CHEMO PHARM(MAM)(1).pptx

CHEMOTHERAPY  ANTIMALARIA ANTI-HELMINTHIC ANTICANCER ANTI-FUNGAL ANTIBACTERIAL ANTI PROTOZOA  Read Principles of chemotherapy Read Cancer chemotherapy slide Resistance to Antimicrobial Drugs Mechanisms of resistance Enzymes that cleave or otherwise inactivate antibiotics...

CHEMOTHERAPY  ANTIMALARIA ANTI-HELMINTHIC ANTICANCER ANTI-FUNGAL ANTIBACTERIAL ANTI PROTOZOA  Read Principles of chemotherapy Read Cancer chemotherapy slide Resistance to Antimicrobial Drugs Mechanisms of resistance Enzymes that cleave or otherwise inactivate antibiotics -β-lactamases Changes in bacterial permeabilities -Prevents entry of antibiotic into cell Mutation in target molecule -Alter binding characteristics of the antibiotics Alteration of metabolic pathways -Some resistant bacteria can acquire PABA from the environment Molecular pumps (efflux systems) -Secretion systems that export antibiotics faster than the rate of import Non-genetic Origins of Drug Resistance Low replication rates -Antibiotic is metabolized or neutralized before it acts -Mycobacteria spp. Alteration of cellular physiology -Bacterial L forms are cell wall-free -Streptococcus spp., Treponema spp., Bacillius spp., others Colonization of sites where antibiotics cannot reach -Gentamicin cannot enter cells -Salmonella are thus resistant to gentamicin Genetic Origins of Drug Resistance Chromosomal Resistance Genes that regulate susceptibility Often found in enzymes, rRNA and secretion system genes Mutations in RNA polymerase render it resistant to the effects of rifampin Efflux pumps with specificity for antibiotics Found in all bacteria All possess large hydrophobic cavity for binding antibiotics  Malaria Transmission Cycle Exo-erythrocytic (hepatic) Cycle: Sporozoires injected Sporozoites infect liver cells and into human host during develop into schizonts, which release blood meal merozoites into the blood Parasites mature in mosquito midgut and Dormant liver stages MOSQUITO HUMAN migrate to (hypnozoites) of P. salivary vivax and P. ovale glands Erythrocytic Cycle: Merozoites infect red blood cells to form Some merozoites schizonts Parasite undergoes sexual reproduction in differentiate into male or the mosquito female gametocyctes  P.falciparum, malariae vivax,ovale, knowlesi Tissue schizonticides That eliminate pre erythrocytic/exo- erythrocytic stages in liver (P.vivax and ovale) Erythrocytic schizonticides act on erythrocytic parasites -(P.falciparum) Gametocides kill gametocytes in blood and prevent transmission to mosquitoes Erythrocytic Tissue Gametocides schizonticide schizonticide 1) Artemesinin Primaquine Primaquine 2) Chloroquine Proguanil 3) Amodiaquine Doxycycline 4) Quinine 5) Mefloquine 6) Halofantrine 7) Lumifantrine 8) Atovaquone LOW EFFICACY Proguanil Pyrimethamine Sulfonamides Tetracyclins Clindamycin  Clinical cure Terminate the episode of malarial fever. Erythrocytic schizonticide are used to terminate the episode of malarial fever Radical cure eliminate both hepatic and erythrocytic stages Vivax & ovale Erythrocytic schizonticide + Tissue schizonticide CQ + primaquine  Recrudescence is when symptoms return after a symptoms free period. It is due to parasites surviving in the blood as a result of inadequate or ineffective treatment. Seen in P.falciparum Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozites in liver cells Seen in vivax and ovale  Causal prophylaxis Pre-erythrocytic phase which is the cause of malarial infection and clinical attacks is the target for this purpose Primaquine is the causal prophylactic for all species of malaria Suppressive propylaxis Schizonticides which suppress the erythrocytic phase and thus attacks of malarial fever can be used as prophylactics Clinical disease does not appear DRU Chloroquine QUININE Amodiaquine Mefloquine Piperaquine GS MOA Binds to heme forming a same except that identical to CQ same same complex----> a quinine-heme : This inhibits the complex is formed but slower onset formation of the non- MOA/use ,adv of action toxic hemozoin.-----> erse compared CQ Heme is toxic to the effect ,resista MP. The increased pH nce and the accumulation of heme result in oxidative damage to the phospholipid membranes----> leading to lysis of both faster acting the parasite and the red than CQ, blood cel cheaper SIDE Retinal damage/loss of Less effective Agranulocytos EFFE vision( long term use). and more toxic is CTS GI (Nausea, vomiting, than chloroquine. hepatotoxicity abdominal *Cinchonism pain, )headache, *Hypoglycemia anorexia, malaise, and *Hemolysis in urticaria G6PD  when chloroquine is administered by the parenteral route, its entry is rapid and removal is slow and this may lead to toxic concentration which may prove fatal. Therefore , to prevent this problem whenever chloroquine has to be administered by parenteral route it should be given as follows. I.V route – slow infusion ; S.C/ I.M – small divided doses. Oral route is safer as the absorption and distribution correlated closely. The peak concentration is achieved in 3- 5 hours after oral administration..  choloroquine resistance is due to decreased accumulation of the drug in the food vacuole - PYRIMETHAMINE Selective anti-malarial action depends on high affinity for plasmodial enzyme.. Pyrimethamine is a slowly acting erythrocytic schizontocide, Pyrimethamine is not used alone for malaria; it is available as a fixed-dose combination with sulfadoxine, a sulfonamide antimicrobial. Resistance to this combination has developed, so it is usually administered with MOAother agents,Adverse such as artemisinin derivatives. (Artesunate-sulphadoxine pyrimethamine) effect(combo) inhibits plasmodial Exfoliative DHFR---> dermatitis, Stevens No synthesis johnson syndrome, THF(required for etc. due to the nucleic acid sulfonamide formation) SULFONAMIDE-PYRTMETHAMINE(S/P) COMBINATION Supra-additive synergistic combination due to sequential block Clinical curative, particularly for P.falciparum. Efficacy against P. vivax is rather low. Due to adverse effect, use is restricted to single dose treatment of uncomplicated chloroquine- resistant falciparum malaria, or in patients intolerant to chloroquine. The major importance of this combination is due to its efficacy against chloroquine-resistant P. Tetracycline and doxycycline Weak erythrocytic schizonticidal All plasmodial species: Cq, MQ, S/P resistant P. falciparum Never used alone Combination with quinine for treatment of CQ resistant falciparum & vivax malaria  Artemisinin MOA Adverse Effect artemisinin derivatives are metabolized in mild the food vacuole nausea, vomiting, and diarrhea of the parasite forming toxic free radicals --- > that damage parasite membrane and proteins It is active against P. falciparum resistant to all other anti-malarial drugs as well as sensitive strains of other malarial species Quick defervescense and parasitemia clearance( Same pore formation in p.membrane -->electrolytes(K) leak out ---->cell death low TI N Broad spectrum too toxic for sytemic use used for most sytemic infections given orally treat superficial candidiasis of mouth, esophagus or *minimal penteration to Csf intestinal tract, /vitreous humor -----given vaginal candidiasis(pessiary) intrathecally in meningitis to compensate for this cutaneous candidasis with flucocystine(makes membrane more permeable to flucocystine) CE Decreased ergosterol content in the cell membrane CT Hypokalemia NOTE infusion related( fever, chills, AMPHOTERICIN IS poorly muscle spasms, vomiting, and absorbed from the a shock-like fall in blood pressure) gastrointestinal tract and AZOLES(fungistatic) IMIDAZOLES (mikt) TRIAZOLES (FIV) used topically for cutaneous infections used systemically for both cutaneous and systemic infections They lack selectivity, selective inhibits human gonadal and steroid synthesis leading less endocrine disturbances to decreased testosterone and cortisol production. It also inhibits cytochrome P450 –dependant hepatic penetrate cns drug –metabolizing enzyme.  