergy)

Fosfomycinuncomplicated UTI (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis

Bacitracintopical

Penicillinase-resistant penicillins (PRPs):Skin infections: cellulitis, impetigo, erysipelasEndocarditis, meningitis, and bacteremia from staphylococciOsteomyelitis and septic arthritis only when the organism is proven sensitive

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Untoward Effects

•Hypersensitivity ~(0.7%-10%)Allergy to one penicillin risk to other penicillin's/cephalosporin’s (in clinical setting it is 1%) also cases with low and mild Penicillin allergy are low risk for cephalosporin’s)

Penicilloic acid

IgE Abs

Penicillin’s

Cephalosporin’s

HypersensitivityNephrotoxic increases with AminoglycosidesDiarrheaIntolerance to alcohol (cefotetan, cefoperazone)Thrombocytopenia/platelet dysfunction and disulfaram-like effect (apparent with these: cefamandole, cefmetazole, cefotetan,and cefoperazone), Vit K deficiency

VancomycinHypersensitivity(macular rashes and anaphylaxis)“red neck syndrome”Ototoxicity (excessive high conc.)

Protein Synthesizing Machinery

Ribosome

mRNA

tRNA

bacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNA

has A, P and E sites for binding with tRNA

forms template for protein synthesis

transcribed from DNA

attaches to 30s ribosomes

brings amino acids

attaches to A, P and E sites of ribosomes

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E AP

uuu cca cau cca aug cca cau

MET

uac

30s

50s

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E AP

uuu cca cau cca aug cca cau

Met

uac

Pro

uac

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E AP

uuu cca cau cca aug cca cau

Met

Pro

gga

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E AP

uuu cca cau cca aug cca cau

Met

Pro

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E AP

uuu cca cau cca aug cca cau

MET

uac

30s

50s

Aminoglycosides

Binds 30S (irreversible inhibitor of protein synthesis)

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E AP

uuu cca cau cca aug cca cau

Met

uac

Pro

uacTetracycline

Binds reversibly at 30 S ribosomal RNACompete with tRNA

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E AP

uuu cca cau cca aug cca cau

Met

Pro

50S ribosomal RNABlocks peptide translocation to P site

Macrolides, Lincosamide, Streptogramins

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E AP

uuu cca cau cca aug cca cau

Met

Pro

gga

Chloramphenicol, Clindamycin

50S ribosomal RNAInhibit peptidyltransferase

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Oxazolidinones

E AP

uuu cca cau cca aug cca cau

30s

50s

Inhibits ribosomal complex formation

a. Enter cell through porins but require electron transport to permeate the inner membrane Energy-Dependent Phase 1(EDP1)

b) Create fissure enhancing AG uptake (EDP2 phase)

Aminoglycosides

Peak and trough levels of Aminoglycosides

therapeutic dose is achieved

avoid toxicity

• concentration-dependent killing

• postantibiotic effect

• Synergistic killing Along with beta-lactam or vancomycin

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Modification of the ribosomal binding site

(AG, Tet, Mac)

Low affinity of drug for bacterial ribosomes

Efflux pumps (Tet, Mac)

Mechanisms of resistance for antibiotics inhibiting protein synthesis

Intracellular penetration

AG, Tet, Mac

Anaerobic conditions(AG)

pH

acetylation, phosphorylation, adenylation of OH or NH2 gr (AG)

Drug Inactivation

Tet: enzyme inactivation

Mac: (hydrolysis by esterase's)

Aminoglycosides

GentamicinTobramycinAmikacin

Gentamicin2-deoxystreptamine

Macrolides

ErythromycinAzithromycinClarithromycin

Ketolide(Telithromycin)

Erythromycin

Tetracyclines

TetracyclineDoxycyclineMinocyclineTigecycline

Tetracyclines

ChloramphenicolSteptogramins

Quinupristin/dalfopristin

Linocosamides

Clindamycin

Linezolid

Oxazolidinones

Streptomycin

Neomycin

Spectinomycin

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along with Penn and Cef for serious UTI, bacteremia, infected burns, osteomyelitis, pneumonia, peritonitis and otitis

along with vancomycin For bacterial endocarditis

Never than a few days unless requiredNever mixed in same solution with Penn as it inactivates

