Pharm Mini 5

AGENTS TO TREAT CYTOMEGALOVIRUSINFECTIONS

Ganciclovir, Valganciclovir, Cidofovir Action: similar action with acyclovir Ganciclovir synthesized as a derivative of acyclovir and the *first antiviral drug approved for use against CMV.* MOA - selectively inhibits CMV phosphorylation and DNA polymerization. Use: oral- End-organ CMV disease in AIDS patients and as maintenance therapy of *CMV retinitis* IV - *CMV colitis, esophagitis, and pneumonitis* topical: *CMV retinitis* Adverse effect: *Myelosuppression* (IV)

Gatifloxacin, Gemifloxacin, Moxifloxacin

improved activity against gram positive organisms, particularly *S. pneumoniae* and some *staphylococci.* NOTE: *Gemifloxacin* is active against *ciprofloxacin-resistant strains of S pneumoniae*

Inhibitors of Folate Metabolism Sulfonamides

sulfanilamide, sulfadiazine, sulfamethoxazole, sulfadoxine, Sulfapyridine, Sulfamethizole, Sulfisoxazole, Sulfacytine Clinical Uses *Sulfisoxazole and sulfamethoxazole* are agents used almost exclusively to treat *urinary tract infections.* *Sulfadiazine + pyrimethamine* is first-line therapy for treatment of *acute toxoplasmosis.* *Sulfasalazine* is widely used in *ulcerative colitis, enteritis,* and other inflammatory bowel disease *Sodium sulfacetamide* (ophthalmic solution or ointment) is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for *trachoma.* Adverse Reactions common: - fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea Urinary disturbance: - Sulfonamides may precipitate in urine producing *crystalluria, hematuria or even obstruction* - Crystalluria is treated by administration of *sodium bicarbonate* to alkalinize the urine and increase fluid intake. - *Allergic nephritis* Hematopoeitic disturbances: - can cause *hemolytic or aplastic anemia,* granulocytopenia, thrombocytopenia, - may provoke *hemolytic reactions* in patients whose red cells are *deficient in glucose-6-phosphate dehydrogenase* - taken near the end of pregnancy increase the risk of *kernicterus* in newborns.

Didanosine

terminates chain elongation when incorporated into viral DNA and also inhibits viral reverse transcriptase Adverse effects: *Pancreatitis (dose dependent)* -*Peripheral neuropathy* -*Hepatitis*

Stavudine

terminates chain elongation when incorporated into viral DNA and also inhibits viral reverse transcriptase Adverse effects: *Peripheral sensory neuropathy* -*Pancreatitis* (like didanosine) -Lipodystrophy, hyperlipidemia, and mitochondrial toxicities -*NO leucopenia (unlike AZT).*

Voriconazole (Triazoles)

Oral & I.V. : 400 mg/d inhibits hepatic P450 enzymes Spectrum similar to Itraconazole: *Candida* (especially those Fluconazole resistant species such as C. krusei) NOTE: IV formulation should not be used in patients with renal failure may causes CNS toxicity USE: drug of choice in the treatment of *invasive Aspergillosis* and also includes *Candida* species and a number of newly emerging fungi. Side Effects: - elevated hepatic enzymes, - *visual disturbance* in 30% of patients (blurring of vision & changes in color vision & brightness)

Itraconazole (Triazoles)

Oral and IV administration some interaction with hepatic microsomal P450 enzymes *no effect on steroid synthesis* Compared to ketoconazole , much *less effect on metabolism of other drugs* Most potent of azoles (efficacy may be limited by bioavailability) *Superior* to ketoconazole in *safety and efficacy* *Less hepatotoxicity and hormonal suppression* Poor penetration into cerebral spinal fluid (however it can be used in certain meningeal fungal infections) NOTE: Compared to ketoconazole and fluconazole, Itraconazole shows increased activity in *Aspergillosis, Blastomycosis, and Histoplasmosis* Clinical Use: Agent of choice treatment of dermatophytes Treatment of blastomycosis treatment of onychomycosis only agent with substantial activity against *Aspergillus species.* Preferred azole for treatment of diseases caused by *dimorphic fungi*: - Histoplasmosis, Blastomycosis, Sporothrix, Paracoccidioidomycosis chronic mucocutaneous candidiasis, esophageal candidiasis - Disseminated Coccidiodomycosis and pseudallescheriasis Itraconazole inhibits metabolism of: midazolam triazolam tacrolimus cisapride oral hypoglycemic drugs *Contraindicated in pregnancy* Adverse effect: *Hepatotoxicity* (less than ketoconazole) nausea, vomiting, abdominal pain, diarrhea, hypokalemia, pedal edema and hair loss

Penicillin V Acid resistant penicillin's

PK: Not destroyed by gastric HCL→ given orally → Acid stable Uses: - *S. pyogens pharyngitis - Prophylactic in rheumatic heart disease*

Ciprofloxacin, Enoxacin, Lomefloxacin, Levofloxacin, Ofloxacin, and Pefloxacin

excellent gram-negative activity and moderate to good activity against gram(+) bacteria. Enterobacter sp, P aeruginosa , Neisseria meningitidis, Hemophilus sp, and Campylobacter jejuni NOTE: *Ciprofloxacin* is the most active agent of this group against gram-negative organisms, *P aeruginosa* in particular - *Levofloxacin* has superior activity against gram-positive, including *S pneumoniae.*

The first-generation cephalosporins

*(cefazolin, cephalexin, cephadroxil, cephalothin , cephradrine, cephapirln)* Are active against Gram-positive cocci as well as the Gram-negative rods- *Proteus mirabilis and E. coli* (both cause urinary tract infections), and *Klebsiella pneumoniae* (causes pneumonia in addition to urinary tract infections) Cephalexin and cefazolin are both used to treat skin and soft tissue infections; cefazolin is also used for surgical prophylaxis. NOTE: classified as *narrow spectrum and susceptible to beta lactamase* Adverse effects: *Pseudomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity* Nausea, vomiting, diarrhea, rash

AGENTS USED IN HERPES VIRUS and VZV

*Acyclovir, Valacyclovir and Famciclovir* - Three oral nucleoside analogs are licensed for the treatment of *HSV and VZV* infections - All have similar mechanisms of action and comparable indications for clinical use. - It all depends on the viral *thymidine kinase (NOT* human)

Amino penicillins

*Ampicillin, Amoxicillin, Amoxicillin/clavulanic acidAmpicillin/sulbactam or tazobactam* Uses: enterococcal (shigella) infections and Listeria meningitis *(ampicillin)* - Uncomplicated ear, nose, and throat infections, endocarditis dental-surgery prophylaxis, component of combination therapy for Helicobacter pylori infection *(amoxicillin)* - Beta-lactamase-producing organisms such as S. aureus, H. influenzae, E. coli, Klebsiella, Acinetobacter, Enterobacter, anaerobes *(amoxicillin/clavulanic acid, ampicillin/ sulbactam)* Disadvantage: Amoxicillin & ampicillin spectrum is *limited by sensitivity to most β* Adverse effects: Rash, nausea, vomiting, diarrhea *(more with ampicillin)* Macupapular rash *(ampicillin)*