Squalene ----(1)----> Lanosterol-----(2)----->Ergosterol (1)-squalene epoxidase ------inhibited by Allyamines (2)-14 alpha demethylase-----inhibited by Azoles KETOCONAZOLE FLUCONAZOLE ITRACONAZOLE VORICONAZOLE only administered -Least active triazole Broad spectrum similar to orally itraconazole but can be used to treat -Effective against yeast -Mainly used for dimorphic more potent systemic infections and some dimorphic org org(coccidiomycosis)bu -Replaced -CI with amphotericin B t itraconzole is better for Alternative for treatment of amphotericin in others Aspergillus, Coccidioides, treatment of -DOES NOT ENTER CSF Cryptococcus, invasive -Bioavailability is decreased - penetate CNS; flucanozole resisitant candida candiaisis and with H-2 blocking drugs, cryptococcus/coccidiomy aspergillosis proton pump inhibitors and cosis menigitis used extensively in the antacids and is impaired with treatment of -reversible visual food. -Prophylaxis BM dermatophytoses, disturbances -Dose dependent transplant especially onychomycosis nausea ,anorexia ,vomitting -used for vulvovaginal candidiasis / SIDE EFFECTS OF does not penetrate csf IMIDAZOLES adequately,not used for meningitis  Posaconazole—The broadest-spectrum triazole, posaconazole has activity against most species of Candida and Aspergillus. It is the only azole with activity against Rhizopus, one of the agents  Flucocystine Griseofulvine Echinocandins (PYRIMIDINE ANTIMETABOLITE) (caspofungin,m icafungin,anidu lafungin) MOA It is converted to antimetabolite 5-florouracil in a fungal but not Interferes with inhibit D-glycan human cell. microtubule synthesis This 5-FU inhibits------> thymidylate synthetase enzyme and------> thus DNA synthesis. function in dermatophytes (F fungicidal and may also inhibit the CNS distribution synthesis and polymerization of nucleic acid not active orally NARROWSPECTRUM given orally not active topically INDICATION yeast Mycotic diseases of especially useful it is fungistatic,effective in combination with itraconazole for skin, hair for aspergillus treating chromoblastomycosis and with amphotericin for (particularly for scalp) , nail. and candida. treating cryptococosis. For cryptococcal meningitis in AIDS patients combo with amphotericin) used for It is also highly effective in athlete's disseminated and foot mucocutaneous Candida infections in replaced by azoles patients who fail and terbinafine to respond  Uses of antifungal drugs Disease Drug used Systemic infections systemic candidiasis Amphotericin, flucytocin, , fluconazole. Cryptococcosis( meningitis) Amphotericin, flucytocin , fluconazole, itraconazole systemic aspergillosis itraconazole Amphotericin, Blastomycosis itraconazole Amphotericin, Histoplasmosis Amphotericin, itraconazole ,fluconazole. Coccidiomycosis fluconazole. itraconazole ,Amphotericin, Paracoccidiomycosis fluconazole. itraconazole ,Amphotericin, Mucormycosis Amphotericin, flucytocin ,Amphotericin, Disseminated sportrichosis Amphotericin, flucytocin Anti fungal drugs used for topical fungal infections Topical anti fungal preparations 1. Topical azole derivatives 2. Ciclopirox olamine 3. Naftifine 4. Terbinafine 5. Butenafine 6. tolnaftate 7. Nystatin and Amphotericin. Terbinafine 1. Mechanism of action—Terbinafine inhibits a fungal enzyme, squalene epoxidase It causes accumulation of toxic levels of squalene, which can interfere with ergosterol synthesis. Terbinafine is fungicidal. 2. Clinical uses and toxicity—Terbinafine is available in both oral and topical forms. Like griseofulvin, terbinafine accumulates in keratin, but it is much more effective than griseofulvin in onychomycosis. Adverse effects include gastrointestinal upsets, rash, headache, and taste disturbances. Terbinafine does not inhibit cytochrome P450 Oral anti fungal agents used for topical infections 1. griseofulvin 2. oral azoles 3. Terbinafine 4. clotrimazole(cutaneous/vulvovaginal candidiasis) 5. itraconazole(onychomycosis) 6. Naftifine(broad spectrum -Effective for tropical treatment of tinea cruris.) 7. Tolnaftate: (Effective in most cutaneous mycosis. It is ineffective against Candida. In tinea pedis cure rate is around 80%.  ANTI-CANCER  Cell cycle phase – specific agents with major activity in a particular phase of cell cycle schedule dependent Cell cycle phase – nonspecific agents with significant activity in multiple phases dose dependent  Chemotherapy Alkylating agents Antibiotics nitrogen mustards doxorubicin, daunorubicin thiotepa, busulfan idarubicin, bleomycin, mitoxantrone nitrosoureas, mitomycin Antimetabolites procarbazine, dacarbazine methotrexate Steroid hormones and their 6-mecaptopurine antagonists 5-flourouracil Prednisone, tamoxifen Microtubule Inhibitors Flutamide vincristine, vinblastine Monoclonal Antibodies Other agents Cetuximab, Rituximab asparaginase Tyrosine Kinase Inhibitors Hydroxyurea Imatinib, Nilotinib Cisplatin, etoposide Erlotinib, Dasatinib  ANTI-METABOLITES DRUG METHOTREXATE MERCAPTOPU CYTARABINE 5- Gemcitabine RINE (pyrimydine FLUOROURACI & antimetabolite) L Thioguanine MOA inhibts DHFR--> THF4 is Drugs are phosphorylated Fluorouracil is A deoxycytidine not formed-- activated by by nucleotide converted in cells analog that >decreased hypoxanthine- kinase , which to 5- is converted into thymydilate synthase -- guanine activates it to-- deoxyuridine- the active >decreased DNA phosphoribosyltra >ara-CTP --> monophosphate diphosphate and production nsferases inhibits DNA (5-FdUMP), which triphosphate (HGPRTases) polymerase inhibits nucleotide form. to toxic thymidylate inhibit nucleotides that synthase and ribonucleotide inhibit several leads to reductase and Doesnt penetrate CNS enzymes “thymineless thereby diminish involved in purine death” of rapidly the pool of metabolism. dividing cells deoxyribonucleosi de triphosphates required for DNA synthesis. CYCLE S cycle specific Resistant tumor S cyle specific used in bladder, SPECIFICI cells have a (Resistance to breast, colon, TY decreased cytarabine can anal, head and activity of occur as a result neck, liver, and HGPRTase, or of its they may decreased uptake ovarian cancers increase their or its decreased  CAPECITABINE same MOA with 5FU INDICATION-metastatic breast /colorectaCA because of deamination to the noncytotoxic ara-U by cytidine Leucovorin is administered with 5-FU, because the reduced folate coenzyme is required in the thymidylate synthase inhibition.deaminase in the intestinal mucosa and liver  ANTI-TUMOR ANTIBIOTICS DRUGS ANTHRACYCLINES BLEOMYCIN Mitomycin MOA -Inhibit topoisomerase2 Bleomycin is a mixture of Mitomycin is a CCNS -generate free radicals glycopeptides that drug that is metabolized by leading to membrane generates free radicals, liver enzymes to form an damage which bind to DNA, cause alkylating agent strand breaks, that cross-links DNA and inhibit DNA synthesis. INDICATION Daunorubicin--treating acute hodgkin lymphoma Mitomycin acts against leukemia (AML, ALL, CML) and testicular cancer hypoxic tumor cells and neuroblastoma. is used in combination Idarubicin: treating acute regimens for myeloid leukemia. adenocarcinomas of the G (2)PHASE SPECIFIC cervix, Doxorubicin stomach, pancreas, and Hodgkin/nonhodgkin lymphoma, lung myelomas, sarcomas, and breast, lung, ovarian, and thyroid cancers. ADVERSE EFFECT irrversible dose pulmonary toxicity severe myelosuppression dependent Hypersensitivity reactions and is cardiotoxicity. cutaneos reaction toxic to the heart, liver, adminster lung, and kidney dexrazoxane(decrease free radical production) Bm suppression alopecia  ALKYLATING AGENT DRUGS CYCLOPHOSPHAMIDE. Platinum Procarbazine & ifophosphamide Mechlorethamin Analogs e (Cisplatin, Carboplatin, Oxaliplatin) MOA phosphamide are first biotransformed to spontaneously used as a component Procarbazine is a hydroxylated intermediates primarily in converts in the body of reactive agent that the liver by the CYP450 system. to a reactive regimens for forms The hydroxylated intermediates then cytotoxic product. testicular carcinoma hydrogen peroxide, undergo breakdown to form the active and for cancers of the which generates free compounds, phosphoramide mustard bladder, radicals that cause and acrolein. lung, and ovary DNA strand scission Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. Phosphoramide mustard prevents cell division by forming cross-linkages between and within DNA strand. SIDE Hemorrhagic cystitis(bladder Gastrointestinal Cisplatin causes myelosuppressant EFFECT fibrosis)------use IV distress, gastrointestinal and causes MESNA+hydration to neutralize myelosuppression, distress and mild gastrointestinal it alopecia, hematotoxicity and is irritation, CNS myelosupression,GI and sterility are neurotoxic dysfunction, distress,SIADH,pulmonary/cardia common (peripheral neuritis peripheral c/neurotoxicity and acoustic neuropathy,  Busulfan is sometimes used in chronic myelogenous leukemia. It causes adrenal insufficiency, pulmonary fibrosis, and skin pigmen_x0002_tation. Carmustine and lomustine are highly lipid-soluble drugs used as adjuncts in the management of brain tumors. Dacar_x0002_bazine is used in regimens for Hodgkin’s lymphoma. It causes alopecia, skin rash, gastrointestinal distress, myelosuppression, phototoxicity, and a flu-like syndrome  Nitrosoureas Carmustine [KAR-mus-teen, BCNU] and lomustine [LOE-mus-teen, CCNU] are closely related nitrosoureas. Because of their ability to penetrate the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors. 1. Mechanism of action The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily in cells that are actively dividing. Therefore, nondividing cells can escape death if DNA repair occurs. Nitrosoureas also inhibit several keyenzymatic processes by carbamoylation of amino acids in proteins in the targeted cells. 