(Gentamicin prefered due to low cost and long experience

Aminoglycosides

GentamicinTobramycinAmikacin

Streoptomycin

With Penn for bacterial endocarditisTularemiaPlagueTuberculosis

Neomycin: topical

Macrolides

Erythromycin, Chlamydial urogenital infections (pregnancy)Chlamydial pneuominia in infantsDiphtheriaPertussisTetanusprophylaxis of rheumtoid fever

AzithromycinLegionnaires diseaseChlamydial urogenital infections Lymphogranuloma venereumPneumonia by Chlamydia pneumoniaPertussisStreptococcal infectionsMycobacterial infectionsToxoplasmosis encephalitis and diarrhea (in AIDS)Non specific urethritis

ClarithromycinHelicobacter pylori infectionsMycobacterial infectionsToxoplasmosis encephalitis and diarrhea (in AIDS)

KetolideRespiratory tract infections (bronchitis, sinusitis)Community acquired pneumonia

TetracyclinesRickettsial infections Mycoplasma infectionsPeumonia, bronchitis, sinusitis caused by Chlamyda peumoniaBrucellosis (along with rifampin or Streptomycin)TuleremiaAcne

DoxycyclineRocky mountain feverLymphogranuloma venereumTrachomaAnthraxcholera

Tetracycline ChloramphenicolMUST BE LIMITED

Typhoid feverBacterial menegitisAnaerobic infections(intrabdominal or brain) Rickettsial infections Brucellosis

SteptograminsDalfopristin (Synercid)(should be reserved for serious infections by multiple-drug-resitant gram+

Infections caused by Vancomycin resistant strainsNoscomal infections (Europe)

Limezoid (Zyvox)should be reserved for serious infections by multiple-drug-resistant gram+ and vancomycin resistant or multi-drug resistant gram+

ClindamycinLung abscess and anerobic lung and pleural space infections, encephalitis, vaginal infectionsSpectinomycin

gonorrhea or gonorrhea in penicillin-allergic patients

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Untoward Effects

Ototoxicity (vestibular or cochlear cells)(largely irreversible); Ethacrynic acid and furosemide further aggravate it

Nephrotoxicity (8-26% of cases)(with cephalosporins)

Neuromuscular blockade

Aminoglycosides MacrolidesAllergic reactions (fever, eosinophilia, skin eruptions)Cholestatic hepatitis

KetolideNausea, vomitingVisual disturbancesPseudomembrane colitisRisk of ventricular arrhythmia

ChloramphenicolHematological toxicity(aplastic aneamia)HypersensitityGray baby syndrome

TetracyclinesGastrointestinal Pseudomembrane colitisPhotosensitivityHepatic toxicity (pregnant woman)Renal toxicity (less with doxycycline) Fanconi syndrome with degraded TetPermanent teeth discoloration in children's

ClindamycinDiarrhoeaPseudomembrane colitis (lethal)Skin rashesMay inhibit neuromuscular transmission or potentiate the effect of neuroblocker agents

DalfopristinPhelebitisRaise blood pressure if gibven along with other agents i.e. histamine

LinezolidWell-tolerated, but myelosuppression has been noted; platelets should be monitored in patients with risk of bleeding or if therapy >2 wksPalpitation, headache

Drug Interactions

Erythromycin/clathrimycin/ketolide

CYP3A4Potentiates the effects of i.e.Carbamazepine, cotoicosteriods, cyclosporin, digoxin, warfarin

Linezolid

serotonin syndrome

If given with Serotonergic drugs

Chloramphenicol,Streptogramins

CYP450Prolong half lives of dicumbarol, warfarinAntiretroviral protease inhibitorsrifabutin

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A 19-year-old woman with no significant past medical history presents to her college medical clinic complaining of a 2-week history of foul-smelling vaginal discharge. She denies any fever or abdominal pain but does report vaginal bleeding after sexual intercourse. When questioned about her sexual activity, she reports having vaginal intercourse, at times unprotected, with two men in the last 6 months. A pelvic examination is performed and is positive for mucopurulent discharge from the endocervical canal. No cervical motion tenderness is present. A first-catch urine specimen is obtained to be tested for chlamydia and gonococcus. A pregnancy test is also ordered as the patient reports she "missed her last period." Pending these results, the decision is made to treat her empirically for gonococcal and chlamydial cervicitis. What are two potential treatment options for her possible chlamydial infection? How does her potential pregnancy affect the treatment decision?

Case Study

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A 45-year-old man with no medical history was admitted to the intensive care unit (ICU) 10 days ago after suffering third-degree burns over 40% of his body. He had been relatively stable until the last 24 hours. Now he is febrile (39.5°C [103.1°F]), and his white blood cell count has risen from 8,500 to 20,000/mm3. He has also had an episode of hypotension (86/50 mm Hg) that responded to a fluid bolus. Blood cultures were obtained at the time of his fever and results are pending. The ICU attending physician is concerned about sepsis and decides to treat with empiric combination therapy directed against Pseudomonas. The combination therapy includes tobramycin. The patient weighs 70 kg (154 lb) and has an estimated creatinine clearance of 90 mL/min. How should tobramycin be dosed using once-daily and conventional dosing strategies? How should each regimen be monitored for efficacy and toxicity?

Case Study

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Key facts about TB

Second only to HIV/AIDS as the greatest killer worldwide

In 2010, 8.8 million people fell ill with TB and 1.4 million died from TB.

Over 95% of TB deaths occur in low- and middle-income countries, and it is among the top three causes of death for women aged 15 to 44.

In 2009, there were about 10 million orphan children as a result of TB deaths among parents. 8 infants exposed to TB at Sacramento hospital (just yesterday)

leading killer of people living with HIV causing one quarter of all deaths.Multi-drug resistant TB (MDR-TB) is present in virtually all countries surveyed.

Millennium Development Goal to reverse the spread of TB by 2015.

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• Mycobacterium tuberculosis: slow growing, dormant and aerobic bacterium. Mycolic acids fatty acids provide advantage

• Reside in Macrophages• Active TB disease, Mtb complexes are always found in the upper

air sacs of the lungs.

PGAG: ArabanioglactanPG: peptidoglycan

Mycolic acid

AG

Cell wall

Cell memb

Mycobacterium PenicillinCephallosprinsVancomycinX

AminoglycosidesStreptomycin(ist line) Kanamycin

Amikacincycloserine

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IsoniazidRifampin Pyrazinamde Ethambutol

Rifabutin

First-line Therapy

Alternative Therapy

Streptomycin

Fluoroquinolones (Moxifloxacin, gatifloxacin)cycloserine capreomycin Kanamycin and amikacin ethionamideclofazimine aminosalicyclic acid

“RIPE”

Isoniazid (INH)(prodrug)

Catalase-peroxidase(KatG)

Mycolic acid synthesis

Ethambutol

arabinosyltransferase

Arabinoglycan

Pyrazinamide

pyrazinoic acid

(prodrug)pyrazinamidase

disrupts mycobacterial cell membrane metabolism and transport functions

Inhibitors of cell wall and cell membrane

Ethionamide (alternate)

INH KasA

AcpM

Fatty acid Synthase II

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Targeting mycobacterium DNA or RNA

Fluoroquinolones (alternate)

targets topoisomerase

Inhibition of DNA synthesis and supercoling

RifamycinD

NA

-

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mycobacterium protein synthesis inhibitors

Streptomycin (toxic)Capreomycin/amikacin (alternate)

Macrolides

Inhibits folate synthesis:

Aminosalicylic Acid (PAS)

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TM-207 (R207910)

Experimentsl drugs targeting mycobacterium

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Pyrazinamde, Isoniazid

Alteration of enzyme converting prodrug

inactive active

Ethionamide

Mechanism of Mycobacterial Resistance

butol)

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Blocks the action of

rifamycin, fluroquinolone, ethambutol, streptomycin, macrolide

Alteration of target protein structure

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Multidrug-Resistant Tuberculosis (MDR TB)and Possible Effective Treatments

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Extensively Drug-Resistant Tuberculosis (XDR TB)Diminishing Options for Treatment

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Drug Interactions of Rifampin

induces Cytochrome P450

Increases elimination of several drugs i.e cyclosporine, anticonvulsantsProtease inhibitors

Rifabutin(can be used)

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Atypical Mycobacteria

• Accounts for 10% of non-tuberculous or atypical mycobacterium infections

• generally non communicable

• less susceptible than M tuberculosis to antituberculous drugs

• erythromycin, sulfonamides, or tetracycline, which are not active against M tuberculosis, may be effective

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Species Clinical Features Treatment OptionsM kansasii  Resembles tuberculosis Ciprofloxacin, clarithromycin, ethambutol,

isoniazid, rifampin, trimethoprim- sulfamethoxazole

M marinum  Granulomatous cutaneous disease Amikacin, clarithromycin, ethambutol, doxycycline, minocycline, rifampin, trimethoprim-sulfamethoxazole

M scrofulaceum  Cervical adenitis in children Amikacin, erythromycin (or other macrolide), rifampin, streptomycin (Surgical excision is often curative and the treatment of choice.)

M avium complex  Pulmonary disease in patients with chronic lung disease; disseminated infection in AIDS

Amikacin, azithromycin, clarithromycin, ciprofloxacin, ethambutol, rifabutin

M chelonae  Abscess, sinus tract, ulcer; bone, joint, tendon infection

Amikacin, doxycycline, imipenem, macrolides, tobramycin

M fortuitum  Abscess, sinus tract, ulcer; bone, joint, tendon infection

Amikacin, cefoxitin, ciprofloxacin, doxycycline, ofloxacin, trimethoprim-sulfamethoxazole

M ulcerans  Skin ulcers Isoniazid, streptomycin, rifampin, minocycline (Surgical excision may be effective

Drugs active against atypical Mycobacteria

•chronic ID skin, peripheral nerves and mucous membranes (eyes, respiratory tract).

•also known as Hansen's disease as bacillus causing it was discovered by G.A. Hansen in 1873.

•common in warm, wet areas in the tropics & subtropics.

Leprosy

•Mycobacterium leprae

Multidrug therapy

Clofazimine (LAMPRENE) Phenazine dyebinds GC rich mycobacterial DNA; anti-inflammatory

inhibits folate synthesis in bacteria

Sulphones (Dapsones)

Rifampin

•Sulphone syndrome: fever, jaundice, malaise•exacerbation of lepromatos leprosy

Untoward Effects

Dapsone

Clofazimine

skin discoloration ranging from red-brown to nearly black

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A 45-year-old homeless man presents to the emergency department complaining of a 2-month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough. He is currently living on the street but has spent time in homeless shelters and prison in the last several years. He reports drinking 2–3 pints of hard alcohol per day for the last 15 years, and also reports a history of intravenous drug use. In the emergency department, a chest x-ray shows a right apical infiltrate. Given the high suspicion for pulmonary tuberculosis, the patient is placed in respiratory isolation. His first sputum smear shows many acid-fast bacilli, and a rapid HIV antibody test returns with a positive result. What drugs should be started for treatment of presumptive pulmonary tuberculosis? Does the patient have a heightened risk of developing medication toxicity? If so, which medication(s) would be likely to cause toxicity?

Case Study

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A man is admitted with E. coli bacteremia. Which of the following is the most appropriate therapy?

VancomycinLinezolidQuinolones, aminoglycosides, carbapenems, piperacillin, ticarcillin, or aztreonamDoxycyclineClindamycinOxacillin

A 34-year-old woman presents with facial pain, a discolored nasal discharge, bad taste in her mouth, and fever. On physical examination she has facial tenderness. What is the most appropriate management?

LinezolidAmoxicillin / clavulanic acid and a decongestantGentamycinErythromycin and a decongestant

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Objectives

1. Know the components of bacterial cell wall and basis of protein synthesis.

2.Know the classification of penicillins and cephalosporins according to their chemical structure and their antimicrobial spectrum.

3. Know the mechanism of antimicrobial activity for penicillins, cephalosporins, bacitracin. cyclosporin. aztreonam,

imipenem, vancomycin, aminoglycosides, tetracyclines, macrolides, chloramphenicol, lincosamide, streptogramins, oxazolidinones,.

4. Know the mechanisms of bacterial resistance for antimicrobial drugs.

5. Know the most common adverse effects of the antimicrobial drugs.

6. Know the most common applications of these antibiotics for the treatment of disease.