The fourth-generation cephalosporin

*Cefepime* Like ceftriaxone, it is highly active against *Enterobacteriaceae, Neisseria, H. influenzae, and Gram-positive organisms* USE: - It is as active as ceftazidime (3rd) against *P. aeruginosa.* - More resistant to the chromosomally encoded β-lactamases of Enterobacter than third-generation cephalosporins. Uncommon adverse effect: is the development of autoantibodies against red blood cell antigens, typically without significant hemolysis. Uses: Same as 3rd generation on *E.coli and K.pneumonia Enterobacteriaceae, Neisseria, H. influenzae, P. aeruginosa, S. aureus and S. pneumoniae* Adverse effects: Cefepime may *produce erythrocyte autoantibodies* without significant hemolysis

2nd generation cephalosporins

*Cefuroxime Cefotetan Cefoxitin Cefaclor, Cefprozil, Cefonicid, Cefamandole Cefmetazole, Loracarbef Ceforanide* Uses: *H. influenzae (cefuroxime, cefamandole, cefonicid, ceforanide, and cefaclor)* Bacteroides and Clostridium spp *(cefotetan, cefoxitin, cefmetazole)* Adverse effects: *Cefotetan and Cefamandole* may produce *disulfiram-like reaction with alcohol ingestion* and block synthesis of vitamin K-dependent coagulation factors *(hypoprothrombinemia)*

Agents for HSV, VZV, CMV and HIV

*Foscarnet* (Non-nucleoside DNA Polymerase Inhibitors) use: effective in the treatment of *CMV retinitis, CMV colitis, CMV esophagitis, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection.* - combination of ganciclovir and foscarnet is synergistic in vitro against CMV and has been shown to be superior in delaying progression of *retinitis* Resistance: In HSV and CMV isolates is due to *point mutations in the DNA polymerase* gene and is typically associated with prolonged or repeated exposure to the drug. Adverse effect: *renal impairment,* severe hypocalcemia, nausea, vomiting, anemia, *elevation of liver enzymes,* and fatigue - CNS toxicity: *headache, hallucinations, and seizures*

Carbapenem

*Imipenem/cilastatin, Meropenem, Ertapenem* Are all broad spectrum and cover most Gram-positive, Gram-negative, and anaerobic organisms. (except MRSA, VRE, and Legionella) *Ertapenem* is much less active against P. aeruginosa and Acinetobacter than the other two agents; the benefit of ertapenem is its once-daily dosing. *Imipenem* is inactivated by the human renal enzyme *dehydropeptidase I*, this drug is always co-administered with the dehydropeptidase inhibitor *cilastatin.* Neither meropenem nor ertapenem is inactivated by the renal enzyme. Adverse effect: All three agents can cause hypersensitivity reactions and IV-site phlebitis; At high plasma drug levels, imipenem and meropenem can cause *seizures.* Drug interaction: Probenecid can increase meropenem levels, and all three agents can *decrease valproate levels.*

Antimicrobial Drugs Targeting the 50S Ribosomal Subunit

*Macrolides and Ketolides ( Erythromycin, Azithromycin, Clarithromycin Telithromycin)* Are named for their large lactone rings. Attached to these rings are one or more deoxy sugars *MOA: Bind to a small region of 23S rRNA of the 50S ribosomal subunit near the peptidyl transferase active center.* Note: *All macrolides are bacteriostatic*

Inhibitor of Polymer Crosslinking III. MONOBACTAMS/CARBAPENEMS

*Mechanism: β-lactams inhibit transpeptidase by forming a covalent ("dead-end") acyl enzyme intermediate* *Monobactam (Aztreonam)* - It has structural similarities to ceftazidime; hence, its gram negative spectrum is similar to that of the third-generation cephalosporins. - Active against most Gram-negative bacteria, including *P. aeruginosa,* but it has no activity against Gram-positive organisms. - *Resistant to B-lactamases* *Aztreonam* is particularly *useful in patients with serious penicillin allergy* who have infections due to resistant Gram-negative organisms; its use is limited by IV-site *phlebitis*, and its short half-life necessitates frequent dosing Uses: *Gram-negative bacteriaUsed in penicillin-allergic patients*

Penicillinase-resistant penicillin's

*Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin* Uses: Skin and soft-tissue infections or systemic infection with beta-lactamase-producing, *methicillin-sensitive S. aureus*  Adverse effects: Diarrhea, nausea, vomiting, pseudomembranous enterocolitis *(cloxacillin, dicloxacillin)* Hepatitis *(oxacillin)* Interstitial nephritis, phlebitis *(methicillin and nafcillin)*

Beta-Lactam Antibiotics

*Penicillins* - bactericidal for sensitive strains - have greatest activity against *gram-positive organisms, gram-negative cocci,* and *non ß-lactamase* producing *anaerobes.* NOTE: They have *little activity* against *gram-negative rods,* and they are susceptible to hydrolysis by Penicillinase (ß-lactamases) Groups of Penicillin based on spectrum of action *1. Penicillin G (IV) - Narrow spectrum penicillinase susceptible (sensitive)* *2. Anti-staphylococcal penicillins* (oxacillin, cloxacillin, dicloxacillin, nafcillin,& methicillin) - *Narrow spectrum penicillinase resistant* *3. Amino penicillins* (ampicillin and amoxicillin) - *Broad spectrum* *4. Carboxy penicillin* (ticarcillin and carbenicillin)- *Extened spectrum anti-psuedomonas penicillins* *5. Ureido penicillins (piperacillin and mezlocillin)*

Ureido penicillins

*Piperacillin , mezlocillin and azlocillin* These drugs have both positive and negative charges on their side chains and are generally *more potent than the carboxy penicillins.* Their spectrum of action is similar to that of the carboxy penicillins; in addition, they have activity against *Klebsiella and enterococci.*

Carboxy penicillins

*Ticarcillin and Carbenicillin* The carboxyl group on the side chain provides a *negative charge* that confers *resistance to some β-lactamases* Is less effective than a positively charged amino group in facilitating diffusion across porin channels. To overcome this limitation in diffusion, high doses are used. Activity is enhanced in combination with *B-lactamase inhibitors* (clavulanic acid or sulbactam) Use: increase activity versus Gm (-) rods including *Pseudomonas aeruginosa* Disadvantage: High dose my lead to *hypernatremia*

Third-generation cephalosporins

*ceftriaxone, cefotaxime, cefoperazone, ceftazidime, ceftizoxime, cefixime, cefpodoxime, proxetil, cefdinir, cefditoren, pivoxil, ceftibuten, and moxalactam* *Broad spectrum* - Compared with second-generation agents, these drugs have *expanded gram-negative coverage*, and some are *able to cross the blood-brain barrier* - Are resistant to many β-lactamases and are thus highly active against: *Enterobacteriaceae* (E. coli, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, and Citrobacter) *Neisseria and H. influenzae* NOTE: *Are less active against Gram-positive organisms* Common uses: treatment of lower respiratory tract infection, community-acquired pneumonia due to S. pneumoniae, uncomplicated gonococcal infection, culture-negative endocarditis, and complicated Lyme disease. Uses: N. gonorrhoeae, Borrelia burgdorferi, H. influenzae, most Enterobacteriaceae *(ceftriaxone)* H. influenzae *(cefotaxime)* P. aeruginosa *(ceftazidime and cefoperazone)* B. fragilis *(Ceftizoxime and moxalactam)* Adverse effects: *Ceftriaxone* may cause *cholestatic hepatitis* *Cefoperazone and moxalactam* may produce *disulfiram-like reaction with alcohol ingestion* and block synthesis of vitamin K-dependent coagulation factors *(hypoprothrombinemia)*