2. Pharmacokinetics Carmustine is administered IV and as chemotherapy wafer implants, whereas lomustine is given orally. Because of their lipophilicity, these agents distribute widely in the body and readily penetrate the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the nitrosoureas  NATURAL PRODUCT ANTICANCER DRUGS DRUGS MICROTUBULE INHIBITORS Vincristine(VX)/Vinblastine(VBL) Paclitaxel and Docetaxel (vinca alkaloids) (Taxanes) MOA Bind to the microtubular protein (tubulin) unlike the Vinca alkaloids. blocking the ability of tubulin to polymerize Promote polymerization and stabilization of the polymer to form microtubules. rather than disassembly, Instead, aggregates consisting of tubulin leading to the accumulation of microtubules. The dimers and the alkaloid drug are formed. microtubules formed are overly stable and nonfunctional, and chromosome This leaves a desegregation does not occur. This results in cell death. dysfunctional spindle apparatus, frozen in Active on the G2/M phase metaphase, preventing chromosomal segregation and cell proliferation BLOCK M PHASE INDICATI VX solid ON Wilms tumor, Ewing soft tissue sarcoma, and tumors, including breast, ovarian, lung, gastroesophageal, Hodgkin prostate, and non-Hodgkin lymphomas,acute bladder, and head and neck cancer leukaemia VBL systemic Hodgkin and non-Hodgkin lymphomas. metastatic testicular carcinoma SIDE VBL and vinorelbine cause gastrointestinal Paclitaxel causes neutropenia, thrombocytopenia, a EFFECT distress, alopecia, and bone marrow high incidence of peripheral neuropathy, and possible suppression. hypersensitivity reactions during infusion. VX does not cause serious myelosuppression Docetaxel causes neurotoxicity  Etoposide and Teniposide 1. Mechanisms—Etoposide, a semisynthetic derivative of podophyllotoxin, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. 2. Pharmacokinetics—Etoposide is well absorbed after oral administration and distributes to most body tissues. Elimination of etoposide is mainly via the kidneys, and dose reductions should be made in patients with renal impairment. 3. Clinical use— These agents are used in combination drug regimens for therapy of lymphoma, and lung, germ cell, and gastric cancers. 4. Toxicity—Etoposide and teniposide are gastrointestinal irritants and cause alopecia and bone marrow suppression.  Topotecan and Irinotecan 1. Mechanisms— The 2 camptothecins, topotecan and irinotecan, produce DNA damage by inhibiting topoisomer_x0002_ase I. They damage DNA by inhibiting an enzyme that cuts and religates single DNA strands during normal DNA repair processes. 2. Pharmacokinetics—Irinotecan is a prodrug that is converted in the liver into an active metabolite, SN-38. Topotecan is eliminated renally, whereas irinotecan and its metabolite are eliminated in the bile and feces. Genetic variation markedly affects irinotecan metabolism (Chapter 5). Excessive toxicity is seen in individuals with variants of UGT1A that result in low glucuronidation activity. 3. Clinical use—Topotecan is used as second-line therapy for advanced ovarian cancer and for small cell lung cancer. Irinotecan is used for metastatic colorectal cancer. 4. Toxicity—Myelosuppression and diarrhea are the 2 most common toxicities  HORMONAL ANTICANCER AGENTS DRUGS GnRH ANALOGS Aromatase Gonadal Hormone Glucocorticoids (Leuprolide, goserelin, inhibitors Antagonists and triptorelin) (Anastrozole and letrozole,Exemes tane MOA GnRH is normally secreted by the Anastrozole and Tamoxifen hypothalamus and stimulates the letrozole inhibit a selective estrogen anterior pituitary to secrete the Prednisone is the aromatase, the receptor modulator , most commonly used gonadotropic hormones: 1) LH the enzyme that blocks the binding of glucocorticoid in primary stimulus for the secretion of testosterone by the testes and 2) FSH catalyzes the estrogen to receptors cancer which stimulates the secretion of conversion of of estrogen-sensitive chemotherapy and is estrogen. androstenedione (an cancer cells in breast widely used in Leuprolide,goserelin and triptorelin androgenic precursor) tissue. combination therapy are synthetic analogs of GnRH. to estrone (an Flutamide for The GnRH analogs occupy estrogenic -competitively blocks leukemias and the GnRH receptor in the hormone).nonsteroi the binding of lymphomas pituitary. Due to continuous dal androgen to androgen stimulation of the receptors in the receptor ,desensitization Exemestane prostate.others occurs leading to inhibition steroidal, irreversible nilutamide of release of FSH and LH. inhibitor of aromatase bicalutamide and Thus, both androgen and enzalutamide estrogen synthesis are reduced INDICATI Prostate cancer Breast CA Breast CA ON Prostate CA  Tyrosine Kinase Inhibitors Imatinib is an example of a selective anticancer drug. MOA It inhiBits the tyrosine kinase activity of the protein product of the bcr-abl oncogene that is commonly expressed in chronic myelogenous leukemia (CML) associated with the Philadelphia chromosome translocation. imatinib is effective for treatment of gastrointestinal stromal tumors that express the c-kit tyrosine kinase, which is also inhibited. Resistance may occur from mutation of the bcr-abl gene. Toxicity includes diarrhea, myalgia, fluid retention, and congestive heart failure. Dasatinib, nilotinib, and bosutinib are newer anticancer kinase inhibitors  Growth Factor Receptor Inhibitors Trastuzumab, a monoclonal antibody, recognizes a surface protein in breast cancer cells that overexpress the HER-2/neu receptor for epidermal growth factor. Acute toxicity of this antibody includes nausea and vomiting, chills, fevers, and headache. Trastuzumab may cause cardiac dysfunction, including heart failure. Several drugs inhibit an epidermal growth factor receptor (EGFR) that is distinct from the HER-2/neu receptor for the epidermal growth factor that is targeted by trastuzumab. The EGFR regulates signaling pathways involved in cellular proliferation, invasion and metastasis, and angiogenesis. It is also implicated in inhibiting the cytotoxic activity of some anticancer drugs and radiation therapy. Cetuximab is a chimeric monoclonal antibody directed to the extracellular domain of the EGFR. It is used in combination with irinotecan and oxaliplatin for metastatic colon cancer and is used in combination with radiation for head and neck cancer. Its primary toxicity is skin rash and a hypersensitivity infusion reaction. Panitumumab is a fully human monoclonal antibody directed against the EGFR; it is approved for refractory metastatic colorectal cancer. Gefitiniband erlotinib are small molecule inhibitors of the EGFR’s tyrosine kinase domain. Both are used as second-line agents for non- small cell lung cancer, and erlotinib is also used in combina_x0002_tion therapy of advanced pancreatic cancer. Rash and diarrhea are the main toxicities. Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents it from interacting with VEGF receptors. VEGF plays a critical role in the angiogen_x0002_esis required for tumor metastasis. Bevacizumab has activity in colorectal, breast, non-small cell lung, and renal cancer. Adverse effects include hypertension, infusion reactions, arterial throm_x0002_bosis, impaired wound healing, gastrointestinal perforation, and proteinuria. Ziv-aflibercept also interferes with VEGF function. It is a recombinant fusion protein of the VEGF binding portions from the extracellular domains of human VEGF receptors 1 and 2, fused to the Fc portion of human IgG1. Sorafenib, sunitinib, and pazopanib are small molecules that inhibit multiple receptor tyrosine kinases (RTKs), including those associated with the VEGF receptor family. They are metabolized by CHAPTER 54 Cancer Chemotherapy 447 CYP3A4, and elimination is primarily hepatic. Hypertension, bleed_x0002_ing complications, and fatigue are the most common adverse eff  C. Rituximab A monoclonal antibody that binds to a surface protein in non-Hodgkin’s lymphoma cells and induces complement-mediated lysis, direct cytotoxicity, and induction of apoptosis. It is currently used with conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low-grade lymphomas. Rituximab is associated with hypersensitivity reactions and myelosuppression. D. Interferons The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions. Alpha-interferons are effective against a number of neoplasms, including hairy cell leukemia, the early stage of chronic myelogenous leukemia, and T-cell lymphomas. Toxic effects of the interferons include myelosuppression and neurologic dysfunction. E. Asparaginase Asparaginase is an enzyme that depletes serum asparagine; i used in the treatment of T-cell auxotrophic cancers (leukemia and lymphomas) that require exogenous asparagine for growth. Asparaginase is given intravenously and may cause severe hypersensitivity reactions, acute pancreatitis, and bleeding. F. Proteasome Inhibitors Bortezomib and carfilzomib are inhibitors of the chymotrypsinlike activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins, such as cyclin-dependent kinases. Inhibition results in down-regulation of the nuclear factor kappa B (NF-κB) signaling pathway. Adverse effects include peripheral neuropathy, thrombo_x0002_cytopenia, heart failure, and hypotension. It is currently used for the treatment of multiple myeloma.  