Micro-Pharm

Neetisha Gupta

Antimicrobial Therapy:

Beta Lactams Block cell wall synthesis by inhibition of peptidoglycan cross-linking Drug Mechanism Clinical use Bacteriocidal/

Bacteriostatic Resistance Toxicity

Penicillin **G = IV form V = Oral **more active during log phase

gram +ve cocci, gram +ve rods, gram –ve cocci and spirochettes

Hypersensitivity reactions, hemolytic anemia

Methicillin, nafcillin, dicloxacillin Penicillinase resistant penicillins

S.aureus (except MRSA; resistant b/c of altered PBP target site)

Hypersensitivity reactions, methicillin!interstitial nephritis

Ampicilli, amoxicillin (aminopenicillins)

Extened spectrum penicillin!Certain gram +ve bacteria and gram –ve rods Haemophilus influenze, E.coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, enterococci

Hypersensitivity reactions; ampicillin rash (in EBV); pseudomembranous colitis

Ticarcillin, carbenicillin, piperacillin (antipseudomonals)

- Bind PBP - Block transpeptidase cross-linking of cell wall - Activate autolysin enzymes Narrow spectrum!for penicillinase resistant penicillin’s Wider spectrum!aminopenicillins **Also combine with clavulanic acid (penicillinase inhibitor) to enhance spectrum

Pseudomonas and gram –ve rods; susceptible to penicillinase; use with clavulanic acid (!-lactamase inhibitor)

Bactericidal !-lactamse cleavage of !-lactam ring, or altered PBP in cases of MRSA or penicillin resistant S.pneumoniae

Hypersensitivity reactions

Block peptidoclycan synthesis Cephalosporins 1st: generation Cefazolin, Cephalexin

!-lactam drug that inhibits cell wall synthesis Gram +ve

P roteus mirabilis E.coli c K lebsiella pneumoniae Soft tissue infections,

bactericidal !-lactamse cleavage of !-lactam ring, or altered PBP in cases of MRSA or penicillin resistant S.pneumoniae

Hypersensitivity reactions. Cross-hypersensitivity with penicillin’s occurs in 5% of pts. " nephrotoxicity of aminoglycosides; disulfiram-like reaction with ethanol

Micro-Pharm

Neetisha Gupta

1st: generation Cefazolin, Cephalexin

Gram +ve P roteus mirabilis E.coli c K lebsiella pneumoniae Soft tissue infections, surgical prophylaxis

2nd generation: Cefoxitin, cefaclor, cefuroxime

H aemophilus influenzae E enterobacter aerogenes N eisseria spp. P roteus mirabilis E.coli c K lebsiella pneumoniae S erratia marcescens

3rd generation: Ceftriaxone, Cefotaxime, Ceftazidime

Serious gram _ve infections; meningitis (able to penetrate BBB)

Azetreonam A monobactam resistant to !-lactamases Synergistic with aminoglycosides

Gram –ve rods: Klebsiella, Pseudomonas, Serratia **No activity against gram +ve or anaerobes **For penicillin-allergic pts. and those with renal insufficiency who cannot tolerate aminoglycosides

Occasional GI upset

Imipenem/Cilastatin, Meropenem

Imipenem is a broad spectrum. !-lactamase-resistant carbapenem. Always administered with cilastatin (inhibitor of renal dihydropeptidase I) to # decrease inactivation in renal tubules

Gram +ve cocci, gram –ve rods and anaerobes Drug of choice for Enterobacter **use is limited to life-threatening infections, or after other drugs have failed

GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels

GLYCOPEPTIDES Vancomycin Inhibit cell wall mucopeptide

formation by binding D-ala-D-ala portion of cell wall precursors Replace ala with lactate

Serious gram +ve MDR organsims (S.aureus, C.difficile)

Bactericidal Terminal D-ala of cell wall component replaced with D-lac; # affinity

N ephrotoxicity O totoxicity T hrombophlebitis

Bacitracin Prevents dephosphorylation !No regeneration of lipid carrier molecule Acting on outer-membrane and cytoplasmic membrane

Topical skin infection, agent against gram +ve **gram –ve resistant

Micro-Pharm

Neetisha Gupta

Cycloserine Inhibits synthesis of cell wall dipeptide D-ala-D-ala

Polymyxin B, E Bind to cell membranes of bacteria and disrupt their osmotic properties Lyse cell membrane **Are cationic, basic proteins that act like detergents