Griseofulvin

*very insoluble*; fungiostatic (derived from Penicillium griseofulvum) Largely replaced in clinical use by itraconazole and terbinafine. Pharmacodynamics: *Disrupts microtubule mitotic spindle formation, causing mitotic arrest at metaphase* Also reported to *inhibit fungal RNA and DNA synthesis* accumulates in keratin precursor cells and binds tightly to keratin in differentiated cells (allows new growth of skin, hair, or nail to be free of dermatophyte infection) Pharmacokinetics: Increased absorption if *taken with fatty foods* induces hepatic cytochrome P450 enzymes Use: *Trichophyton, Microsporum, Epidermophyton, Dermatophytosis, Onychomycosis, Tinea capitis* Adverse effect: headache (15%), hepatotoxicity (rare), leukopenia, neutropenia Contraindicated: pregnancy

P-Aminosalicylic Acid (PAS)

- *a folate synthesis antagonist* that is active almost exclusively against M. tuberculosis . It is structurally similar to p -aminobenzoic acid (PABA) and to the sulfonamides. Pharmacokinetic: - is readily absorbed from the GIT - widely distributed in tissues and body fluids except the cerebrospinal fluid. - is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. - Very high concentrations of aminosalicylic acid are reached in the urine, which can result in *crystalluria.* *Adverse effect:* fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia

Cycloserine

- *inhibitor of cell wall synthesis* - concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis - cleared renally; dosed should be adjusted by if creatinine clearance is less than 50 mL/min. Adverse effect: The most serious toxic effects are *peripheral neuropathy* and CNS dysfunction, including *depression and psychotic reactions.*

Fluconazole (Triazoles)

- *most widely used* antifungal drug a hydrophilic triazole that is available in both oral and IV formulations Pharmacokinetics: The bioavailability of oral fluconazole is *nearly 100%,* and, unlike ketoconazole and itraconazole, its absorption is not influenced by gastric pH. Once absorbed, fluconazole diffuses *freely into CSF,* sputum, urine, and saliva. Fluconazole is excreted primarily by the kidneys - *limited drug-drug interactions;* among azoles, least effect on cytochrome P450 hepatic microsomal enzyme system *Wide therapeutic window* 80%: excreted unchanged by the kidney dosage adjustment required for patients with diminished creatinine clearance. Clinical use: - drug of choice for *systemic candidiasis and cryptococcal meningitis* - drug of choice for *coccidioidal meningitis* (alternative to intrathecal amphotericin B maintenance therapy) - blastomycosis, histoplasmosis, and sporotrichosis oropharyngeal and esophageal candidiasis catheter-acquired candidemia (immunocompetent patient-- along with removal of catheter) Initial and maintenance treatment for *AIDS-associated cryptococcal meningitis* (probably following an initial 2 week course of IV amphotericin B) Clinical use: -Reduces incidence of deep *candidiasis* and among patients receiving allogenic bone marrow transplants. -Reduction of the frequency of *cryptococcosis and mucosal candidiasis* in AIDS patients with CD4 T cell count < 200 per microliter {particularly effective in AIDS-patient subgroups with CD4 T cell count < 50 per microliter NOTE: *Ineffective:* Aspergillosis *Fatal cases of Stevens-Johnson syndrome and alopecia*

Lincosamide (Clindamycin)

- An antibiotic that is elaborated by Streptomyces lincolnensis MOA: like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with *aminoacyl translocation* reactions. Use: treatment of skin and soft-tissue (MRSA) infections caused by *streptococci and staphylococci.* - Treatment of serious anaerobic infections caused by *Bacteroides* and the treatment of mixed infections involving other anaerobes. - prophylaxis of endocarditis in patients with valvular heart disease. - It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.

Pyrazinamide

- Is a prodrug; it must be converted to its active form, *pyrazinoic acid*, by the enzyme pyrazinamidase. MOA: inhibit mycolic acid synthesis by *inhibiting fatty acid synthase I* - Bacteriostatic or bactericidal depending on the concentration and susceptibility of the organism. - important first-line drug used in conjunction with isoniazid and rifampin in short-course Pharmacokinetics: - well absorbed orally and widely distributed in body tissues - active in vitro at an acidic pH 5.5 or less (is taken up by macrophages) - half-life is 8 -11 hours (adults) - excreted mainly by glomerular filtration - renal excretion approximately 70% Adverse effects: *Arthralgias ( 40%) , hepatic injury (1-5%), hyperuricemia* (provoke acute gout) GIT symptoms ( nausea, vomiting), dysuria, malaise, fever, photosensitivity, hepatotoxicity, anemia(rare) Resistance: due to mutations in the pyrazinamidase gene, which result in the inability to convert the prodrug into its active form.

Famciclovir

- It is active in vitro against *HSV-1, HSV-2, VZV, EBV, and HBV* use: oral famciclovir is effective for the treatment of *first and recurrent genital herpes,* for chronic daily suppression of genital herpes, for treatment of *herpes labialis,* and for the treatment of *acute zoster*

Inhibitors of the Ergosterol Synthesis Pathway Terbinafine (allylamines)

- Oral and topical formulation oral bioavailability is 40% Elimination half-life is extremely long, approximately 300 hrs Accumulates extensively in the skin, nails, and fat. Clinical Use: oral terbinafine up to 90% cure rate for *onychomycosis*- more effective than griseofulvin or itraconazole Treatment of *dermatophytoses* *Tinea infection* (tinea corporis, tinea cruris, tinea pedis, and tinea capitis) NOTE: *Onychomycosis:* disease of the nails of the fingers and toes caused by Epidermophyton floccosum, several species of Trichophyton, and Candida albicans Adverse Effects: - GIT disturbance, headaches - rarely oral form of terbinafine can lead to *hepatotoxicity,* Stevens-Johnson syndrome, neutropenia, and exacerbation of *psoriasis or subacute cutaneous lupus erythematosus.* NOTE: Liver function enzymes should be monitored during the treatment course. Drug interaction: Increase plasma levels of terbinafine with cimetidine (cytochrome P450 inhibitor) Decreased plasma level of terbinafine with rifampin (cytochrome P450 inducer) Contraindications: patients with *renal or hepatic failure and in pregnant women*

Acyclovir

- bioavailability of oral acyclovir is low (15-20%) and is unaffected by food. an intravenous formulation is available. - diffuses in the tissues, body fliuds including CSF - half-life of 2-3 hrs - cleared primarily by glomerular filtration Use: Intravenous acyclovir is the drug of choice for *herpes simplex encephalitis, neonatal HSV infection, serious HSV or VZV infxn.* In immunocompromised patients with VZV infection

Tetracyclines (chlortetracycline, oxytetracycline, tetracycline, demeclocycline, methacycline, doxycycline, and minocycline)