ANTI BACTERIA CLASSIFICATION Cell wall inhbitors MOA RESISTANCE TOXICITY OTHERS Beta-lactam antibiotics are The formation of beta- Allergy(urticaria,severe inhibitors of these bactericidal drugs. They lactamases(penicilinases) by pruritus,anaphylaxis bacterial inhibit bacteria causes resistance due to etc) enzymes cell wall synthesis by enzymatic hydrolysis of the beta- (eg, clavulanic -binding to specific enzymes lactam ring Gastrointestinal acid, (penicillin-binding proteins disturbances—Nausea sulbactam, [PBPs]) located in the bacterial -Structural change in target PBPs and diarrhea may tazobactam) cytoplasmic membrane ---> occur with oral are often used in -changes in the porin structures in penicillins(particularly combination with inhibit the transpeptidate the outer cell wall ampicilin) penicillins to reaction that cross-links the membrane may contribute to prevent their linear peptidoglycan chain resistance by impeding access of inactivation constituents of the cell wall----> penicillins to PBPs. The result is the formation of a weakened cell wall and wide spectrum ultimately cell death. are used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. Narrow spectrum Very-narrow-spectrum Wider-spectrum penicillinase- penicillinase-resistant drugs susceptible drugs — Penicillin G is the prototype of a a. Ampicillin and amoxicillin— subclass of penicillins that have methicillin (the prototype, but Their clinical uses include indications are susceptible to beta-lactamases. rarely used owing to its similar to penicillin G as well Clinical uses include therapy of nephrotoxic potential), nafcillin, as infections resulting from Listeria infections caused and oxacillin. monocytogenes, and some gram - by common streptococci, Primary use is in the treatment ve (enterococci,Escherichia coli, meningococci, gram-positive bacilli, of known or Proteus mirabilis, Haemophilus and spirochetes,nesseria , suspected staphylococcal influenzae, infections. Moraxella catarrhalis,) although syphilis, gas gangrene Methicillin-resistant (MR) resistant strains occur. ((Clostridium perfringens) staphylococci (S aureus [MRSA] and S In enterococcal and listerial epidermidis [MRSE]) are resistant to infections, ampicillin is synergistic Activity against enterococci all penicillins and are often resistant with is enhanced by coadministration to multiple antimicrobial drugs aminoglycosides. of aminoglycosides. b. Piperacillin and ticarcillin— Penicillin V is These drugs have activity an oral drug used mainly in against several gram-negative oropharyngeal infections. rods, including Pseudomonas, Enterobacter, and in some cases Most strains of Klebsiella species. Most drugs pneumococci/staph/nesseria are in this subgroup have synergistic now resistant to actions with aminoglycosides penicillins (penicillin-resistant S against such organisms. pneumoniae [PRSP] strains). MOA RESISTANCE OTHERS Cephalosporins bind to PBPs -Bacteria are resistant Most first- and second- on bacterial cell membranes through the production of generation cephalosporins to inhibit bacterial cell wall other beta-lactamases that do synthesis by mechanisms can inactivate not enter the cerebrospinal similar to those of the cephalosporins. fluid even when the penicillins. meninges are inflamed -Resistance can also result Cefoperazone and Cephalosporins are from decreased membrane ceftriaxone are excreted Bactericidal permeability to mainly in the bile. cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also Allergic reactions resistant to -skin rashes to anapylactic cephalosporins shock Structural differences from penicillins render They may increase the cephalosporins less nephrotoxicity of susceptible to penicillinases aminoglycosides when the produced by staphylococci, two are administered together 1ST GENERATION 2ND GENERATION Drugs: Cefazolin (parenteral) and Drugs : Cefotetan ,Cefoxitin ,Cefuroxime cephalexin (oral). have slightly less activity against Active against gram+ve cocci, including gram+ve organisms than the first- staphylococci and common streptococci. generation drugs but have an extended Many strains of E coli and K pneumoniae are gram-negative coverage also sensitive.. Examples of clinical uses include infections Clinical uses include treatment of infections caused by caused by these organisms and surgical the anaerobe Bacteroides fragilis (cefotetan, prophylaxis in selected conditions. cefoxitin) and sinus, ear, and respiratory These drugs have minimal activity against infections caused by H influenzae or M gram-ve cocci, enterococci, methicillin- catarrhalis (cefamandole, cefuroxime, resistant staphylococci, and most gram- cefaclor) ve rods Third-generation drugs— Fourth-generation drugs— DRUGS: ceftazidime, cefoperazone, cefotaxime ,Ceftriaxone ,Cefixime Cefepime is more resistant to beta-lactamases produced by gram-negative organisms, including include increased activity against gram-ve Enterobacter, Haemophilus, Neisseria, and some organisms resistant to other beta-lactam penicillinresistant pneumococci. drugs and ability to penetrate the blood- Cefepime combines the gram-positive activity of brain barrier (except cefoperazone and first-generation agents with the wider gram- cefixime). negative spectrum of third-generation cephalosporins. Active against Providencia, Serratia marcescens, Ceftarline has activity in infections caused by and beta-lactamase producing strains of H methicillin-resistant influenzae and Neisseria; staphylococci. less active against Enterobacter strains that produce extended-spectrum beta-lactamases. Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin- NOTE ALL ENETROCOCCI ARE RESISTANT TO resistant pneumococci (PRSP strains), but GENERATIONS OF CEPHALOSPORINS resistance is reported. Individual drugs also have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime). Drugs in this subclass should usually be reserved for treatment of serious infections.  (Imipenem, Doripenem, Meropenem, (Aztreonam) and Ertapenem) MOA These drugs are carbapenems (chemically same different from penicillins but retaining the beta-lactam ring structure) synergistic effect with aminoglycosides RESISTANCE Low susceptibility to beta-lactamases. resistant to beta-lactamases However, MRSA strains of staphylococci are produced by certain gram-negative rods, resistant. including Klebsiella, Pseudomonas, and Serrati SPECTRUM Have wide activity against gram+ve cocci the drug has no activity against gram +ve (including some penicillin-resistant bacteria or anaerobes. pneumococci), gram-ve rods, and anaerobes. With the exception of ertapenem, the carbapenems are active against P aeruginosa and Acinetobacter species. For pseudomonal infections, they are often used in combination with an aminoglycoside. Carbapenems are currently co-drugs of choice for infections caused by Enterobacter, Citrobacter, and Serratia species.  TOXICITY Imipenem is rapidly inactivated by renal dehydropeptidase I and is administered in fixed combination with cilastatin, an inhibitor of this enzyme. Cilastatin increases the plasma half_life of imipenem and inhibits the formation of a potentially nepHrotoxic metabolite. The other carbapenems are not significantly degraded by the kidney. Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). There is partial cross allergenicity with the penicillins. Meropenem is similar to imipenem except that it is not metabolized by renal dehydropeptidases and is less likely to cause seizures. Ertapenem has a long half-life but is less active against enterocci and Pseudomonas, and its intramuscular injection causes pain and irritation AZTREONAM Adverse effects include gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity. Although skin rash may occur, there is no cross-allergenicity with penicillins... Fosfomycin MOA: Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of N-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation. Resistance: decreased intracellular accumulation of the drug. Fosfomycin is excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs) for many urinary tract pathogens. In a single dose, the drug is less effective than a 7-day course of treatment with fluoroquinolones. With multiple dosing, resistance emerges rapidly and diarrhea is common. Fosfomycin may be synergistic with beta-lactam and quinolone antibiotics in specific infections. C. Bacitracin MOA:Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram-positive organisms. Because of its marked nephrotoxicity, the drug is limited to topical use. D. Cycloserine MOA:Cycloserine is an antimetabolite that blocks the incorporation of d-Ala into the pentapeptide side chain of the peptidoglycan. Because of its potential neurotoxicity (tremors, seizures, psychosis), cycloserine is only used to treat tuberculosis caused by organisms resistant to first-line antituberculous drugs. E. Daptomycin Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin- resistant strains of enterococci and staphylococci. The drug is eliminated via the kidney. Creatine phosphokinase should be monitored since dap_x0002_tomycin may cause myopathy not used for pneumonia due imto its inactvation by surfactant  Vancomycin MOA: Vancomycin is a bactericidal glycoprotein that binds to the d-Ala-d-Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation. This action prevents elongation of the peptidoglycan chain and interferes with crosslinking. Resistance: in strains of enterocci (vancomycin-resistant enterococci [VRE]) and staphylococci (vancomycin-resistant S aureus [VRSA]) involves a decreased affinity of vancomycin for the binding site because of the replacement of the terminal d-Ala by d-lactate. Clinical use Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA),and in combination with a third-generation cephalosporin such as ceftriaxone for treatment of infections due to penicillin-resistant pneumococci (PRSP). Vancomycin is also a backup drug for treament of infections caused by Clostridium difficile. Teicoplanin and telavancin, other glycopeptide derivatives, have similar characteristics. Vancomycin-resistant enterococci are increasing and pose a potentially serious clinical problem because such organisms usually exhibit multiple-drug resistance. Vancomycin is not absorbed from the gastrointestinal tract and may be given orally for bacterial enterocolitis. When given parenterally, vancomycin penetrates most tissues and is eliminated unchanged in the urine. Toxic effects chills, fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release.  PROTEIN SYNTHESIS INHIBITOR  Tetracycline MOA CLINICAL USE( Broad spectrum) Binds reversibly to the 30S subunit of DRUGS Primary uses—Tetracyclines are recommended the bacterial ribosome-----> Tetracycline in the treatment of infections caused by This action prevents Doxycycline Mycoplasma pneumoniae (in adults), binding of tRNA to the mRNA– Minocycline chlamydiae, rickettsiae, vibrios, and ribosome complex,-----> thereby Tigecycline some spirochetes. inhibiting bacterial protein synthesis Doxycycline is currently an alternative to macrolides in the initial treatment of community-acquired pneumonia. used in GI ulcers caused by Helicobacter pylori in Lyme disease (doxycycline), and in the meningococcal carrier state (minocycline). Side effect Resistance Hepatotoxic -Efflux pumps Alternative drugs in the treatment of syphilis. photosensitivity -Formation They are also used in the treatment of vestibular toxicity respiratory infections caused by susceptible of ribosomal protection -vertigo have been reported with organisms, for prophylaxis doxycycline and minocycline. proteins that interfere against infection in chronic bronchitis, in the Nephrotoxic with tetracycline treatment of leptospirosis, and in th -Fanconi syndrome /Renal tubular acidosis binding Tooth enamel dysplasia and bony iiregularities.  Tigecycline—Unique features of this glycylcycline derivative of minocycline include a broad spectrum of action that includes organisms resistant to standard tetracyclines. The antimicrobial activity of tigecycline includes gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains), beta- lactamase–producing gram-negative bacteria, anaerobes, chlamydiae, and mycobacteria. The drug is formulated only for intravenous use.  chloramphenicol MOA binds reversibly to the bacterial 50S ribosomal subunit-----> inhibitIng protein synthesis at the peptidyl transferase reaction. ACTIVITY Due to its toxicity, it is rarely used as a systemic drug. -used as a backup drug for severe infections caused by Salmonella species and for the treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. -can also be used for rickettsial diseases and anaerobes(Bacteroides fragilis) Commonly used as a topical antimicrobial agent The drug is primarily bacteriostatic, but it may exert bactericidal activity depending on the dose and organism TOXICITY Bone marrow toxicity. Gray baby syndrome( drecreased rbc , cvs collapse ,cyanosis) Gastrointestinal disturbances  MACROLIDES((erythromycin, azithromycin, and clarithromycin) MOA ERYTHROMYCIN AZITHROMYCIN CLARITHROMYCI ADVERSE N EFFECT (mainly due to erythromycin) Macrolides, , Effective in the treatment of Has a similar spectrum of Has almost the GI irritation bind to the activity but more active same spectrum of 50S ribosome, M pneumoniae, antimicrobial hypersensitivity- inhibiting the Corynebacterium, against H influenzae, activity and clinical based acute translocation Campylobacter jejuni, Moraxella catarrhalis, uses as cholestatic steps of protein Chlamydia and Neisseria. erythromycin. hepatitis synthesis and trachomatis, Chlamydophila Because The drug is also _x0002_ also interfere pneumoniae, Legionella of its long half-life, a used inhibits several with pneumophila, single dose of for prophylaxis forms of hepatic transpeptidatio Ureaplasma urealyticum, and azithromycin is effective in against and cytochrome n Bordetella pertussis. the treatment of M P450 and can treatment of urogenital avium complex increase the The drug is also infections caused by C and plasma active against gram-positive trachomatis, and a as a component of levels of many cocci (but not penicillin- 4-d course of treatment drug regimens for drugs resistant has been effective in ulcers caused by Streptococcus pneumoniae community-acquired H pylori [PRSP] strains) and beta- pneumonia lactamase–  4. Telithromycin Telithromycin has an antimicrobial spectrum similar to that of azithromycin. Moreover, the structural modification within ketolides neutralizes the most common resistance mechanisms that render macrolides ineffective.  Resistance to the macrolides in gram-positive organisms involves efflux pump mechanisms and the production of a methylase ,that adds a methyl group to the ribosomal binding site  CLINDAMYCIN MOA inhibits bacterial protein synthesis via a mechanism similar to that of the macrolides, although it is not chemically related. Mechanisms of resistance include methylation of the binding site on the 50S ribosomal subunit and enzymatic inactivation. Gram-negative aerobes are intrinsically resistant because of poor penetration of clindamycin through the outer membrane. Cross-resistance between clindamycin and macrolides is common. Pharmacokinetics Good tissue penetration occurs after oral absorption. Clindamycin undergoes hepatic metabolism, and both intact drug and metabolites are eliminated by biliary and renal excretion. B. Clinical Use The main use of clindamycin is in the treatment of severe infections caused by certain anaerobes such as Bacteroides. Clindamycin has been used as a backup drug against gram-positive cocci (it is active against community-acquired strains of methicillin-resistant S aureus) and is recommended for prophylaxis of endocarditis in valvular disease patients who are allergic to penicillin. Also active against Pneumocystis jirovecii and is used in combination with pyrimethamine for AIDS-related toxoplasmosis. The Toxicity includes gastrointestinal irritation, skin rashes, neutropenia, hepatic dysfunction, and possible superinfections such as C difficile pseudomembranous colitis.  