Anti-Infective Medications PDF

ANTI-INFECTIVE MEDICATIONS Anti-Bacterial Anti-Viral Anti-Fungal Anti-Protozoal Anti-Helminthic/Anti-Parasitic Anti-Neoplastic/Anti-Cancer Drugs ANTIBACTERIAL DRUGS  MICROORGANISMS AND INFECTIONS Microbes attach to host receptors Attracted to a specific body tissue, invade and...

ANTI-INFECTIVE MEDICATIONS Anti-Bacterial Anti-Viral Anti-Fungal Anti-Protozoal Anti-Helminthic/Anti-Parasitic Anti-Neoplastic/Anti-Cancer Drugs ANTIBACTERIAL DRUGS  MICROORGANISMS AND INFECTIONS Microbes attach to host receptors Attracted to a specific body tissue, invade and multiply Most survive in more than one type of environment Symptoms are result of immune response With most oral antibiotics, liberal fluid intake is recommended Always be aware of pregnancy category before administering medication  HOST DEFENSE MECHANISMS Breaks in skin and mucous membranes Impaired blood supply Neutropenia Malnutrition Poor personal hygiene Suppression of normal flora Diabetes, advanced age or immunosuppression  WHAT IS AN ANTIBIOTIC? An antibiotic is a selective poison. It has been chosen so that it will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways. For example, an antibiotic might inhibit a bacteria's ability to turn glucose into energy, or the bacteria's ability to construct its cell wall. Therefore the bacteria dies instead of reproducing.  HISTORY OF ANTIMICROBIAL THERAPY 1909 Paul Ehrlich Differential staining of tissue, bacteria Search for magic bullet that would attack bacterial structures, not ours. Developed salvarsan, used against syphilis.  HISTORY OF ANTIMICROBIAL THERAPY 1929 Penicillin discovered by Alexander Fleming 1940 Florey and Chain mass produce penicillin for war time use, becomes available to the public. 1935 Sulfa drugs discovered 1944 Streptomycin discovered by Waksman from Streptomyces griseus  CHARACTERISTICS OF ANTI- INFECTIVES Includes antibacterials, antivirals and antifungals Antibacterials (antibiotics) refer to drugs which treat bacterial infections Narrow spectrum Broad spectrum Bactericidal (kills) vs. Bacteriostatic (inhibits growth)  MINIMUM INHIBITORY CONCENTRATION lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium  MODE OF ANTIBACTERIAL ACTION CONCENTRATION-DEPENDENT KILLING ACTION TIME-DEPENDENT KILLING ACTION POST-ANTIBIOTIC EFFECT  TYPES OF ANTIBIOTIC AGENTS Antibiotics differ by mode of action Bacteriostatic compounds inhibit the growth of bacteria Bactericidal compounds directly kill the bacteria Location and severity of infection affect choice of antibiotic  TYPES OF ANTIBIOTIC AGENTS BACTERICIDAL can eradicate an infection in the absence of host defense mechanisms kills bacteria BACTERIOSTATIC inhibits microbial growth but requires host defense mechanisms to eradicate the infection does not kill bacteria TYPES OF ANTIBIOTIC AGENTS CELL WALL SYNTHESIS INHIBITORS Beta Lactams Cell Membrane Inhibitors Vancomycin Bacitracin NUCLEIC ACID SYNTHESIS INHIBITORS Folate Synthesis Inhibitors DNA Gyrase Inhibitors RNA Polymerase Inhibitors PROTEIN SYNTHESIS INHIBITORS 50s Inhibitors 30s Inhibitors  CELL WALL SYNTHESIS INHIBITORS Cell Membrane Inhibitors Polymyxin Vancomycin Bacitracin Beta Lactams Penicillins Cephalosporins Carbapenems Monobactams  BETA LACTAMS Contain a beta-lactam ring that is part of their chemical structure An intact beta-lactam ring is essential for antibacterial activity Include: Penicillins Cephalosporins