- broad-spectrum *bacteriostatic* antibiotics that inhibit protein synthesis. Action: *Bind reversibly to the 16S rRNA of the 30S subunit* and inhibit protein synthesis by blocking the binding of *aminoacyl tRNA to the A site* on the mRNA-ribosome complex. - It enter *Gram-negative bacteria* by passive diffusion through *porin* proteins in the outer membrane, followed by active (energy-dependent) transport across the inner cytoplasmic membrane. - Its uptake into *Gram-positive bacteria,* occurs similarly via an energy-dependent transport system. Pharmacokinetics: Absorption: after oral administration 30% for chlortetracycline; 60-70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95-100% for doxycycline and minocycline. - 40-80% bound by serum proteins - excreted in both urine and bile NOTE: impaired absorption with food high in calcium(dairy) and by divalent cations (Ca2+ ,Fe 2+) or trivalent cations (Al 3+) ; antacids (except for *doxycycline and minocycline*) Drug interaction: Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of tetracyclines Contraindication: pregnancy and young children Adverse effect: Dizziness, vertigo, nausea and vomiting, diarrhea *liver and kidney toxicity* NOTE: *Doxycycline* is safer for use in patients with renal failure with lower incidence of adverse effects. Use: Active against many *gram-positive and gram negative* bacteria, including certain anaerobes, *rickettsiae, chlamydia,& mycoplasmas* - used in combination regimens to treat gastric and duodenal ulcer disease caused by *Helicobacter pylori* Note: The antibacterial activities of most tetracyclines are similar except for doxycycline and minocycline, has additional coverage for *tetracycline-resistant strains.* *Doxycycline* - has particular usefulness in *prostatitis,* because it reaches high levels in prostatic fluid. *Minocycline* - appears in saliva at high concentrations and is used in the *meningococcal carrier state* *Demeclocycline* - Demeclocycline is used in *syndrome of inappropriate secretion of ADH* (SIADH) (blocks ADH receptor function in collecting ducts)

Rifabutin

- derived from rifamycin and is related to rifampin. - It has significant activity against *M tuberculosis , M avium and M fortuitum* - Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Pharmacokinetic: - is both a *substrate and inducer* of cytochrome P450 enzymes. Use: indicated in place of rifampin for treatment of *TB in patients with HIV infection* who are receiving antiretroviral therapy with a protease inhibitor or with a non-nucleoside reverse transcriptase inhibitor (eg, efavirenz), which are also are cytochrome P450 substrates.

Amikacin

- is a semi-synthetic derivative of kanamycin - It is *resistant to many enzymes that inactivate gentamicin and tobramycin* Use: - Many gram-negative bacteria, including many strains of *Proteus, Pseudomonas, Enterobacter, and Serratia* - Strains of multidrug-resistant *Mycobacterium tuberculosis* Adverse effect: nephrotoxic and ototoxic

Caspofungin

- the first echinocandin to be approved. Clinical use: - used as primary therapy for *esophageal candidiasis and candidemia* - as salvage therapy for *Aspergillus* infections. Pharmacokinetic: - penetrates poorly into the CSF - highly protein-bound (97%) in the plasma - metabolized in the liver via peptide hydrolysis and N-acetylation - does not require dose adjustment for renal insufficiency, but dose adjustment is required for patients with moderate hepatic dysfunction. *cyclosporine* significantly *increases* the plasma concentration of caspofungin and elevates liver function enzymes

Resistance: ß-Lactams

4 mechanism of resistance to ß-Lactam antibiotics: *1. Elaboration of the enzyme ß-lactamase,* which hydrolyzes the ß-lactam ring. *2. Alteration of penicillin-binding proteins* (PBPs): either by mutation of existing PBP genes or, more importantly, by acquiring new PBP genes (e.g. staphlococcal resistance to methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal resistance) *3. Impaired penetration of drug to target PBPs* Seen in gram-negative bacteria is due to alteration of genes that specify outer membrane proteins (porins) and reduce permeability to penicillins. (e.g. resistance of Enterbacteriaceae to some cephalosporins and that of Pseudomonas spp. to ureidopenicillins) *4. Efflux* Gram-negative organisms also may produce an efflux pump, which consists of cytoplasmic and periplasmic protein components that efficiently transport some ß-lactam antibiotics from the periplasm back across the outer membrane.

Naftifine (allylamines)

A squalene epoxidase inhibitor that has *broad-spectrum antifungal activity.* Naftifine is only available topically as a *cream or gel.* Clinical use: it is effective in *tinea corporis, tinea cruris, and tinea pedis*

INHIBITORS OF VIRAL RELEASE Zanamivir and Oseltamivir

Action: Inhibit influenza virus *neuraminidase,* causing newly-synthesized virions to *remain attached to host cell.* - Inhibition of viral neuraminidase results in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Use: Unlike amantadine and rimantadine, oseltamivir and zanamivir have activity against *both influenza A and B influenza viruses* *Pharmacokinetic:* Oseltamivir is an orally administered Zanamivir is taken via inhalation

Inhibition of Viral Uncoating Amantadine and Rimantadine

Action: are inhibitors of viral uncoating that are active exclusively against influenza A virus (and not against influenza B or C viruses). - They *block the M2 proton ion channel of the virus particle and inhibit uncoating* of the viral RNA within infected host cells, thus preventing its replication. Use: drug of choice for *Influenza A only* Pharmacokinetics: - Taken orally - *Amantadine* well distributes & penetrates into CNS - *Amantadine is not* metabolized and is excreted by kidney - *Rimantadine* doesn't cross the BBB - *Rimantadine* is metabolized by liver; its metabolite is excreted by the kidney

Aminoglycosides

Adverse effects: * All aminoglycosides are *ototoxic and nephrotoxic* (encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency) Unusual A/E: very high doses can produce a *curare-like* effect with neuromuscular blockade that results in respiratory paralysis. NOTE: *Neomycin, kanamycin, and amikacin* are the *most ototoxic* agents. *Streptomycin and gentamicin* are the *most vestibulotoxic.* *Neomycin, tobramycin, and gentamicin* are the *most nephrotoxic.* Drug combination: *loop diuretics* (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin B) can potentiate nephrotoxicity. Clinical uses: - Are mostly used against *gram-negative enteric bacteria,* especially when the isolate may be drug-resistant and when there is suspicion of sepsis. - They are almost always used in *combination with a ß-lactam antibiotic* to extend coverage to include potential *gram-positive pathogens* and to take advantage of the synergism between these two classes of drugs. - *Penicillin-aminoglycoside* combinations also are used to achieve bactericidal activity in treatment of *enterococcal endocarditis, S. viridans* and patients with *staphylococcal endocarditis*

Rifampin

Adverse effects: *Yellow orange sweat, tears and urine* rash, GIT symptoms (heartburn), *hepatotoxicity,* cholestatic jaundice, flu-like syndrome; acute renal failure, nephrotoxic, immunosuppression, *teratogenic* Drug interactions: PAS - ↓ absorption of Rifampicin Steroids, oral contraceptives, digoxin, sulfonylureas, warfarin, ketoconazole, chloramphenicol, methadone → ↓ efficacy of thesse drugs (Rifampicin acts as a *hepatic P450 enzyme inducer*)

Inhibitors of Fungal Membrane Stability: Polyenes

Amphotericin B Broadest spectrum of antifungal action activity against yeasts: - Candida albicans - Candida neoformans activity against endemic mycoses: - Histoplasma capsulatum - Blastomyces dermatitidis - Coccidiodes immitis pathogenic molds - Aspergillus fumigatus - Mucor

Sites of action of antibacterial drug classes

Antibacterial drug classes can be divided into three general groups A. Drugs inhibits specific steps in bacterial cell wall synthesis. Ex. *Fosfomycin* and *cycloserine* inhibit early steps in peptidoglycan monomer synthesis *Vancomycin* binds to peptidoglycan intermediates, inhibiting their polymerization; *Penicillins, cephalosporins, monobactams, and carbapenems inhibit peptidoglycan* cross-linking *Ethambutol, pyrazinamide, and isoniazid* inhibit processes necessary for synthesis of the cell wall and outer membrane of Mycobacterium tuberculosis Drugs targeting transcription and translation inhibit bacterial processes that mediate RNA and protein synthesis: Ex: *Rifampin* inhibits bacterial DNA-dependent RNA polymerase; *Aminoglycosides, spectinomycin, and tetracyclines* inhibit the bacterial 30S ribosomal subunit; *Macrolides, chloramphenicol, lincosamides, streptogramins, and oxazolidinones* inhibit the bacterial 50S ribosomal subunit. C. Drugs that inhibit specific enzymes involved in DNA synthesis and integrity: Ex: *Sulfonamides and trimethoprim* inhibit the formation or use of folate compounds that are necessary for nucleotide synthesis; *Quinolones* inhibit bacterial type II topoisomerases.