LINEZOLID The first of a novel class of antibiotics (oxazolidinones), linezolid is active against drug-resistant gram-positive cocci, including strains resistant to penicillins (eg, MRSA, PRSP) and vancomycin (eg, VRE). The drug is also active against L monocytogenes and corynebacteria. MOA Linezolid binds to a unique site located on the 23S ribosomal RNA of the 50S ribosomal subunit, and there is currently no cross-resistance with other protein synthesis inhibitors. Resistance (rare to date) involves a decreased affinity of linezolid for its binding site. Available in both oral and parenteral formulations and should clincial use reserved for treatment of infections caused by multidrugresistant gram-positive bacteria. Toxicity Thrombocytopenia and neutropenia occur, most commonly in immunnosuppressed patients. Linezolid has been implicated in the serotonin syndrome when used in patients taking selective serotonin reuptake inhibitors (SSRIs)  STREPTOGRAMINS Quinupristin-dalfopristin, a combination of 2 streptogramins, is bactericidal and has a duration of antibacterial activity longer than the half-lives of the 2 compounds (postantibiotic effects). Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant (MRSA) and vancomycin-resistant staphylococci (VRSA), and resistant E faecium; E faecalis is intrinsically resistant via an efflux transport system. Administered intravenously, the combination product may cause pain and an arthralgia-myalgia syndrome. Streptogramins are potent inhibitors of CYP3A4 and increase plasma levels of many drugs, including astemizole, cisapride, cyclosporine, diazepam, nonnucleoside reverse transcriptase inhibitors, and warfarin  Aminoglycosides MOA MOR CLINICAL USE Aminoglycosides are changes in minimal activity against strict anaerobes bactericidal inhibitors of the ribosomal binding When used alone, protein synthesis. site. aminoglycosides are not reliably effective in the treatment of Inside the cells suceptibility to group infections caused by gram-positive cocci. They bind to the 30S transferases Antibacterial synergy may occur when ribosomal subunit and aminoglycosides are used in combination with cell wall interfere with synthesis inhibitors. protein synthesis in 3 ways: Streptomycin in combination with penicillins is often more (1) they block formation of effective in enterococcal carditis than regimens that include the initiation complex; Streptococci, including other (2) they cause misreading Streptococcus aminoglycosides. of the code on the mRNA pneumoniae, and This combination is also used in the treatment of template enterococci tuberculosis, plague, and tularemia. (3) they inhibit are relatively resistant Other aminoglycosides are usually effective in these translocation to gentamicin and conditions. most other aminogly_x0002_cosid Multidrug-resistant strains es owing to failure of of Mycobacterium tuberculosis that are resistant to the drugs to penetrate streptomycin may be susceptible to amikacin. intracellular accumulation in by bacteria is oxygen dependent. Gentamicin is also available for topical use. Drugs Gentamicin Tobramycin Amikacin Streptomycin Neomycin Spectinomyci others They are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, Escherichia coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratiaspecies. These aminoglycosides also have activity against strains of Haemophilus influenzae, Moraxella catarrhalis, and Shigellaspecies, although they are not drugs of choice for infections caused by these organisms. b-lactams for gonorrheoa ,tuberculosis  toxicity Ototoxicity -irreversible Auditory or vestibular damage may be increased by the use of loop diuretics CI in pregnancy Nephrotoxicity -Acute tubular necrosis Gentamicin and tobramycin most nephrotoxic Neuromuscular blockade Skin Reactions -Allergic skin reactions Neomycin is the agent most likely to cause this adverse effect Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical or oral use (eg, to eliminate bowel flora). Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve.  Effectiveness aminoglycosides, results from a concentration-dependent killing action. As the plasma level is increased above the MIC, aminoglycosides kill an increasing proportion of bacteria and do so at a more rapid rate. Many antibiotics, including penicillins and cephalosporins, cause time dependent killing of microorganism Aminoglycosides are also capable of exerting a postantibiotic effect such that their killing action continues when their plasma levels have declined below measurable levels. Consequently, aminoglycosides have greater efficacy when administered as a single large dose than when given as multiple smaller doses The toxicity (in contrast to the antibacterial efficacy) of aminoglycosides depends both on a critical plasma concentration and on the time that such a level is exceeded. The time above such a threshold is shorter with administration of a single large dose of an aminoglycoside than when multiple smaller doses are given.  note Tobramycin is almost identical to gentamicin in both its pharmacodynamic and pharmacokinetic properties. However, for reasons that are unclear, it is much less active than either gentamicin or streptomycin when used in combination with a penicillin in the treatment of enterococcal endocarditis  Sulfonamides&Trimethoprim, (Anti-folate drugs) Sulfonamides have a common chemical nucleus resembling p-aminobenzoic acid (PABA). Solubility may be decreased in acidic urine, resulting in precipitation of the drug or its metabolites. Because of the solubility limitation, a combination of 3 separate sulfonamides (triple sulfa) has been used to reduce the likelihood that any one drug will precipitate. The sulfonamides may be classified as short-acting (eg, sulfisoxazole), intermediate-acting (eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of kernicterus in the neonate if used in the third trimester of pregnancy  The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet  Trimethoprim This drug is structurally similar to folic acid. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal secrations Clinical use Resistance Toxicity 1. Sulfonamides—The sulfonamides are active against -Decreased intracellular Hypersensitivity(com gram+ve and gram-ve organisms, Chlamydia, and accumulation of the drugs, mon) Nocardia. Hematotoxicity -Increased production of -pancytopenia Specific members of the sulfonamide group are used by the PABA by bacteria, Nephrotoxicity following routes for the conditions indicated: or a decrease in the -due to ppt in acid urine a. Simple urinary tract infections—Oral (eg, triplesulfa, sensitivity of causing crystalluria and sulfisoxazole). dihydropteroate synthase hematuria b. Ocular infections—Topical (eg, sulfacetamide). to the GI(nausea,vomitting) c. Burn infections—Topical (eg, mafenide, silver sulfadiazine). sulfonamides. Drug interactions d. Ulcerative colitis, rheumatoid arthritis—Oral (eg, -Competition with sulfasalazine). Clinical resistance to warfarin and e. Toxoplasmosis—Oral sulfadiazine plus pyrimethamine (a trimethoprim most methotrexate for dihydrofolate reductase inhibitor) plus folinic acid. commonly results from plasma protein binding the production of transiently increases 2. Trimethoprim-sulfamethoxazole (TMP-SMZ)— dihydrofolate reductase the plasma that has a reduced levels of these drugs. combination is effective orally in the treatment of affinity for the drug UTI and in respiratory, ear, and sinus infections Trimethoprim caused by megaloblastic anemia, Haemophilus influenzae and Moraxella catarrhalis. leukopenia, and granulocytopenia. In the immunocompromised patient, i These effects are used for infections due to usually ameliorated by Aeromonas hydrophila and is the drug of choice for supplementary folinic prevention and acid treatment of pneumocystis pneumonia. FLUOROQUINOLONES. Mechanism of Action The fluoroquinolones interfere with bacterial DNA synthesis by inhibiting topoisomerase II (DNA gyrase), especially in gram-ve organisms, a -This block the relaxation of supercoiled DNA that is catalyzed by DNA gyrase, a step required for normal transcription and duplication. Inhibiting topoisomerase IV, especially in gram+ve organisms. This interferes with the separation of replicated chromosomal DNA during cell division. Fluoroquinolones are usually bactericidal against susceptible organisms. Like aminoglycosides, the fluoroquinolones exhibit postantibiotic effects,  Fluoroquinolines are classified by “generation” based on their antimicrobial spectrum of activity. Norfloxacin, a first-generation fluoroquinolone derived from nalidixic acid, Activity against the common pathogens that cause urinary tract infections. Ciprofloxacin and ofloxacin (second-generation fluoroquinolones) have greater activity against gram-ve bacteria and are also active against the gonococcus, many gram-positive cocci, mycobacteria, and agents of atypical pneumonia (Mycoplasma pneumoniae, Chlamydophila pneumoniae). Third-generation fluoroquinolones (levofloxacin, gemifloxacin, and moxifloxacin) are slightly less active than ciprofloxacin and ofloxacin against gram-ve bacteria but have greater activity against gram+ve bacteria Antacids can decrease oral bioavailability of fluoroquinolones.  