Resistant gram –ve infections

Neurotoxicity,acute renal tubular necrosis

Protein synthesis Inhibitors !30s inhibitors: buy AT 30 ! 50s inhibitors: CCELL at 50 Aminoglycosides Gentamycin Neomycin Amikacin Tobramycin

Inhibit formation of initiation complex and cause misreading of mRNA **require O2 for uptake thus ineffective against anaerobes

Severe gram –ve rod infections **Neomycin for bowel prep

Bactericidal Modification via acetylation, adenylation or phosphorylation

N ephrotoxicity O totoxicity T eratogen

Tetracyclines Doxycycline, Demeclocycline,Minocycline

Bind to 30s and prevent attachment of aminoacyl-tRNA; limited CNS penetration

V.cholera, Acne, Chlamydia, Ureaplasma, Urealyticum, M.pneumoniae, Tularemia, H.pylori, Borrelia burgdorferi (lyme disease), Rickettsia Mneumonic: VACCUM The BedRoom

Bacteriostatic # uptake or "transport out of cell

GI distress, Calcium chelator discoloration of teeth and inhibition of bone growth in children, photosensitivity, Contraindicated in pregnancy

Chloramphenicol Inhibits 50s peptidyl-transferase activity

Meningitis (H.influenzae, Neisseria, S.pneumoniae)

Bacteriostatic Modification via acetylation

Anemia, aplastic anemia, gray baby syndrome (in premature infants b/c they lack liver UDP-glucuronyl transferase)

Clindamycin, Lincosamide Blocks peptide-bond formation at 50s ribosomal subunit

Treat anaerobic infections (i.e: Bacteroides fragilis, C.perfringens)

Bacteriostatic Pseudomembranous colitis, fever, diarrhea

Macrolides: Erythromycin, Azithromycin, Clarithromycin

Inhibit protein synthesis by blocking translocation; bind to the 23s rRNA of the 50s ribosomal subunit

URI, pneumonias, STD –gram +ve cocci (strep infections in pts. allergic to penicillin), Mycoplasma,

Bacteriostatic Methylation of rRNA near erythromycin’s ribosome-binding site

Prolonged QT interval (esp. erythromycin), GI discomfort, acute cholestatic hepatitis, eosinophilia, skin

Micro-Pharm

Neetisha Gupta

Macrolides: Erythromycin, Azithromycin, Clarithromycin

Inhibit protein synthesis by blocking translocation; bind to the 23s rRNA of the 50s ribosomal subunit

URI, pneumonias, STD –gram +ve cocci (strep infections in pts. allergic to penicillin), Mycoplasma, Legionella, Chlamydia, Neisseria

Bacteriostatic Methylation of rRNA near erythromycin’s ribosome-binding site

Prolonged QT interval (esp. erythromycin), GI discomfort, acute cholestatic hepatitis, eosinophilia, skin rashes, Increases serum [ ] of theophyllines, oral anticoagulants

Lincomycin, Oxazolidinones Blocks formation of initiation complex Vancomycin resistant Enterococci, MRSA< MRSE< PRP

Bacteriostatic

Inhibition of precursor synthesis/blocking folate synthesis Sulfonamides: SMX, sulfisoxazole, sulfadiazine

PABA antimetabolites inhibit dihydropteroate synthetase

Gram +ve, gram –ve, Nocardia, Chlamydia, simple UTI

Bacteriostatic Altered enzyme (bacterial dihydropteroate synthetase), #uptake, or "PABA synthesis

Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity, photosensitivity, kernicterus in infants, displace other drugs from albumin (i.e. warfarin)

Trimethoprim Inhibits bacterial dihydrofolate reductase

Used in combo with sulfonamides !causing sequential block of folate synthesis recurrent UTIs, Shigella, Salmonella, Pneumocystis jiroveci

Bacteriostatic Megaloblastic anemia, leucopenia, granulocytopenia

Inhibition of DNA synthesis Fluoroquinolones Naldixic acid Ciproflaxin Levofloacin Gatiflaxin

Inhibits DNA gyrase (topoisomerase II)

Gram –ve rods of urinary and GI tracts (incl. Pseudomonas), Neisseria

Bactericidal Altered gyrase or reduced uptake

GI upset, superinfections, skin rashes, headache, dizziness Contraindicated in pregnant women and in children b/c found to damage growing cartilage Tendonitis and tendon rupture in adults, leg cramps and myalgias in kids

Metronidazole Forms toxic metabolites in the bacterial cell that damages DNA

Treats: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes

Bactericidal Antiprotozoal Disulfiram-like reaction with alcohol; headache, metallic taste

Micro-Pharm

Neetisha Gupta

Antimycobacterial drugs Rifampin, Isoniazid, Pyrazinamide, Ethambutol ! TREATMENT of TB Isoniazid and Ethionamide

Active against actively repicating mycobacteria; inhibit mycolic acid

TB Neurotoxicity, hepatoxicity, Pyridoxine (B6) can prevent neurotoxicity

Ethambutol Inhibits syntehsis of arabinolactan Optic neuropathy(red-green color blindness)

Rifampin 4 R’s RNA polymerase inhibitor Revs up microsomal P-450 Red/orange body fluids Rapid resistance if used alone

Inhibits DNA-dependent RNA polymerase

TB; delays resistance to dapsone when used for leprosy Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H.influenzae B

Minor hepatotoxicity and drug interactions ( "P-450); orange body fluids

ANTI-FUNGAL THERAPY Amphotericin B Binds ergosterol; forms membrane

pores that allow leakage of electrolytes

Wide spectrum systemic mycoses Cryptococcus, Blastomyces, Coccidioides, Aspergillus, Histoplasma, Candida, Mucor

Fever/chills (“shake and bake”), hypotension, nephrotoxicity, arrhthmias, anemia, IV, phlebitis **Hydration reduces nephrotoxicity Liposomal amphotericin reduces toxicity

Nystatin Binds to ergosterol, disrupting funfal membranes

“Swish and swallow” for oral candidiasis topical for diaper rash or vaginal candidiasis

TOO TOXIC FOR SYSTEMIC USE

Flucytosine Inhibits DNA synthesis by conversion to 5-fluorouracil

Systemic fungal infections (Candida, Cryptococcus) in combo with Amphotericin

Nausea, vomiting, diarrhea, bone marrow suppression

Caspofungin Inhibits cell wall synthesis by inhibiting synthesis of !-glucan

Invasive Aspergillosis GI upset, flushing

Terbinafine Inhibits fungal enzyme: squalene epoxidase

Dermatophytoses (esp. onychomycosis)

Griseofulvin Interferes with microtubule function; disrupts mitosis; Deposits in keratin

Oral tx of superficial infections; inhibits growth

Teratogenic, carcinogenic,

Micro-Pharm

Neetisha Gupta

Nonsurgical prophylaxis: Antibiotics to avoid in pregnancy (SAFE Moms Take Really Good Care)

Gonorrohoea!ceftriaxone Sulfonamides!Kernicterus Fluoroquinolones!Cartilage damage

Syphilis!Benzathine penicillin G Aminoglycosides!ototoxicity Ribavirin!teratogenic

Pneumocystis jiroveci! TMP-SMX (DOC), aerosolized pentamidine Griseofulvin!Teratogenic Chloramphenicol!Gray baby syn.

Meningococcal infection!Rifampin (DOC), minocycline Erythromycin!acute cholestatic hep in moms

Endocarditis w/ dental or surgical procedures!Penicillins Metronidazole!mutagenesis Tetracycline!teeth discoloration, (-) of bone growth

Treatment of highly resistant bacteria:

MRSA!Vancomycin

VRE!Linezolid and streptogramins (quinupristin/dalfopristin)

Griseofulvin Interferes with microtubule function; disrupts mitosis; Deposits in keratin containing tissues (i.e nails)

Oral tx of superficial infections; inhibits growth of dermatophytes (tinea ringworm)

Teratogenic, carcinogenic, confusion, headaches, "P-450 and warfarin metabolism

Azoles Fluconazole, Ketoconazole, Clotrimazole, Miconazole, Itraconazole, voriconazole

Inhibit fungal sterol (ergosterol) synthesis

Fluconazole!can cross BBB used for cryptococcal meningitis in AIDS Ketoconazole for Blastomyces, Coccidiodes, Histoplasma, Candida albicans;hypercortisolism Clotrimazole and miconazole for topical fungal infections

Hormone synthesis inhibition !gynecomastia Liver dysfuntion (inhibts cytochrome P-450), fever, chills

Interferons Glycoproteins from human leukocytes that block various stages of viral RNA and DNA synthesis. Induce ribonuclease that degrades mRNA.

IFN-$!chronic hepatitis B,C, Kaposi sarcoma IFN-!! MS IFN-%!NADPH oxidase deficiency

Neutropenia

Micro-Pharm

Neetisha Gupta