Cellular targets of antifungal drugs

Antifungal agents act on distinct molecular targets namely: *Flucytosine* inhibits fungal DNA synthesis. *Griseofulvin* inhibits fungal mitosis by disrupting mitotic spindles. *Allylamines, benzylamines,imidazoles, and triazoles* inhibit the ergosterol synthesis pathway in the endoplasmic reticulum. *Polyenes* bind to ergosterol in the fungal membrane and thereby disrupt plasma membrane integrity. *(Amphotericin B)* *Echinocandins* inhibit fungal cell wall synthesis.

Amphotericin B

Clinical Use: Drug of choice for nearly all *life-threatening* fungal infections. *(Candida albicans & Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatidis & Coccidioides immitis, Aspergillus)* Initial induction treatment -- then one of the newer azole drugs (ketoconazole (Nizoral), itraconazole (Sporanox), fluconazole (Diflucan)) Amphotericin B treatment induction: important in: immunosuppressed patients severe fungal pneumonia cryptococcal meningitis (altered mental status present) long-term antifungal treatment may be acquired (azole maintenance therapy) may be used in neutropenic cancer patients Clinical Use: Intrathecal treatment: *fungal meningitis* (due to difficulty maintaining CSF access and poor patients tolerance) Local Administration: *mycotic corneal ulcers* (topical or subconjuctival injection) *keratitis* (topical or subconjuctival injection) *fungal arthritis* (joint injection) *Candiduria:* bladder irrigation (no systemic toxicity)

Neomycin

Clinical Uses Topical Administration: formulated as a *neomycin-polymyxin-bacitracin* combination, can be applied to infected skin lesions or in the nares for suppression of *staphylococci* Oral Administration In preparation for *elective bowel surgery,* 1 g of *neomycin* is given orally every 6-8 hours for 1-2 days to reduces the aerobic bowel flora *-Sterilization of gut before surgery* *Adverse effect:* nephrotoxicity and ototoxicity neomycin-containing ointments to skin and eyes has resulted in severe allergic reactions. - *the most ototoxic and nephrotoxic*

Quinolones

Clinical Uses: - effective in *UTI,* caused by many organism including *P aeruginosa.* - effective for *bacterial diarrhea* caused by *Shigella , Salmonella, toxigenic E coli, and Campylobacter* - infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections - *Ciprofloxacin* is a drug of choice for prophylaxis and treatment of *Anthrax* - *Ciprofloxacin and levofloxacin* effective in treating *chlamydial urethritis or cervicitis* - *Levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin* are so-called *respiratory fluoroquinolones* - are effective and used increasingly for treatment of upper and lower respiratory tract infections. *(Chlamydiae, Mycoplasma, and Legionella)* Adverse Effects: most common: nausea, vomiting, and diarrhea. occasional: headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop. - Photosensitivity (lomefloxacin and pefloxacin) - *QT prolongation* (gatifloxacin, levofloxacin, gemifloxacin,and moxifloxacin) Contraindiction: *pregnancy* and patients *under 18 years of age* may damage growing cartilage and cause an *arthropathy.*

Histoplasmosis

Clinical presentations: Histoplasmosis fever weight loss lymphadenopathy hepatosplenomegaly Bone marrow involvement (33%): thrombocytopenia neutropenia anemia Abnormal chest x-ray (50% of patients: diffuse interstitial infiltrate or diffuse small nodules) Treatment: initially- *Amphotericin B* maintenance -- amphotericin B or oral itraconazole

Flucytosine

Clinical use: - *synergistic killing of Aspergillus* by combination with amphotericin B - as single agent limited to *candidiasis, cryptococcus (neoformans & meningitis) and chromomycosis* Adverse effects: Blood: *bone marrow suppression* leading to leukopenia and thrombocytopenia, GIT: nausea, vomiting, diarrhea, and hepatic dysfunction. note: *Narrow therapeutic window* (toxicity of higher levels; rapid development of resistance at lower, sub-therapeutic levels) *Contraindicated* during pregnancy

Butenafine (benzylamine)

Is a topical antifungal agent with a mechanism of action and spectrum of antifungal activity similar to that of the allylamines. NOTE: Topical allylamines and benzylamines are *more effective* than topical azole agents against common dermatophytes, especially those causing *Tinea pedis.* However, topical terbinafine and butenafine are *less effective* than topical azoles against *Candida* skin infections.

Streptomycin as mycobacterial

Isolated from a strain of Streptomyces griseus. The antimicrobial activity of streptomycin is typical of that of other aminoglycosides, as are the mechanisms of resistance. Resistance: Ribosomal resistance to streptomycin develops readily, limiting its role as a single agent. Clinical Uses : A. *Mycobacterial Infections* (second-line agent for treatment of TB) B. *Non-tuberculous Infections* (plague, tularemia, and sometimes brucellosis)

Valacyclovir

L-valyl ester of acyclovir Use: - treatment of first or recurrent *genital herpes* - suppression of *frequently recurring genital herpes* - As a 1-day treatment for *orolabial herpes* - Treatment for *varicella and herpes zoster* Note: Higher doses have also been shown to be effective in preventing *CMV disease* after organ transplantation Adverse effect: nausea, headache, vomiting, or rash occasionally occur At high doses: *confusion, hallucinations, and seizures*

Norfloxacin

Least active of the fluoroquinolones against both gram (-) and gram (+) organisms

Ketoconazole (Imidazoles)

Less selective than itraconazole (Sporanox) or fluconazole (Diflucan) for fungal cytochrome P450 enzymes * By inhibiting human cytochrome P450:* it inhibits adrenal and gonadal steroid hormone biosynthesis. Endocrine effects: - *gynecomastia* - *infertility* - *menstrual irregularities* NOTE: can be used for prostate CA and adrenal CA Alters metabolism of other drugs, increasing toxicity ex: - increased cyclosporine levels - increased arrhythmias associated with: Some antihistamines astemizole terfenadine Common toxicities: nausea, anorexia, vomiting (occasional) Uncommon toxicities: *hepatotoxicity* (idiosyncratic) -- may be serious/fatal *endocrine effects:* gynecomastia, decrease serum testosterone, decreased libido, decreased adrenal cortical reserve, decreased potency in males, menstrual irregularities *Contraindicated in pregnancy* (present in breast milk)