E. Clinical Use Fluoroquinolones are effective in the treatment of infections of the urogenital and gastrointestinal tracts caused by gram-negative organisms, including gonococci, E coli, Klebsiella pneumoniae, C jejuni, Enterobacter, P aeruginosa, Salmonella, and Shigellaspecies. Activity against gonorrheoa is rapidly declining due to resistance.use in tuberculosis is limited Ofloxacin eradicates Chlamydia trachomatis, but a 7-d course of treatment is required. Levofloxacin has activity against most organisms associated with community-acquired pneumonia, including chlamydiae, mycoplasma, and legionella species. Gemifloxacin and moxifloxacin have the widest spectrum of activity, which includes both gram-positive and gram-negative organisms, atypical pneumonia agents, and some anaerobic bacteria. Fluoroquinolones have also been used in the meningococcal carrier state, in the treatment of tuberculosis, and in prophylactic management of neutropenic patients. Toxicity Gastrointestinal distress is the most common. The fluoroquinolones may cause skin rashes, headache, dizziness, insomnia, abnormal liver function tests, phototoxicity, and both tendinitis and tendon rupture. The fluoroquinolones are not recommended for children or pregnant women because they may damage growing cartilage and cause arthropathy. Fluoroquinolones may increase the plasma levels of theophylline and other methylxanthines, enhancing their toxicity. Newer fluoroquinolones (gemifloxacin, levofloxacin, moxifloxacin) prolong the QTc interval. They should be avoided in patients with known QTc prolongation and those on certain antiarrhythmic drugs (Chapter 14) or other drugs that increase the QTc interval  ANTI- MYCOBACTERIA DRUGS ISONIAZID(INH) RIFAMPIN ETHAMBUTHOL PYRIZINAMIDE MOA Inhibits inhibits DNA-dependent inhibits -acyl carrier protein RNA polymerase in M arabinosyltransferases not known reductase tuberculosis ---> -B-ketoacyl-Acp resulting in decrease in RNA involved in the synthesis leading to inhibition of synthesis of mycolic acid arabinogalactan, a component of mycobacterial cell walls Resistance occurs via resisitance occurs if used mutations alone in the gene that encodes enzymes involved in the Distributed to most body bioactivation of tissues, including the central pyrazinamide and by nervous system (CNS). increased expression of drug efflux drug is well absorbed systems. orally and distributed to most tissues, including the CNS CLINICA most important Tb -used in combination -used in combination -used in L USE drug -in INH intolerant individuals combination used in latent Tb rifampin can be used solely for latent Tb  INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). Rifabutin is equally effective as an antimycobacterial agent and is less likely to cause drug interactions than rifampin. Preferred over rifampin in the treatment of tuberculosis or other mycobacterial infections in AIDS patients, especially those treated with cytochrome P450 substrates including protease inhibitors or efavirenz. Rifaximin, a rifampin derivative that is not absorbed from the gastrointestinal tract, has been used in traveler’s diarrhea  Streptomycin This aminoglycoside is now used more frequently than before because of the growing prevalence of strains of M tuberculosis resistant to other drugs. Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe  Alternative Drugs Several drugs with antimycobacterial activity are used in cases that are resistant to first- line agents; they are considered second-line drugs because they are no more effective, and their toxicities are often more serious than those of the major drugs. Amikacin is indicated for the treatment of tuberculosis suspected to be caused by streptomycin-resistant or multidrugresistant mycobacterial strains. To avoid emergence of resistance, amikacin should always be used in combination drug regimens. Ciprofloxacin and ofloxacin are often active against strains of M tuberculosis resistant to first-line agents. The fluoroquinolones should always be used in combination regimens with two or more other active agents. Ethionamide is a congener of INH, but cross-resistance does not occur. The major disadvantage of ethionamide is severe gastrointestinal irritation and adverse neurologic effects at doses needed to achieve effective plasma levels. p-Aminosalicylic acid (PAS) is rarely used because primary resistance is common. In addition, its toxicity includes gastrointestinal irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function. Other drugs of limited use because of their toxicity include capreomycin (ototoxicity, renal dysfunction) and cycloserine (peripheral neuropathy, CNS dysfunction)  DRUGS FOR LEPROSY A. Sulfones Dapsone (diaminodiphenylsulfone) remains the most active drug against M leprae. Mechanism of action inhibition of folic acid synthesis. Because of increasing reports of resistance, it is recommended that the drug be used in combinations with rifampin and/or clofazimine. Dapsone can be given orally, penetrates tissues well, undergoes enterohepatic cycling, and is eliminated in the urine, partly as acetylated metabolites. Toxicity gastrointestinal irritation, fever, skin rashes, and methemoglobinemia. Hemolysis may occur, especially in patients with G6PDH deficiency. Acedapsone is a repository form of dapsone that provides inhibitory plasma concentrations for several months. In addition to its use in leprosy, dapsone is an alternative drug for the treatment of Pneumocystis jiroveci pneumonia in AIDS patients. B. Other Agents Drug regimens usually include combinations of dapsone with rifampin (or rifabutin, ) with or without clofazimine. Clofazimine, a phenazine dye that may interact with DNA, causes gastrointestinal irritation and skin discoloration ranging from red-brown to nearly black.  DRUGS FOR ATYPICAL MYCOBACTERIAL INFECTIONS Mycobacterium avium complex (MAC) is a cause of disseminated infections in AIDS patients. Currently, clarithromycin or azithromycin with or without rifabutin is recommended for primary prophylaxis in patients with CD4 counts less than 50/µL. Treatment of MAC infections requires a combination of drugs, one favored regimen consisting of azithromycin or clarithromycin with ethambutol and rifabutin. Infections resulting from other atypical mycobacteria (eg, M marinum, M ulcerans), though sometimes asymptomatic, may be treated with the described antimycobacterial drugs (eg, ethambutol, INH, rifampin) or other antibiotics (eg, amikacin, cep  ANTI-PROTOZOA  DRUGS FOR AMEBIASIS Tissue amebicides (chloroquine, emetines, metronidazole, tinidazole) act on organisms in the bowel wall and the liver; luminal amebicides (diloxanide furoate, iodoquinol, paromomycin) act only in the lumen of the bowel. The choice of a drug depends on the form of amebiasis. For asymptomatic disease, diloxanide furoate is the first choice. For mild-to-severe intestinal infection, metronidazole or tinidazole is used with a luminal agent, and this regimen is recommended in amebic hepatic abscess and other extraintestinal disease ( The mechanisms of amebicidal action of most drugs in this subclass are unknown  LUMINAL AMOEBICIDE DRUG Diloxanide Furoate Iodoquinol Emetines INDICATI used as the sole agent used as an alternative to Used parenterally ON for the treatment of diloxanide for mild to- (subcutaneously or asymptomatic amebiasis and is severe intestinal intramuscularly) as backup also useful in mild intestinal infections. drugs for treatment of severe disease when used with other intestinal or hepatic amebiasis drugs. when metronidazole cannot be used MOA converted in the gut to the. metine and dehydroemetine diloxanide freebase form, which is inhibit protein synthesis by the active amebicide. blocking ribosomal movement along messenger RNA TOXICITY mild toxic effect-GI Systemic absorption after may cause severe toxicity, high doses may lead to including gastrointestinal thyroid enlargement, skin distress, reactions due to iodine muscle weakness, and toxicity and possibly cardiovascular dysfunction neurotoxic (arrhythmias effects, including and congestive heart failure) peripheral neuropathy and visual dysfunction.  