Carbapenems Monobactams  BETA LACTAMS: MOA Inhibit synthesis of bacterial cell walls by binding to proteins in bacterial cell membranes binding produces a defective cell wall that allows intracellular contents to leak out most effective when bacterial cells are dividing binds to penicillin-binding proteins (PBPs) located in the bacterial cytoplasmic membrane inhibits the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall activates autolytic enzymes that cause lesions in the bacterial cell wall capable of entering the blood brain barrier  PENICILLINS Derived from a fungus Prototype is Penicillin G Widely distributed except in CSF (except if inflammation is present) and in intraocular fluid Most serious complication is hypersensitivity. Can cause seizures and nephropathy.  PENICILLINS PENICILLINS – drug of choice for Syphilis Penicillin G (IV) Penicillin V (Oral) SE: Seizures Anti-Staphylococcal Penicillins Amino-Penicillins (Extended Spectrum Penicillins) Anti-Pseudomonal Pencillins  ANTI-STAPHYLOCOCCAL PENICILLINS Cloxacillin Oxacillin Nafcillin Dicloxacillin Methicillin SE: Interstitial Nephritis, Neutropenia  EXTENDED SPECTRUM PENICILLINS (AMINO-PENICILLINS) Ampicillin Amoxicillin Enhanced effect when used with beta-lactamase inhibitors (Clavulanic Acid, Sulbactam) SE: Pseudomembranous colitis  ANTI-PSEUDOMONAL PENICILLINS Ticarcillin Carbenicillin Piperacillin  CEPHALOSPORINS Also derived from a fungus Broad spectrum with activity against both gram positive and gram negative bacteria Less active against gram positives than penicillins Do not penetrate CSF well w/exception of Ceftin (cefuroxime) and 3rd generation agents  CEPHALOSPORINS Progressively more effective against gram negative pathogens as progress generationally Indications: surgical prophylaxis, treatment infections of the respiratory tract, skin, bone and joints, urinary tract, brain and spinal cord and in septicemia Contraindicated in anaphylaxis to a penicillin May develop a delayed reaction 5 classes of Cephalosporins  1 ST GENERATION CEPHALOSPORINS Cefazolin, Cefadroxil, Cephalexin Uses: UTI, Skin and soft tissue infections, bone infections, surgical prophylaxis (Cefazolin) SE: Hypersensitivity  2 ND GENERATION CEPHALOSPORINS Cefaclor, Cefuroxime, Cefoxitin, Cefprozil, Cefotetan Uses: UTI, Skin and soft tissue infections SE: Disulfiram reaction Cefotetan and Cefoxitin – good activity against abdominal and pelvic infections Cefuroxime – improved action against pneumococcus and H. influenzae  3 RD GENERATION CEPHALOSPORINS Cefoperazone, Cefotaxime, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefixime, Cefpodoxime Proxetil, Cefdinir, Cefditoren Pivoxil, Ceftibuten, Moxalactam Ceftriaxone, Cefixime → Drug of Choice (DOC) for Gonorrhea CefTRIaxone = TRI = 3 = 3rd generation Cephalosporin  4 TH GENERATION CEPHALOSPORINS Cefepime, Ceftaroline, Cefpirome Wide coverage against gram (+) and gram (-) bacteria Uses: Ceftaroline – MRSA  CARBAPENEMS Broad spectrum, bactericidal, beta-lactam anti-microbials. Inhibit synthesis of cell walls. All are parenteral Indicated for organisms resistant to other drugs Examples: Meropenem, Ertapenem  MONOBACTAMS Aztreonam Uses: Klebsiella, Pseudomonas, Serratia SE: GI upset, Vertigo, Headache Aztreonam is also known as the “silver bullet”  INDICATIONS FOR MONOBACTAMS Urinary tract infections Lower respiratory tract infections Skin infections Intra-abdominal and gynecologic