Ethambutol

MOA: It disrupts arabinogalactan synthesis by *inhibiting arabinosyl transferase.* - Disruption of the arabinogalactan synthesis leads to increased permeability of the cell wall. - Bacteriostatic Pharmacokinetics: - well absorbed from the GIT, - passes poorly in various body compartments except CSF of patients with *TB meningitis.* - 20% of the drug is excreted in feces and 50% in urine in unchanged form. Adverse effects: *retrobulbar (optic) neuritis* (dose-related), hypersensitivity, hyperuricemia, neutropenia, thrombocytopenia, *peripheral neuropathy* *Note:* periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used. Resistance: develops fairly rapidly (from mutations in the arabinosyl transferase gene)

Streptomycin (bactericidal)

MOA: It inhibits protein synthesis by *combining irreversibly with the 30S subunit* of the70S ribosomes, found typically in prokaryotes. - Specifically, it binds with the 12S protein involved in the initiation of protein synthesis. *(bactericidal)* Other uses: effective for brucella, calymmabacterium, E.coli, and Hemophilus Pharmacokinetics: - *poorly absorbed* from the GIT - penetrates into cells poorly and is active mainly against *extracellular tubercle bacilli.* - therapeutic concentration attained in bile, pleural fluids, extracellular fluids - with meningeal inflammation, concentration in CSF reaches 20% of serum levels; - excreted primarily by kidneys Adverse effects: *ototoxicity* (major concern: vestibular), minimally *nephrotoxic,* eosinophilia, erythroderma, anaphylaxis Resistance: rapidly develops

Vancomycin

MOA: These agents interrupt cell wall synthesis by *inhibiting transglycosylation reaction* and thereby blocking the addition of peptidoglycan units to the growing polymer chain. Use: *Intravenous vancomycin* is most commonly used to treat sepsis or endocarditis caused by *methicillin-resistant Staphylococcus aureus (MRSA).* *Oral vancomycin* is used to treat gastrointestinal infections with *C. difficile;* like bacitracin, the drug is poorly absorbed and therefore stays within the gastrointestinal tract. NOTE: Resistance is uncommon, but vancomycin-resistant staphylococcal (VRSA) and enterococcal (VRE) strains are slowly emerging. Adverse effects: *Neutropenia, ototoxicity, nephrotoxicity, anaphylaxis* *"Red-man syndrome"* (flushing and erythroderma), drug fever, hypersensitivity rash

Isoniazid

MOA: inhibits DNA synthesis by *inhibiting fatty acid synthetase* responsible for synthesis of mycolic acid; interferes with glycolysis; acts primarily on *intra and extracellular bacilli* bactericidal for actively growing tubercle bacilli. Pharmacokinetics: - rapidly absorbed from the GIT penetrates well into all body fluids and tissues - *crosses placenta and BBB* acetylated in liver to acetyl hydrazone; rate of *acetylation is genetically determined* Adverse effects: *peripheral neuropathy , hepatotoxicity* (jaundice), *hemolysis* in patients with *G6PD deficiency;* others: *pyridoxine deficiency;* skin rashes, fever, acne, psychosis Drug interactions: *Antacids* - ↓ Isoniazid (INH) absorption *Phenytoin, Carbamazepine, benzodiazepines, azole type anti-fungals, alcohol* - ↑ serum concentrations of these drugs *Para-Amino Salicylic (PAS), Ethionamide - synergism* Resistance: inactivating mutation in the mycobacterial enzyme catalase-peroxidase, which converts isoniazid into its anti-mycobacterial form.

Nystatin

Mechanism of Action: Increases the permeability of the cell membrane of sensitive fungi by binding to sterols Pharmacokinetics: not absorbed systemically from the skin, vagina, or gastrointestinal tract no significant blood or tissue levels after oral intake very toxic to administer parenterally Clinical Use Drug of choice against *most Candida organisms* most often used for *treating local candidal infections* - oropharyngeal thrush - vaginal candidiasis - intertriginous (chaffed skin) candidal infections

Raltegravir

Mechanism: Binds to *Integrase*, a viral enzyme essential to the replication of HIV-1 and HIV-2. By doing so, it *inhibits strand transfer,* the final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells PK: Drug interacton: *polyvalent cations (Mg, Ca & Fe) may bind integrase inhibitors and interfere with their activity.* -*avoid antacids* Adverse effects: *Increases in creatine kinase levels (myopathy or rhabdomyolysis)*

Maraviroc

PD: *CCR5 receptor antagonist* Contraindicated : *severe or end-stage renal impairmen*t who are taking concurrent CYP3A inhibitors or inducer Drug interaction: dose must be decreased with strong CYP3A inhibitors (*delavirdine, ketoconazole, itraconazole, clarithromycin, or any protease inhibitor* PK: - *have excellent penetration into the cervicovaginal fluid* Adverse effects: *postural hypotension (particularly in the setting of renal insufficiency)* muscle and joint pain, abdominal pain, diarrhea, and sleep disturbance. -*hepatotoxic*

Saquinavir

PD: *Inhibit HIV protease required for viral maturation* PK: *lowest oral (4%) bioavailability of all protease inhibitors.* - should be *taken within 2 hours after a fatty meal* for enhanced absorption wide distribution Adverse effects: *Lipodystrophy and hyperglycemia*

Indinavir

PD: *Inhibit HIV protease required for viral maturation* PK: -*must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption* (60-65%) half-life is 1.5-2 hrs, PB 60%, and the drug has a *high level of CSF penetration* (76%) Adverse effects: *indirect hyperbilirubinemia and nephrolithiasis due to urinary crystallization* of the drug. *Thrombocytopenia elevations of serum aminotransferase* levels, nausea, diarrhea, insomnia, dry throat, dry skin *Lipodystrophy and hyperglycemia*

Efavirenz

PD: *bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- dependen DNA polymerase activity.* PK: *- T1/2 = 40-55 hrs* Uses: all NNRTIs are highly selective non-competitive inhibitors of *HIV* reverse transcriptase Adverse effects: CNS: Dizziness, drowsiness, insomnia, nightmares, and Headache, *Depression, mania, and psychosis* Contraindication: *pregnancy*

Delavirdine

PD: *bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- dependent DNA polymerase activity.* Uses: *all NNRTIs are highly selective non-competitive inhibitors of HIV reverse transcriptase* Adverse effects Rash Nausea dizziness Headache *increased serum aminotransferase levels*

Enfuvirtide

PD: *binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes* PK: - only parenterally administered Antiretroviral agent. Adverse effects: - injection site reactions, *painful erythematous nodules.* - insomnia, headache, dizziness, and nausea. Hypersensitivity reactions may rarely occur

Telbivudine

PD: *competitively inhibits HBV DNA polymerase and causes chain termination After incorporation into viral DNA* Uses: *HBV*

Adefovir dipivoxil

PD: *competitively inhibits HBV DNA polymerase and causes chain termination After incorporation into viral DNA* Uses: - *HBV* - Others: *HIV & herpesviruses* Adverse effects: dose-dependent *nephrotoxicity*

*Lamivudine* (Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors)

PD: *inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA* PK: -eliminated in urine *synergistic* with zidovudine , abacavir and stavudine -*NOT* used with zalcitabine it inhibit each others intracellular phosphorylation -*NOT* affect mitochondrial DNA synthesis or bone marrow precursor cells Uses: - *HBV* Note: *10 - 20 times more effective on hepatitis B than HIV*

Lamivudine

PD: *terminates the synthesis of proviral DNA chain* *inhibits the reverse transcriptase of HIV* - *synergistic* with zidovudine , abacavir and stavudine -*NOT* used with zalcitabine it inhibit each others intracellular phosphorylation -*NOT* affect mitochondrial DNA synthesis or bone marrow precursor cells Uses: HIV infection

Zidovudine ( AZT )

PD: *terminates the synthesis of proviral DNA chain* * inhibits the reverse transcriptase of HIV* PK: Well absorbed orally *Glucuronylated in liver* Uses: -HIV infection and prophylaxis *most important drug in HAART* (high active anti-retroviral therapy) *Bone Marrow Depression*, leucopenia, anemia, headache, Seizures - AZT Toxicity is potentiated if glucuronylation is decreased by co-administration of drugs like *Probenecid, acetaminophen, lorazepam, indomethacin and cimetidine*

Ritonavir

PD: Inhibit HIV protease required for viral maturation PK: - *has a high bioavailability (75%) that increases with food.* Adverse effects: - *elevated serum aminotransferase levels* concurrent use of saquinavir and ritonavir is contraindicated due to an increased *risk of QT prolongation* *Lipodystrophy and hyperglycemia*

Interferon-α cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions

PD: activate signaling cascades that lead to *production of anti-viral proteins*, including protein *kinase R*, which turn off host translational machinery in virus-infected cells Uses: *HBV and HBC* Other : -*Kaposi's sarcoma-Chronic myeloid leukemia-Hairy cell leukemia*-*Malignant melanoma-Renal cell carcinoma*

Nevirapine

PD: bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- dependent DNA polymerase activity. Uses: all *NNRTIs* are highly selective non-competitive inhibitors of *HIV* reverse transcriptase Note: effective in the *prevention of transmission of HIV from mother to newborn* when Administered to women at the onset of labor and followed by a 2 mg/kg oral dose to the neonate within 3 days after delivery. Adverse effects: *Serious: Hepatitis within first 18 wks of treatment*

Entecavir

PD: competitively *inhibits all three functions of HBV DNA polymerase*: *1. base priming* *2. reverse transcription of the negative strand* *3. synthesis of the positive strand of HBV DNA* PK: -oral bioavailability approaches 100% but is decreased by food Uses: - Has significantly higher rates of HBV DNA viral suppression

Penicillin G procaine

PK: * 12 - 24 hour duration - Given IM and not IV - Acid unstable Uses: *1- Syphilis* *2- Rheumatic fever prophylaxis* *3- Streptococcal pharyngitis*

Penicillin G benzathine

PK: * 2-4 week duration - Painful at injection site - Acid unstable Uses: *1- Syphilis* *2- Rheumatic fever prophylaxis* *3- Streptococcal pharyngitis*

Clindamycin

Pharmacokinetic: - penetrates well into most tissues, except for brain and cerebrospinal fluid. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. - Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. - Half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure. Adverse Effects Diarrhea, nausea, and skin rashes. Impaired liver function and neutropenia sometimes occur. NOTE: Administration of clindamycin is *a risk factor for diarrhea and colitis due to C. Difficile*

Erythromycin

Pharmacokinetic: - PO/IV acid labile (take on empty stomach) - may crosses blood brain barrier in inflamed meninges - concentrated in the liver excreted in bile Use: drug of choice for *mycoplasma pneumoniae, neonate w/chlamydia pneumonia and pertussis* Drug interaction: increase toxicity of drugs like *theophylline, warfarin and carbamazepine* due to erythromycin's inhibition of CYP450 - produce long QT arrhythmia when combined with *terfenidine* Adverse reaction: GIT upset, *cholestatic hepatitis*

Trimethoprim

Pharmacokinetics - given orally alone or in combination w/sulfamethoxazole, which has a similar half-life - Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. - trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug ( 1:5 ratio) - about 30-50% of the sulfonamide and 50-60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. - Trimethoprim (a weak base) concentrates in *prostatic fluid* and in *vaginal fluid.* Clinical Uses *Oral Trimethoprim:* * - Acute urinary tract infections* * - Community-acquired organisms* *Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)* - *P jiroveci pneumonia,* shigellosis, systemic salmonella infections, *urinary tract infections, prostatitis, and non-tuberculous mycobacterial infection* *Intravenous Trimethoprim-Sulfamethoxazole* - *pneumocystis pneumonia,* enterobacter and serratia shigellosis, typhoid fever or *urinary tract infection* Adverse Effects *- Megaloblastic anemia, leukopenia, and granulocytopenia* - The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides: Nausea and vomiting, drug fever, vasculitis, renal damage, and CNS disturbances. - Patients with AIDS and *pneumocystis pneumonia* have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole: Fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia.

Penciclovir

The active metabolite of famciclovir, is available for *topical use.* Penciclovir cream (1%) shortens the duration of recurrent *herpes labialis or genitalis*

Cryptococcosis

Therapy: - initiated immediately when antigen or culture tests our positive for cryptococcal infection Standard therapy in HIV patients: *Amphotericin B in combination with flucytosine* Due to neutropenia, more than half of patients will not be able to receive the full course of flucytosine treatment. NOTE: Since over 50 percent of HIV patients will suffer a relapse, following Amphotericin B treatment, patients should be maintained on *fluconazole* indefinitely. *Fluconazole* is sometimes used as prophylaxis against candidal and cryptococcal infections when CD4 T cell count < 100 per microliter.

Fluoroquinolones

They are also active against atypical mycobacteria Use : *Moxifloxacin* is the most active against M tuberculosis in vitro. *Levofloxacin* tends to be slightly more active than ciprofloxacin against M tuberculosis , whereas *Ciprofloxacin* is slightly more active against atypical mycobacteria. Dose: The standard dosage of ciprofloxacin is 750 mg orally twice a day. The dosage of levofloxacin is 500-750 mg once a day. The dosage of moxifloxacin is 400 mg once a day.

Candidiasis

Treatment Oral or vaginal Candida: *topical nystatin* (Mycostatin) or *clotrimazole* (Mycelex) troches. In severe cases: systemic therapy-- *ketoconazole (Nizoral) or fluconazole (Diflucan)* Fluconazole (Diflucan) may be preferable (ketoconazole may be less well absorbed in patients with high gastric pH) Another option for management of severe cases: *IV amphotericin B, then oral fluconazole.*

Penicillin G

Uses: *mainly on G (+) aerobic cocci* Penicillin-sensitive *S. aureus and S. pyogenes,* *G (+) rods, Clostridia species* *G (-) aerobic cocci, N. meningitidis,* Others: *Syphilis-T.pallidumYaws Leptospirosis* Prophylaxis of *rheumatic fever* Disadvantages: - Inactivated by *penicillinase*

Bacitracin

Uses: Most active against infection of mouth, nose, eyes, skin (S. aureus and streptococci infection)- topical GI decontamination of C. difficile or vancomycin-resistant enterococci (oral) Advantage: it remains within the gut lumen and is occasionally administered orally to treat *Clostridium difficile colitis* or to eradicate *vancomycin-resistant enterococci* (VRE) in the GIT Adverse effects: If systemic absorption occurs: *nephrotoxicity, neurotoxicity, bone marrow suppression* With topical application: contact *dermatitis, blurred vision, red eye*