Metronidazole and Tinidazole 1. Pharmacokinetics— Metronidazole and tinidazole are effective orally and distributed widely to tissues. The half-life of metronidazole is 6–8 h, and that of tinidazole 12–14 h. Elimination of the drugs requires hepatic metabolism. 2. Mechanism of action— Metronidazole undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobic parasites) to form reactive cytotoxic products. The mechanism of tinidazole is assumed to be similar. 3. Clinical use— Both are the drug of choice in severe intestinal wall disease and in hepatic abscess and other extraintestinal amebic disease. Both drugs are used with a luminal amebicide. The duration of treatment required with metronidazole is longer than with tinidazole. Metronidazole is the drug of choice for trichomoniasis: tinidazole may be effective against some metronidazole-resistant organisms. Other clinical uses of metronidazole include treatment of giardiasis (tinidazole is equally effective), and infections caused by Gardnerella vaginalis and anaerobic bacteria (B fragilis, C difficile). Metronidazole is also used in combination regimens for gastrointestinal ulcers associated with H pylori. Toxicity— Adverse effects of metronidazole include gastrointestinal irritation (it is best taken with meals), headache, paresthesias, and dark coloration of urine. Tinidazole has a similar adverse effect profile, but may be better tolerated than metronidazole. More serious toxicity includes neutropenia, dizziness, and ataxia. Drug interactions with metronidazole include a disulfiram-like reaction with ethanol and potentiation of coumarin anticoagulant effects. Safety of metronidazole and tinidazole in pregnancy and in nursing mothers has not been established. E. Paromomycin This drug is an aminoglycoside antibiotic used as a luminal amebicide and may be superior to diloxanide in asymptomatic infection. Paromomycin may also have some efficacy against cryptosporidiosis in the AIDS patient and in leishmaniasis. Systemic absorption in renal insufficiency may lead to headaches, dizziness, rashes, and arthralgia. Tetracyclines (eg, doxycycline) are sometimes used with a luminal amebicide in mild intestinal disease. F. Nitazoxanide This agent has activity against various protozoans (including Entamoeba) and helminths. It is currently approved in the United States for treatment of gastrointestinal infections caused by G lamblia and Cryptosporidium parvum. Nitazoxanide appears to have activity against metronidazole-resistant protozoal strains.  DRUGS FOR PNEUMOCYSTOSIS & TOXOPLASMOSIS A. TMP-SMZ 1. Clinical use—TMP-SMZ is the first choice in prophylaxis and treatment of pneumocystis pneumonia (PCP). Prophylaxis in AIDS patients is recommended when the CD4 count drops below 200 cells/µL. Oral treatment with the double-strength formulation 3 times weekly is usually effective. The same regimen of TMP-SMZ is prophylactic against toxoplasmosis and infections caused by Isospora belli. For treatment of active PCP, daily oral or intravenous administration of TMP-SMZ is required. 2. Toxicity— Adverse effects from TMP-SMZ occur in up to 50% of AIDS patients. Toxicity includes gastrointestinal distress, rash, fever, neutropenia, and thrombocytopenia. These effects may be serious enough to warrant discontinuance of TMP-SMZ and substitution of alternative drugs. (S  Pentamidine 1. Mechanism of action— Pentamidine’s mechanism of action is unknown but may involve inhibition of glycolysis or interference with nucleic acid metabolism of protozoans and fungi. Preferential accumulation of the drug by susceptible parasites may account for its selective toxicity. 2. Clinical use— Aerosol pentamidine (once monthly) can be used in primary and secondary prophylaxis of P jiroveci pneumonia, although oral trimethoprim-sulfamethoxazole (TMP-SMZ) is usually preferred. Daily intravenous or intramuscular administration of the drug for 21 d is needed in the treatment of active pneumocystosis in the HIV-infected patient. Pentamidine is also used in trypanosomiasis (see later discussion). 3. Toxicity— Severe adverse effects follow parenteral use, including respiratory stimulation followed by depression, hypotension resulting from peripheral vasodilation, hypoglycemia, anemia, neutropenia, hepatitis, and pancreatitis. Systemic toxicity is minimal when pentamidine is used by inhalation. C. Antifols: Pyrimethamine and Sulfonamides 1. Clinical use— Combination of pyrimethamine with sulfadiazine has synergistic activity against Toxoplasma gondii through the sequential blockade of 2 steps in folic acid synthesis. Pyrimethamine plus clindamycin (or sulfadiazine) is a regimen of choice for prophylaxis against and treatment of toxoplasmosis. For treatment of active toxoplasmosis, the drug combination is given daily for 3–4 wk, with folinic acid to offset hematologic toxicity. For Toxoplasma encephalitis in AIDS, high-dose treatment with pyrimethamine plus sulfadiazine (or clindamycin) plus folinic acid must be maintained for at least 6 wk. 2. Toxicity—High doses of pyrimethamine plus sulfadiazine are  Antibiotic-associated colitis may occur during treatment with clindamycin. D. Atovaquone 1. Mechanism and pharmacokinetics— Atovaquone inhibits mitochondrial electron transport and probably folate metabolism. Used orally, it is poorly absorbed and should be given with food to maximize bioavailability. Most of the drug is eliminated in the feces in unchanged form. 2. Clinical use and toxicity— Atovaquone is approved for use in mild to moderate pneumocystis pneumonia. It is less effective than TMP-SMZ or pentamidine but is better tolerated. As noted, it is also used in combination with proguanil (as Malarone) for chemoprophylaxis and treatment of chloroquine-resistant malaria. Common adverse effects are rash, cough, nausea, vomiting, diarrhea, fever, and abnormal liver function tests. The drug should be avoided in patients with a his_x0002_tory of cardiac conduction defects, psychiatric disorders, or seizures. E. Miscellaneous Agents Other alternative drug regimens for the treatment of pneumocystis pneumonia include trimethoprim plus dapsone, primaquine plus clindamycin, and trimetrexate plus leucovorin  DRUGS FOR TRYPANOSOMIASIS A. Pentamidine Pentamidine is commonly used in the hemolymphatic stages of disease caused by Trypanosoma gambiense and T rhodesiense. Because it does not cross the blood-brain barrier, pentamidine is not used in later stages of trypanosomiasis. Other clinical uses include pneumocystosis and treatment of the kala azar form ofleishmaniasis. B. Melarsoprol This drug is an organic arsenical that inhibits enzyme sulfhydryl groups. Because it enters the CNS, melarsoprol is the drug of choice in African sleeping sickness. However, treatment failures do occur, possibly because of resistance. Melarsoprol is given parenterally because it causes gastrointestinal irritation; it may also cause a reactive encephalopathy that can be fatal. C. Nifurtimox This drug is a nitrofurazone derivative that inhibits the parasite unique enzyme trypanothione reductase. Nifurtimox is the drug of choice in American trypanosomiasis, an alternative agent in African forms of the disease, and has also been effective in mucocutaneous leishmaniasis. The drug causes significant toxicity, including allergies, gastrointestinal irritation, and CNS effects. D. Suramin This polyanionic compound is a drug of choice for the early hemolymhatic stages of African trypanosomiasis (before CNS involvement). It is also an alternative to ivermectin in the treatment of onchocerciasis ( Suramin is used parenterally and causes skin rashes, gastrointestinal distress, and neurologic complications  E)Eflornithine This agent, a suicide substrate of ornithine decarboxylase, is effective in some forms of African trypanosomiasis. It is available for both oral and intravenous use and penetrates into the CNS. It causes gastrointestinal irritation and hematotoxicity; seizures have occurred in overdose. DRUGS FOR LEISHMANIASIS Leishmania, parasitic protozoa transmitted by flesh-eating flies, cause various diseases ranging from cutaneous or mucocutaneous lesions to splenic and hepatic enlargement with fever. Sodium stibogluconate(pentavalent antimony), the primary drug in all forms of the disease, appears to kill the parasite by inhibition of glycolysis or effects on jknucleic acid metabolism. Stibogluconate must be administered parenterally and is potentially cardiotoxic (QT prolongation). Alternative agents include pentamidine, paromomycin, or miltefosine (for visceral leishmaniasis), fluconazole or metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis)