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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)
4
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
19
E AP
uuu cca cau cca aug cca cau
Met
uac
Pro
uac
20
E AP
uuu cca cau cca aug cca cau
Met
Pro
gga
21
E AP
uuu cca cau cca aug cca cau
Met
Pro
22
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
33
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
34
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
35
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.
36
• 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
37
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
39
Targeting mycobacterium DNA or RNA
Fluoroquinolones (alternate)
targets topoisomerase
Inhibition of DNA synthesis and supercoling
RifamycinD
NA
-
40
mycobacterium protein synthesis inhibitors
Streptomycin (toxic)Capreomycin/amikacin (alternate)
Macrolides
Inhibits folate synthesis:
Aminosalicylic Acid (PAS)
41
TM-207 (R207910)
Experimentsl drugs targeting mycobacterium
42
Pyrazinamde, Isoniazid
Alteration of enzyme converting prodrug
inactive active
Ethionamide
Mechanism of Mycobacterial Resistance
butol)
43
Blocks the action of
rifamycin, fluroquinolone, ethambutol, streptomycin, macrolide
Alteration of target protein structure
44
Multidrug-Resistant Tuberculosis (MDR TB)and Possible Effective Treatments
45
Extensively Drug-Resistant Tuberculosis (XDR TB)Diminishing Options for Treatment
46
Drug Interactions of Rifampin
induces Cytochrome P450
Increases elimination of several drugs i.e cyclosporine, anticonvulsantsProtease inhibitors
Rifabutin(can be used)
48
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
49
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
53
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
54
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
55
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.