infections Septicemia  BETA-LACTAMASE INHIBITORS Inhibits inactivation of penicillins by bacterial beta-lactamase (penicillinase) Clavulanic Acid, Sulbactam, Tazobactam Synergistic with Penicillins Usual combinations include Amoxicillin-Clavulanate Ampicillin-Sulbactam Piperacillin-Tazobactam  ANTIBIOTIC DRUGS OF LAST RESORT Imipenem Amikacin Meropenem Linezolid Streptogramin Vancomycin I AM your Last Shot at Victory  PROTEIN SYNTHESIS INHIBITORS “AT CELLS” 30s and 50s Aminoglycosides Tetracyclines Chloramphenicol Erythromycin (Macrolides) Lincosamides (Clindamycin) Linezolid Streptogramins Buys AT 30, CELLS at 50  AMINOGLYCOSIDES Gentamicin Neomycin Amikacin Tobramycin Streptomycin Spectinomycin  AMINOGLYCOSIDES MOA: Binds to 30s subunit Gentamicin Tobramycin Uses: For Ocular infections SE: Vestibulotoxic and Nephrotoxic  AMINOGLYCOSIDES Spectinomycin Uses: Drug-resistant gonorrhea SE: Anemia Neomycin, Kanamycin, Paromomycin Uses: Skin infections, Visceral leishmaniasis (Paromomycin) SE: most ototoxic aminoglycoside – Kanamycin Streptomycin Uses: Tuberculosis, Tularemia, Enterococcal endocarditis SE: Teratogenic – can cause congenital deafness in the newborn  TETRACYCLINES MOA: Binds at 30s subunit Doxycycline Minocycline Tigecycline Demeclocycline Lymecycline  TETRACYCLINES Doxycycline Uses: Community Acquired Pneumonia (CAP) and Bronchitis SE: GI disturbances, teratogenic (tooth enamel dysplasia/discoloration) Blocks attachment of T-RNA to the acceptor site  CHLORAMPHENICOL MOA: Binds at 50s subunit Uses: Meningitis SE: GI disturbance, aplastic anemia, gray baby syndrome premature neonates are deficient in the enzyme hepatic glucuronosyltransferase = Gray Baby Syndrome Decreased red blood cells Cyanosis Cardiovascular collapse Ashen Gray Skin  MACROLIDES (ERYTHROMYCIN) MOA: Binds at 50s subunit Erythromycin Azithromycin Clarithromycin  MACROLIDES (ERYTHROMYCIN) Uses: Community-acquired pneumonia, Pertussis, Diphtheria, Chlamydial infections SE: GI upset, QT prolongation, Cholestatic hepatitis  LINCOSAMIDES MOA: Binds at 50s subunit Clindamycin Lincomycin Uses: Skin and soft tissue infections, Endocarditis, Toxoplasmosis SE: Pseudomembranous colitis  NUCLEIC ACID SYNTHESIS INHIBITORS Antimetabolites Sulfonamides Trimethoprim TMP-SMX Fluoroquinolones Norfloxacin Ciprofloxacin Levofloxacin  NUCLEIC ACID SYNTHESIS INHIBITORS MOA of Antimetabolites Sulfonamides bacteriostatic inhibitors of folic acid synthesis Trimethoprim selective inhibitor of bacterial dihydrofolate reductase TMP-SMX when the 2 drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis  NUCLEIC ACID SYNTHESIS INHIBITORS MOA of Quinolones Interfere with bacterial DNA synthesis by inhibiting Topoisomerase II and Topoisomerase IV. Exhibit post antibiotic effect May damage growing cartilage and cause arthropathy SE: tendon rupture  QUINOLONES CLASSIFICATIONS 1st generation: Nalidixic acid, Cinoxacin, Oxolinic Acid For urinary tract infections 2nd generation: Ciprofloxacin, Ofloxacin, Norfloxacin, Lomefloxacin For gonococci, mycoplasma, gram (+) and gram (-) bacteria 3rd generation: Levofloxacin, Gemifloxacin, Moxifloxacin For streptococci and enterococci 4th generation: Trovafloxacin, Alatrofloxacin For anaerobes SE: GI distress, CNS effects, tendonitis and tendon rupture  ANTIMYCOBACTERIAL DRUGS Anti-mycobacterial Drugs 1) Mycobacterium tuberculosis (Tuberculosis) 2) Mycobacterium leprae (Leprosy)  ANTIMYCOBACTERIAL DRUGS DRUG THERAPY FOR MYCOBACTERIAL INFECTIONS Chemotherapy is complicated by numerous factors limited information about mechanisms of drug action development of resistance intracellular location of mycobacteria chronic nature of mycobacterial disease patient compliance Chemotherapy always involves the use of drug combinations delay the emergence of resistance to enhance efficacy  ANTIMYCOBACTERIAL DRUGS (ANTI-TB DRUGS) First line agents against Tuberculosis: Isoniazid (H) Rifampicin (R) PyraZinamide (Z) Ethambutol (E) For active TB: All 4 drugs (HRZE) For latent TB: (HR)  DRUGS USED IN LEPROSY Drugs against Leprosy (Mycobacterium leprae) Clofazimine MOA: binds to guanine bases in bacterial DNA Uses: Leprosy SE: GI irritation, skin discoloration Dapsone MOA: inhibition of folic acid synthesis Uses: Leprosy, PCP pneumonia Most active drug against M. leprae  MISCELLANEOUS ANTIBACTERIALS Metronidazole MOA: Reactive reduction by ferredoxin forming free radicals that disrupt electron transport chain. Bactericidal. Uses: Vaginitis, Brain abscess, Protozoal infections SE: Metallic taste Drug of choice for the following diseases: Amoebiasis Giardiasis Pseudomembranous colitis ANTIVIRAL AGENTS Joseph Peter V. Arguillas, MD  VIRUSES Intracellular parasites Enter host, bind to receptors on cell membranes Use cellular metabolic activities for replication May be DNA or RNA viruses DNA viruses incorporate into chromosomal DNA, produce new viruses RNA viruses must be converted to DNA by reverse transcriptase in order to replicate Induce antibodies and immunity Protein coat allows host recognition as foreign vs. self  VIRAL ILLNESSES Herpes Simplex Virus 1 Herpes Simplex Virus 2 Cytomegalovirus Varicella-Zoster Influenza RSV Rotavirus HIV and AIDS  UNDERSTANDING VIRUSES Viral replication A virus cannot replicate on its own It must attach to and enter a host cell It then uses the host cell’s energy to synthesize DNA, RNA, Protein Viruses are difficult to kill because they live inside the cells Any drug that kills a virus may also kill cells  VIRAL INFECTIONS Competent immune system Best response to viral infections A well-functioning immune system will eliminate or effectively destroy virus replication Immunocompromised patients have frequent viral infections Cancer patients, especially leukemia or lymphoma Transplant patients, due to pharmacologic therapy AIDS patients, disease attacks immune system  ANTIVIRAL DRUGS CLASSIFICATIONS Blocks Viral Attachment and Entry Efuvirtide, Docosanol, Maraviroc, Palivizumab Blocks Uncoating of Virus Amantadine, Rimantadine Blocks Nucleic Acid Synthesis NRTIs, NNRTIs, Nucleoside and Nucleotide analogs Blocks Integration/Transcription Integrase Inhibitors (Raltegravir) Blocks Viral Protein Synthesis Protease Inhibitors (Indinavir) Blocks Viral Release Neuraminidase inhibitors (Oseltamivir)  ANTIVIRAL DRUGS CLASSIFICATIONS Drugs for HIV Drugs for Influenza Amantadine Zanamivir Drugs for HBV and HCV Drugs for Herpesvirus Acyclovir Ganciclovir Foscarnet  DRUGS FOR HERPESVIRUS Acyclovir, Valacyclovir, Penciclovir, Famciclovir, Docosanol MOA: Activated by viral thymidine kinase (TK) to different forms that inhibit viral DNA polymerase Indications: HSV-1, HSV-2, Varicella Zoster Virus SE: Nausea, Diarrhea, Headache, Delirium, Hypotension, Nephrotoxicity Docosanol inhibits fusion between the HSV envelope and plasma membranes  DRUGS FOR HERPESVIRUS Ganciclovir, Cidofovir MOA: Inhibits viral DNA polymerase, causing chain termination. Indications: CMV (Cytomegalovirus) SE: Leukopenia, Thrombocytopenia, Mucositis, Hepatotoxicity, Seizures, Neutropenia  DRUGS FOR HERPESVIRUS Foscarnet (Pyrophosphate Analogue) MOA: Inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase. Binds to pyrophosphate binding site. Indications: CMV retinitis, Acyclovir-resistance, HSV infection in patients with AIDS SE: Nephrotoxicity, Electrolyte abnormalities (hypocalcemia), Genitourinary ulceration, CNS effects (headache, hallucinations, seizures)  DRUGS FOR INFLUENZA UNCOATING INHIBITOR Amantadine, Rimantadine MOA: Inhibit early step replication and prevent uncoating by binding to M2 proton channels Uses: Influenza A SI: GI irritation, Dizziness, Cerebellar dysfunction, Livedo reticularis Amantidine is also used in treating Parkinsonism  DRUGS FOR INFLUENZA NEURAMINIDASE INHIBITOR Oseltamivir, Zanamivir, Peramivir MOA: Inhibits Neuraminidase. Decreases release of progeny virus. Uses: Influenza A and B, Shortens duration of symptoms SE: Oseltamivir: Gastrointestinal effects Zanamivir: Bronchospasm in asthmatics OSELTAMIVIR: Presently the drug of choice for influenza (including H1N1)  DRUGS FOR HEPATITIS B AND C Interferon-A (IFN-A) [X] MOA: Degrades viral RNA via activation of host cell RNAse (ribonuclease) Uses: HBV infection, HCV infection, Kaposi sarcoma, Genital warts Alopecia, Myalgia, Depression, Flu-like syndrome, Thyroid dysfunction, Hearing loss Contraindications: autoimmune disease, history of cardiac arrhythmias and ___________ ?  DRUGS FOR HEPATITIS B AND C Ribavirin [X] MOA: Inhibits guanosine triphosphate formation. Prevents capping of viral mRNA. Blocks RNA-dependent RNA polymerases. HCV infection, RSV (Respiratory Syncytial Virus) infection SE: Hemolytic anemia, Conjunctival and bronchial irritation, Teratogen  DRUGS FOR HEPATITIS B AND C Lamivudine, Adefovir, Entecavir, Telbivudine, Tenofovir, Clevudine MOA: Inhibits HBV DNA polymerase. Hepatitis B infection, HIV infection (Lamivudine) SE: Adefovir: Lactic acidosis, renal and hepatic toxicity Entecavir: Headache, Dizziness, Fatigue, Nausea ANTIFUNGAL AGENTS  FUNGI (MYCOSES) Mild or life threatening Widely present in environment Development of antifungals difficult because fungal cells closely resemble human cells Dermatophytes—tinea capitis, tinea pedis, tinea cruris, tinea corporis Examples: Candida, Aspergillosis, Cryptococcus, Histoplasmosis,  ANTIFUNGAL DRUGS DRUGS ACTING ON FUNGI Alters cell membrane permeability Azoles, Polyenes, Terbinafine Blocks Beta-glucan synthesis Echinocandins Block nucleic acid synthesis Flucytosine Disrupt microtubule functions Griseofulvin  MICROTUBULE INHIBITORS Griseofulvin MOA: Interferes with microtubule function. Inhibits synthesis and polymerization of nucleic acids. Fungistatic. Uses: Dermatophytosis SE: Headache, Confusion, GI irritation, Photosensitivity, Hepatotoxicity, Disulfiram reaction  MICROTUBULE INHIBITORS Allylamine MOA: Interfere with ergosterol synthesis by inhibiting fungal squalene oxidase. Fungicidal. Uses: Dermatophytosis, Onychomycosis SE: Headache, Confusion, GI irritation, Photosensitivity, Hepatotoxicity, Disulfiram reaction  CELL MEMBRANE PERMEABILITY INHIBITORS POLYENES Nystatin, Natamycin MOA: Binds to ergosterol in fungal cell membranes, forming artificial pores. Fungicidal. Uses: Candidiasis (Oropharyngeal, Esophageal, Vaginal) SE: Nephrotoxicity  CELL MEMBRANE PERMEABILITY INHIBITORS POLYENES Amphotericin B MOA: Binds to ergosterol in fungal cell membranes, forming artificial pores. Fungicidal. Uses: Systemic fungal infections SE: Nephrotoxicity, Infusion reactions (chills, fever, hypotension) Control infusion reactions by slowing rate of infusion and premedication with antihistamines Has the widest antifungal spectrum  CELL MEMBRANE PERMEABILITY INHIBITORS AZOLES Clotrimazole, Miconazole, Ketoconazole, Itraconazole MOA: Inhibit fungal P450-dependent enzymes blocking ergosterol synthesis. Fungistatic. Uses: Mucocutaneous candidiasis, Dermatophytosis, Seborrheic dermatitis, Pityriasis versicolor SE: Nonsignificant when administered topically Limited to topical use because of systemic toxicity  AZOLES Ketoconazole, Itraconazole Uses: Dermatophytosis, Chronic mucocutaneous candidiasis Limited to topical use because of systemic toxicity Resistance is due to changes in the sensitivity of target enzyme  AZOLES Fluconazole Uses: Cryptococcal meningitis, Candidiasis Alternative to Amphotericin B in the treatment of C. neoformans Good CNS penetration ANTIPROTOZOAL AGENTS  ANTIPROTOZOAL DRUGS DRUGS FOR MALARIA Chloroquine, Artemisins, Mefloquine, Primaquine, Tafenoquine, Quinine, Antifolates DRUGS FOR AMEBIASIS Metronidazole, Diloxanide, Emetine, Iodoquinol DRUGS USED FOR OTHER PARASITES Pentamidine, Melarsoporol, Nirfurtimox, Suramin, Sodium stibogluconate, Eflornithine  DRUGS FOR AMEBIASIS Disease forms of Amebiasis: Asymptomatic intestinal colonization Luminal agent (diloxanide furoate, iodoquinol, paromomycin Amebic Colitis (Dysentery) Metronidazole or Tinidazole plus Luminal agent* Amebic Liver Abscess Metronidazole or Tinidazole plus Luminal agent* ANTIHELMINTHIC AGENTS  ANTIHELMINTHIC AGENTS Drugs against Nematodes Albendazole, Mebendazole, DEC, Mebendazole, Pyrantel Pamoate Drugs against Cestodes Praziquantel, Albendazole, Mebendazole, Niclosamide Drugs against Trematodes Praziquantel, Bithionol  DRUGS AGAINST NEMATODES Albendazole MOA: Microtubule inhibitors Uses: Ascariasis, Hookworm, Pinworm SE: Reversible leukopenia, Alopecia, Elevation of liver function tests, Bone marrow suppression  DRUGS AGAINST NEMATODES Diethylcarbamazine MOA: Microtubule inhibitors and paralysis of the worms Uses: Filariasis SE: Filarial Fever Causes Mazzoti reaction ANTINEOPLASTIC AGENTS  CANCER CHEMOTHERAPY LOG-KILL HYPOTHESIS Anticancer drugs kill a fixed proportion of a tumor cell population, not a fixed number of tumor cells Drug combinations are done to achieve 1) Synergism 2) Prevention of drug resistance Targets both cancer cells that are highly dividing (use of cell cycle specific) and cancer cells with low growth fraction (use of cell cycle non-specific drugs) at the same time.  CANCER CHEMOTHERAPY CANCER TREATMENT MODALITIES PRIMARY INDUCTION CHEMOTHERAPY drug therapy is administered as the primary treatment NEOADJUVANT CHEMOTHERAPY use of chemotherapy in patients with localized cancer before performing local therapy surgery goal is to render the local therapy more effective ADJUVANT CHEMOTHERAPY chemotherapy done after local treatment procedures such as surgery or radiation reduce the risk of local and systemic recurrence and to improve disease-free and overall survival  CHEMOTHERAPY AND ITS TOXICITIES Cisplatin/Carboplatin Vincristine Doxorubicin Bleomycin Cyclophosphamide Methotrexate 5-Flurouracil 6-Mercaptopurine Chemo-Man