Azithromycin

Uses: Same as erythromycin. -active against *M avium complex and T.gondii* *Compared to erythromycin and clarithromycin:* - slightly more active against *H influenzae* - highly active against *Chlamydia sp*

Clarithromycin

Uses: Same as erythromycin. more active against *Mycobacterium avium* complex - *Mycobacterium leprae , Toxoplasma gondii, and H influenzae*

Chloramphenicol

a *bacteriostatic* broad-spectrum antibiotic that is active against both aerobic and anaerobic Gram-positive and Gram-negative organisms. The most highly susceptible organisms include: *Hemophilus influenzae* *Neisseria meningitidis* *Rickettsiae* *Bacteroides* NOTE: significant resistance is due to production of *chloramphenicol acetyltransferase,* a plasmid-encoded enzyme that inactivates the drug. Pharmacokinetics - oral and IV administration - Chloramphenicol is *widely distributed* to virtually all tissues and body fluids, including the *central nervous system and cerebrospinal fluid,* such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. - The drug penetrates cell membranes readily. - inactivated either by *conjugation with glucuronic acid* (principally in the liver) - inactive degradation products (about 90% of the total) are eliminated in the urine. A small amount of active drug is excreted into bile and feces. serious adverse effect: *"gray baby syndrome"* and *aplastic anemia* drug interaction: Half-lives of these drugs are prolonged, and serum concentrations are increased *(phenytoin, tolbutamide, chlorpropamide, and warfarin)*

Sulfones

a member of the sulfone class of dihydropteroate synthase inhibitors Clinical use: treatment of *Leprosy* and *Pneumocystis carinii pneumonia.* NOTE: Because the mechanism of action of dapsone is the same as that of the sulfonamides, dapsone and trimethoprim can also be used as a synergistic drug combination. Adverse effect : about 5% of patients develop *methemoglobinemia* after administration of the drug. Susceptible patients are typically *deficient* in the erythrocyte enzyme *glucose-6-phosphate dehydrogenase*

Capreomycin

a peptide *protein synthesis inhibitor* antibiotic obtained from Streptomyces capreolus . Use: Strains of M tuberculosis that are resistant to *streptomycin or amikacin* usually are susceptible to capreomycin - Daily injection of 1 g intramuscularly. Such concentrations in vitro are inhibitory for many mycobacteria, including *multidrug-resistant strains of M tuberculosis* Adverse effect: *nephrotoxic and ototoxic* (tinnitus, deafness, and vestibular disturbances

Cycloserine

a structural analogue of D-Ala, is a second-line agent used to treat *multidrug resistant M. tuberculosis infection.* ACTION: inhibits both the alanine racemase that converts L-Ala to D-Ala and the D-Ala-D-Ala synthetase that joins together two D-Ala molecules. *Cycloserine* is an *irreversible inhibitor* of these enzymes and, in fact, binds these enzymes more tightly than does their natural substrate, D-Ala. *M. tuberculosisM. avium complex*

Echinocandins (caspofungin, micafungin, and anidulafungin)

are a new class of antifungal agents that target fungal cell wall synthesis by noncompetitively inhibiting the synthesis of *β-(1,3)-D-glucans.* - fungicidal against *Candida species* (Candida glabrata and Candida krusei) and - fungistatic against *Aspergillus species* Pharmacokinetic: - available only in parenteral ( oral has insufficient bioavailability) - highly bound to protein. - metabolized in liver by hydrolysis and N-acetylation. - excreted in the urine and feces equally

Imidazoles and Triazoles

azoles have a wide range of antifungal activity; they are generally fungistatic rather than fungicidal against susceptible organisms. clinical use: *most Candida species*, blastomycoses, Cryptococcus neoformans, H. capsulatum, Coccidiodomycosis, P. brasiliensis, dermatophytes *Aspergillus* (itraconazole) *Pseudallesceria boydii* (amphotericin-resistant organism) Intermediate activity: Fusarium, Sporothrix schenckii, Scedosporium apiospermum, Resistance: Pathogens mediating *zygomycosis* (invasive fungal infections caused by Zygomycetes species) and *Candida krusei* are *resistant to azoles.*

Ethionamide

chemically related to isoniazid and similarly *blocks the synthesis of mycolic acids.* Pharmacology: - It is poorly water soluble and available only in oral form. - Cerebrospinal fluid concentrations are equal to those in serum. - It is metabolized by the liver. Adverse effect: like INH is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.

Fosfomycin

is a *phosphoenolpyruvate (PEP) analogue* that inhibits bacterial enol pyruvate transferase by covalent modification of the enzyme's active site. Action: inhibit the production of peptidoglycan monomers by inhibiting the synthesis of UDP-NAM from UDP-NAG Fosfomycin enters the cell via transporters for glycerophosphate or glucose-6-phosphate that are normally used by bacteria to take up these nutrients from the environment. Use: effective against *Gram-negative bacteria* that infect the urinary tract, including *E. coli and Klebsiella and Serratia* species, because fosfomycin is excreted unchanged in the urine. NOTE: Fosfomycin is *less effective* against *Gram-positive bacteria* because these bacteria generally lack selective glycerophosphate and glucose-6-phosphate transporters.

Gentamicin

is an isolated from Micromonospora purpurea - It is effective against both gram-positive and gram-negative organisms, and many of its properties resemble those of other aminoglycosides Use: Is active alone, but also as a synergistic companion with *ß-lactam* antibiotics, against *Escherichia coli, Proteus, Klebsiella pneumoniae, Enterobacter, Serratia* and other gram-negative rods that may be resistant to multiple other antibiotics. *Infective burn wound & Septicemia* Note: given in combination with Vancomycin or Penicillin to promote bactericidal effect especially with *resistant strains* of *Streptococci and enterococci.* Adverse effects: *Nephrotoxicity, Ototoxicity*

Kanamycin & Amikacin

used for treatment of tuberculosis caused by *streptomycin-resistant strains,* but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete. *Indication: Multi-drug resistant TB infection (both)* - is also active against atypical mycobacteria (amikacin) *note:* There is no cross-resistance between streptomycin and amikacin, Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosages are the same as those for streptomycin.

β-lactam spectrum of action

β-lactam's spectrum of action is determined by two factors: A. *The degree to which it can penetrate the outer membrane & cell wall* - *Gram-positive bacteria* - both hydrophilic and hydrophobic agents diffuse through the thick peptidoglycan layer. - *Gram-negative bacteria*- hydrophilic agents pass through the outer membrane pores (porin) much more readily than do hydrophobic agents. - Hydrophilic agents tend to have *broad spectra of action (ampicillin, amoxicillin, and, especially, piperacillin, ticarcillin, carbenicillin, and mezlocillin),* - Hydrophobic agents tend to have *narrow spectra of action (oxacillin, cloxacillin, dicloxacillin, nafcillin, methicillin, and penicillin G)* This means that some Gram-negative bacteria are inherently resistant to narrow spectrum β-lactams simply by virtue of the permeability barrier presented by their outer membrane. *B. Ability to bind to specific transpeptidases* bacteria typically have several transpeptidases that differ subtly in their substrate specificity and crosslinking activity; these differences are especially prominent between rods and cocci. NOTE: *Most β-lactams* have *selectivity for several different transpeptidases* except for *methicillin* which is specific for just one, *S. aureus*.