Antimicrobial Therapy PDF

Antimicrobial Therapy Antimicrobial therapy: Antimicrobial: Drugs that are toxic for invading organisms but not to mammalian cells. Criteria for selecting Antimicrobial agent Identification of microorganism the susceptibility of microorganism to a particular agent Em...

Antimicrobial Therapy Antimicrobial therapy: Antimicrobial: Drugs that are toxic for invading organisms but not to mammalian cells. Criteria for selecting Antimicrobial agent Identification of microorganism the susceptibility of microorganism to a particular agent Empiric Therapy: some patients require immediate administration of drug(s) prior to bacterial identification and susceptibility testing the site of the infection Patient factors the safety of the agent the cost of therapy. Special Considerations When using Antimicrobial Drugs Do not use antimicrobial drugs for mild infection. Should be used only for individuals at risk of severe infection. If an antimicrobial can be used topically or locally, do so. This reserves the use of systemic drugs for serious disease. Do not dismiss the principles of asepsis Use should be based on a definitive diagnosis Do not use a broad-spectrum antibiotic if the infecting organism is sensitive to a specific antibiotic. Drugs should be administered in full therapeutic doses Be careful regarding antibiotic withdrawal times in animals to be slaughtered for human consumption and antibiotic withdrawal times in dairy cows Identification of the infecting organism Gram staining and direct microscopic visualization: provide rapid assessment of the pathogen Used to identify the presence and morphologic features of organisms in body fluids that are normally sterile (blood, serum, CSF, pleural fluid, synovial fluid, peritoneal fluid, and urine). culture the organism: to get a conclusive diagnosis and determine the susceptibility obtain a sample for culture prior to initiating treatment. Definitive identification may require other laboratory techniques, such as detection of microbial antigens, DNA, or RNA detection of host immune response Determining antimicrobial susceptibility Is a guide in choosing antimicrobial therapy. A practical approach is to measured Minimal Inhibitory Concentration (MIC) MIC is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation. MIC is estimated by using sensitivity disks Some pathogens (Streptococcus pyogenes usually have predictable susceptibility patterns to certain antibiotics). Bacteriostatic versus bactericidal drugs: Bacteriostatic drugs: arrest the growth and replication of bacteria Limit the spread of infection to allow the immune system to attack and eliminates the pathogen. If the drug is removed before the immune system scavenged the organisms, viable organisms may begin a second cycle of infection. Bactericidal drugs: kill bacteria are of choice in seriously ill and immunocompromised patients. CHEMOTHERAPEUTIC SPECTRUM Narrow-spectrum antibiotics Chemotherapeutic agents acting only on a single or a limited group of microorganisms Extended-spectrum antibiotics is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram- negative bacteria. Example, ampicillin is considered to have an extended spectrum because it acts against gram-positive and some gram-negative bacteria Broad-spectrum antibiotics Drugs affect a wide variety of microbial species Examples: tetracycline, fluoroquinolones and carbapenems. Time Vs concentration determinant killing How high it Concentration-dependent killing: gets The higher the drug concentration relative to pathogen MIC, the greater the rate and extent of antimicrobial activity. Giving aminoglycosides by a once-a-day bolus infusion to achieves high peak levels How long above MIC Time-dependent Killing (concentration-independent): Clinical efficacy determined by the duration (time) that blood concentrations of a drug remain above the MIC. Continuous (24 hours) infusions can be utilized instead of intermittent dosing to achieve prolonged time above the MIC to kill more bacteria. For example, dosing schedules for the penicillins that ensure blood levels greater than the MIC would provide the most clinical efficacy. Effect of the site of infection on therapy Adequate levels of antibiotic must reach the site of infection for the effective eradication of invading microorganisms. Structure of capillaries of some tissues limit drug diffusion (BBB) The penetration of antibacterial agent in the CSF are influenced by: Lipid solubility of the drug: Lipid-soluble chloramphenicol have significant penetration into the CNS as compared to penicillin ( low solubility in lipids). In infections such as meningitis, the barrier is not function as effectively, and permeability is increased. Some β-lactam antibiotics can enter the CSF when the meninges are inflamed. Molecular weight of the drug: drugs of low molecular weight has enhanced ability to cross the blood–brain barrier, as compared to drugs with a high molecular weight Protein binding of the drug: A high degree of protein binding of a drug restricts its entry into the CSF. Patient factors Immune system: host defense system ultimately eliminate the invading organisms. High doses of bactericidal or longer courses may be required in case of: malnutrition, autoimmune diseases, pregnancy, immunosuppressive drugs. Renal dysfunction: Poor kidney function may cause accumulation of certain antibiotics. creatinine levels are used as index of renal function. Hepatic dysfunction: Antibiotics that are eliminated by the liver (erythromycin) must be used with caution when treating patients with liver dysfunction. Age: Renal or hepatic elimination processes are often poor in newborns and elderly patients Pregnancy and lactation: Many antibiotics cross the placental barrier or enter the nursing infant via milk. COMBINATIONS OF ANTIMICROBIAL DRUGS It is advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility of Superinfections emergence of resistant organisms minimizes toxicity. some situations require combinations of antimicrobial drugs such as the treatment of tuberculosis Advantages of drug combinations Certain combinations of antibiotics, such as β-lactams and aminoglycosides, show synergism (combination is more effective than either of the drugs used separately). Disadvantages of drug combinations Combined therapy may cause interference with each others actions Co-administration of an agent that causes bacteriostasis (tetracycline) interfere with a second agent that kill multiplying bacteria (penicillins) DRUG RESISTANCE Bacteria are resistant to an antibiotic if the maximal level of an antibiotic does not halt the growth or kill the bacteria. Mechanisms of Resistance Alteration of an antibiotic’s binding site through mutation Resistance to β-lactam antibiotics involves alterations of bacterial penicillin-binding proteins. Decreased accumulation: Decreased uptake or increased efflux limit drug access to the site of action in sufficient concentrations Altering the number and structure of porins (channels). presence of efflux pump as seen with tetracycline. Enzymatic inactivation: destroy or inactivate the antimicrobial agent 1. β-lactamases inactivate the penicillin and cephalosporins 2. Acetyltransferases: inactivate chloramphenicol or aminoglycosides Some mechanisms of resistance to antibiotics. PROPHYLACTIC USE OF ANTIBIOTICS used for the prevention rather than for the treatment of infections Is restricted to clinical situations in which the benefits outweigh the potential risks (bacterial resistance). COMPLICATIONS OF ANTIBIOTIC THERAPY Hypersensitivity Penicillin can cause hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. Direct toxicity certain antibiotics may cause toxicity by directly affecting cellular processes in the host. Aminoglycosides cause ototoxicity by interfering with membrane function in the auditory hair cells. Superinfections overgrowth of opportunistic organisms, especially fungi or resistant bacteria. Broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, oral, intestinal, and genitourinary tracts,  Classification of Antimicrobial drugs Their chemical structure (for example, β-lactams or aminoglycosides) Their mechanism of action (for example, cell wall synthesis inhibitors, protein synthesis inhibitors) Antibiotics mechanism of action Cell Wall Inhibitors Cell Wall Inhibitors Selectively inhibiting the transpeptidase enzyme that catalyzes the final step in cell wall biosynthesis, the cross-linking of peptidoglycan. Inhibition of cell wall synthesis require actively proliferating microorganisms. Most important members of this group β-lactam antibiotics (contain β-lactam ring that is essential to their activity) Vancomycin Carbapenems Bacitracin Polymyxins Penicillins: Members of this family differ from one another in the R General structure of penicillins. (1) Thiazolidone ring (2) β-Lactam ring: its cleavage destroy antibiotic activity (3) Site of action of β-lactamases (penicillinases). (4) Site of amidase cleavage to yield 6-aminopenicillanic acid nucleus used in producing semisynthetic penicillins (5) carboxyl group is the site of salt formation (e.g., sodium, procaine, potassium etc) that stabilize the penicillins and affect solubility and absorption rate. Mechanism of action of Penicillins: Inhibits transpeptidase which is involved in cross-linking of bacterial cell wall and causes cell lysis These drugs are bactericidal Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. They are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. Penicillins are primarily effective against Gram(+) aerobes and anaerobes. The broad-spectrum, semisynthetic penicillins are also effective against some Gram(–) pathogens. 1. Natural penicillins a. Penicillin G (Procaine benzylpenicillin): used for the treatment of infections caused by Gram(+) and nonpenicillinase producing pathogens of all animal species. b. Penicillin V: Used for long-term oral therapy of Gram(+) bacterial infections in dogs, cats, and horses. 2. Penicillinase-resistant penicillins Methicillin Oxacillin Cloxacillin. use for severe staphylococcal infections caused by β- lactamase-producing organisms 3. Broad-spectrum penicillins A. Aminopenicillins. Ampicillin and amoxicillin active against many Gram(–) aerobes (E. coli, Proteus, Haemophilus spp.) as well as Gram(+) pathogens. They are acidstable but are not penicillinase stable. GI absorption of Amoxicillin is better than Ampicillin. B. Carboxypenicillins Carbenicillin and ticarcillin have antipseudomonal actions when used alone or in combination with gentamicin or tobramycin. useful for ear and skin infections in dogs caused by Pseudomonas spp. C. Piperacillin has an extended Gram(–) spectrum including Pseudomonas, Enterobacter, and Klebsiella spp. 4. Potentiated penicillins (β-lactamases inhibitors) Clavulanic acid: has minimal antibacterial action but it inhibits many of the β-lactamases produced by penicillin-resistant organisms. It is combined with amoxicillin or ticarcillin in commercial preparations. Augmentin- (Amoxicillin/clavulanic acid) human formulation Clavamox- Vet formulation Sulbactam: has an action similar to clavulanic acid and is combined with ampicillin. The potentiated penicillins are used in small animals for extended spectrum antimicrobial action. Pharmacokinetics: Many penicillins are broken down by gastric HCl and are thus poorly absorbed orally. These include penicillin G, methicillin, and ticarcillin. Acid stable penicillins are well absorbed orally. These include penicillin V, ampicillin, amoxicillin, oxacillin, cloxacillin. Penetration into CNS, bones, prostate, and eye is limited unless those sites are inflamed. Most excreted unchanged in the urine. The remainder is metabolized by the liver Administration: Penicillins are generally administered IM. Acid-stable penicillins are administered orally 2–3 times a day. Procaine penicillin G is slowly absorbed from IM sites and may provide therapeutic levels for 24 hours with a single dose. Resistance: Inactivation of penicillins by bacteria-producing penicillinases (β- lactamases) is the most common mechanisms of resistance. Failure of the drug to bind to penicillin-binding proteins (PBPs) may also occur. Adverse effects: Allergic reactions may occur in animals, especially horses. Signs include skin eruptions, anaphylaxis. Hyperkalemia and cardiac arrhythmias may result from IV administration of potassium penicillin in all species. Cephalosporins β-lactam antibiotics (have the same mode of action as penicillins) Cephalosporins are bactericidal First generation cephalosporins include Cephalexin, cefadroxil, cephapirin, cephalothin Used as first alternate to penicillins in the treatment of Gram(+) pathogens (staph and strep) Some Gram (-) (E cloi, proteus, kelpsella) Has Aerobic but no anaerobic coverage and is used for skin infection Second-generation cephalosporins include Cefaclor, cefoxitin Their antibacterial spectrum is broader than that of first-generation Have better Gram(–) coverage in addition to Gram (+). anaerobic coverage (intra-abdominal infection)  Third-generation cephalosporins: Ceftiofur, Cefoperazone, cefotaxime, cefixime, cefopodoxime. have extended spectrum action against Gram(–) but less Gram (+) organisms resistant to β-lactamases cephalosporinases penetrate the blood–brain barrier Aerobic and no Anaerobic coverage Ceftiofur: is used in the treatment of respiratory disease in cattle, horses, sheep, and swine intramammary mastitis in cattle. urinary tract and soft tissue infections in dogs and cats. Cefoperazone: used in dogs to treat soft tissue infections Cefotaxime: used in dogs, cats, and foals to treat Gram(–) sepsis, soft tissue infections meningitis, and CNS infections. Cefopodoxime: treatment of skin infections in dogs and cats. Cefixime: treatment of urinary tract and respiratory infection  Fourth-Generation cephalosporins: Cefepime cefquinone Gram (-) including Pseudomonas which show resistance to other cephalosporins. Less active against gram (+) bacteria Pharmacokinetics. Most cephalosporins are unstable in gastric acid and must be given parenterally. Cephalexin and cefadroxil, cefaclor, and cefixime are acid stable and are well absorbed orally. Eliminated by glomerular filtration and active tubular secretion like penicillins.  Administration. The acid-stable (cephalexin, cefadroxil, cefaclor, and cefixime) are administered orally every 8–12 hours in dogs and cats. Parenteral cephalosporins are administered IM, IV, or SC every 8–12 hours in all species. Adverse effects. cephaolsporins are among the safest antimicrobials Prolonged treatment or high doses may produce hemopoietic effects with anemia and bone marrow depression. Hypersensitivity and allergic reactions Carbapenems (Imepenem and Meropenem) Mechanism of action: Similar to other β-lactam antimicrobial drugs Broad spectrum Therapeutic uses: Treat serious infections like peritonitis associated with ruptured GI or intestinal spillage during surgery. Effective against Gram(+) and Gram(–) aerobic and anaerobic bacteria including Pseudomonas and Enterobacteriaciae. Pharmacokinetics. Administer by IV acid hydrolysis and poor absorption prevent oral administration 75% eliminated by renal filtration Metabolism of Imepenem by the kidney dehydropeptidase (DHP-1) causes nephrotoxicity Imepenem used with cilastatin (DHP-1 inhibitor) to decrease toxicity Adverse effects: hypersensitivity reactions (pruritis, fever, and rarely anaphylaxis). anorexia, vomiting, and diarrhea, seizures and tremors MONOBACTAMS (Aztreonam) Mechanism of action: binds to penicillin binding proteins present in Gram(–) aerobic bacteria and disrupt cell wall synthesis It is stable to most β-lactamases. Bacteriocidal Therapeutic uses: A strict G- and has no activity against G+ bacteria Mainly used for G- bacteria and is used to replace aminoglycosides Used against pseudomonas Pharmacokinetics: has a similar distribution to penicillin G. Penetrate CSF excreted by the kidneys Adverse effects: Hypersensitivity reactions may occur Vancomycin Mechanism of action: Vancomycin blocks bacterial cell wall synthesis by inhibiting polymer release from the cell membrane It is bactericidal for Gram(+) organisms. Has no activity against G- bacteria (because it is very large molecule and cannot pass through the outer membrane of gram-negative bacteria) Therapeutic uses: Used for methicillin-resistant staphylococcal infections of bone and soft tissue in dogs and cats. Used in dogs for the treatment of multidrug-resistant enteric infection. Pharmacokinetics: Vancomycin is not absorbed orally. It distributes to the ECF and transcellular fluids excreted unchanged by glomerular filtration. Adverse effects: Ototoxicity and nephrotoxicity Bacitracin Mechanism of action: inhibits cell wall synthesis It is bactericidal for Gram(+) bacteria and Spirochetes. Therapeutic uses: used in topical ointments and solutions and is frequently combined with polymixin B and/or neomycin Pharmacokinetics: Bacitracin is not absorbed orally. It is nephrotoxic for systemic use. Adverse effects: Systemic toxicity does not occur with topical or oral administration of bacitracin. Polymyxin B Mechanism of action: interacts with phospholipids in the bacterial cell membrane to produce a detergent-like effect and cause membrane disruption It is bactericidal to Gram(–) organisms. Therapeutic uses: used topically to treat Gram(–) bacterial infections of the skin, eye, and ear in all species. administered orally to cattle and swine for the treatment of Gram(–) enteric infections. Pharmacokinetics: Polymyxin B is not absorbed orally. It is too nephrotoxic for parenteral use. Adverse effects: does not produce systemic toxicity when administered topically or orally Protein Synthesis Inhibitors  Protein Synthesis Inhibitors Targeting bacterial ribosomes and inhibit bacterial protein synthesis. Selectivity bind to bacterial ribosomes, and this minimizes adverse consequences to mammalian cells. Bacterial ribosome composed of 30S and 50S subunits while mammalian ribosomes have 40S and 60S subunits. High concentrations of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of Interaction with mitochondrial mammalian ribosomes, since the structure of mitochondrial ribosomes more closely resembles bacterial ribosomes. TETRACYCLINES Tetracyclines consist of four rings. Substitutions on these rings alter the pharmacokinetics and spectrum of antimicrobial activity. Mechanism of action: inhibit protein synthesis by binding to the 30S ribosome and preventing attachment of aminoacyl tRNA to the mRNA-ribosome complex Bacteriostatic broad spectrum: active against Gram(+) and Gram(–) aerobes and anaerobes  Therapeutic uses: Large animals: (cattle, sheep, horses, and swine ) Tetracycline, chlortetracycline, and oxytetracycline: used to treat local and systemic bacterial, chlamydial, rickettsial, and protozoal infections Small animals. Doxycycline, minocycline, and tetracycline: used to treat respiratory and urinary tract infections (Borrelia, Brucella, Haemobartonella and Ehrilichia spp. Pharmacokinetics: Doxycycline and minocycline are lipid soluble and penetrate the CNS, eye, and prostate Renal excretion is the major route of elimination Administration with dairy products decreases absorption, particularly for tetracycline Administration: orally or IV IM injections produce pain and irritation oral use disrupt ruminal or colonic microflora of horses Resistance: decreased of drug uptake active transport of the tetracycline out of the bacterial cell. Adverse effects: Tetracyclines (except doxycycline and minocycline) are nephrotoxic Suprainfections of fungi, yeast, or resistant bacteria may occur in the GI tract with prolonged administration Antianabolic effects are seen at high doses because of binding to mitochondrial ribosomes. Chloramphenicol group Chloramphenicol, florfenicol Mechanism of action. bind to bacterial 50S ribosome unit to inhibit peptide bond formation and protein synthesis are bacteriostatic and broad spectrum and are effective against most anaerobic bacteria. Therapeutic uses. Not allowed for use in food-producing animals because the potential danger of residue- induced toxicity in humans used in dogs, cats, horses, and birds for local and systemic infections Treat respiratory, CNS, and ocular infections, and infections caused by anaerobes and Salmonella spp.  Pharmacokinetics Rapidly absorbed from the GI tract and widely distributed to all tissues including the CNS and eye. Metabolized by liver Administration: orally, IM, IV, or SC Resistance: Resistant due to inactivation of chloramphenicol by acetyltransferase of resistant bacteria Adverse effects: Aplastic anemia is often fatal (stop of producing enough blood cells; WBC, RBC and platelets) and this is the reason for the drug’s ban in food- producing animals. Florfenicol is not known to produce aplastic anemia and its permitted to be used in beef cattle. MACROLIDES: Erythromycin Azithromycin Clarithromycin Tulathromycin Tylosin Tilmicosin Mechanism of action: Bacteriostatic inhibit bacterial protein synthesis by binding to the 50S ribosome to prevent translocation of amino acids to the growing peptide chain. Their antimicrobial activity is primarily against Gram(+) aerobes and anaerobes and Mycoplasma spp.  Therapeutic uses: Erythromycin: treatment of infections caused by Gram(+) aerobes and anaerobes in dogs, cats, and horses. Tylosin: treatment of local and systemic infections caused by Mycoplasma and Gram(+) bacteria. Tilmicosin: treatment of respiratory disease caused by Pasteurella spp. Azithromycin: is effective against Staphylococcus, Streptococcus, and Mycoplasma. Tulathromycin: treatment of bovine and swine respiratory diseases. Clarithromycin: treatment of mycobacterial infections including canine leproid granuloma, feline leprosy, and for Helicobacter  Pharmacokinetics: Macrolides are absorbed orally if protected from gastric acid destruction by enteric coated preparations are widely distributed to all tissues except those of the CNS. Resistance: due to decrease drug binding to 50S ribosome. Adverse effects: Erythromycin is agonist of the motilin (stimulates contraction of GI) can produce abdominal pain and diarrhea. Tilmicosin produces cardiovascular toxicity in species other than cattle by increasing myocardial Ca2+ concentrations.  LINCOSAMIDES Lincomycin, clindamycin, and pirlimycin Mechanism of action: bind to bacterial 50S ribosome to inhibit protein synthesis Bacteriostatic combined therapy with chloramphenicol should be avoided because they have same binding site Therapeutic uses: Lincomycin: used to treat swine dysentery, and the treatment of staphylococcal, streptococcal, and mycoplasmal infections. Clindamycin: used in dogs and cats for periodontal disease, osteomyelitis, dermatitis, and deep soft tissue infections caused by Gram(+) organisms. used for treating toxoplasmosis in dogs and cats and neosporosis in dogs. Pirlimycin: used for bovine mastitis.  Pharmacokinetics: Oral absorption is 50% for lincomycin and 90% for clindamycin. Distributed well to bone and soft tissues(tendon sheaths). Distribution to CNS is low unless the meninges are inflamed. Parent drug and metabolites are excreted in urine, bile, and feces. Administration: Lincomycin: IM or added to drinking water. Clindamycin: orally or IM Pirlimycin: given by intramammary infusion. Resistance: Alteration of binding to bacterial ribosomes Cross-resistance between lincosamides and macrolides is common. Adverse effects: may produce a severe diarrhea due to altered GI flora of horses, rabbits, hamsters, and guinea pigs AMINOGLYCOSIDES Mechanism of action: bind to the 30S ribosomal fragment and inhibit the rate of protein synthesis Therapeutic uses: Neomycin: used orally to treat enteric infections and topically to treat skin, ear, and eye infections. Gentamicin and amikacin: used in all species to skin, respiratory tract, ear, eye, urinary tract infections and septicemia. Tobramycin: similar to gentamicin and more potent antipseudomonal activity and reduced nephrotoxicity. Kanamycin: used as an oral preparation combined with bismuth subcarbonate and aluminum to treat bacterial enteritis in dogs.  Pharmacokinetics. not absorbed from the GI tract because of their high polarity. Aminoglycosides tend to accumulate in the renal cortex and otic endolymph, which predisposes them to their toxicity. excreted unchanged in the urine by glomerular filtration. Administration: IM or SC for systemic infections. Because the bactericidal effects of aminoglycosides are concentration- dependent, some clinicians advocate a high dose once daily to allow full clearance to reduce renal and cochlear toxicity. Used orally to treat enteric infections Resistance: Inactivation of aminoglycosides by bacterial enzymes Amikacin is more resistant to enzymatic degradation than others Adverse effects are relatively more toxic than other classes of antimicrobials. Used with caution in animals with decreased renal function and should not be used with other ototoxic or nephrotoxic drugs such as furosemide or amphotericin B. Ototoxicity due to a damage of cochlear sensory cells and/or vestibular cells of the inner ear resulting in deafness and ataxia Nephrotoxicity is due to the damage of the membranes of proximal tubular cells which results of impaired absorption, proteinuria, and decreased glomerular filtration rate. Aminocyclitols (Spectinomycin and apramycin) are chemically related to the aminoglycosides bacteriostatic Mechanism of action: They bind to the 30S ribosome and inhibit protein synthesis. They are active against Gram(–) aerobes and Mycoplasma Therapeutic uses: Spectinomycin: treatment of enteric and respiratory infection Apramycin: treat enteric infections, especially colibacillosis Pharmacokinetics: Less than 10% is absorbed orally. Parenterally administered spectinomycin distributes to the ECF and is excreted unchanged by the kidney. Adverse effects: There is no significant toxicity Tiamulin Mechanism of action: binds to the 50S bacterial ribosome to inhibit protein synthesis active against Gram(+) cocci, Mycoplasma, spirochetes, and some Gram(–) pathogens such as Haemophilus spp. Therapeutic uses: treatment of Haemophilus pneumonia and swine dysentery. Pharmacokinetics: Absorbed orally, widely distributed, and metabolized by the liver. Elimination of metabolites occurs in feces (70%) and urine (30%). Adverse effects. Dermatitis with erythema and pruritus may be observed if pigs are overcrowded and is due to the irritant metabolites in urine. Nucleic acid synthesis FLUOROQUINOLONES Mechanism of action: inhibit bacterial DNA gyrase, an enzyme which controls DNA supercoiling as the replicating strands separate. Some affect only G- and others includes G+ in addition to G- bactericidal. Therapeutic uses Enrofloxacin: Treat dermal, respiratory, and urinary tract infections (including prostatitis) in dogs, cats, and birds Treat respiratory infections in cattle. Danofloxacin: used to treat bovine respiratory infections Difloxacin: treat dermal, respiratory, and urinary tract infections in dogs. Orbifloxacin and Marbofloxacin: used to treat dermal, respiratory, and urinary tract infections of dogs and cats.  Administration. Orally or parenteral in all species. Enrofloxacin is administered SC for treatment of respiratory infections in cattle. Resistance: Reduced intracellular concentration due to Decreased porin channels efflux pumps. (Pumps drug out of the cell) Growth of mutants in which fluoroquinolones did not bound to DNA gyrase. Adverse effects. Erosion of articular cartilage in young dogs and foals, Enrofloxacin might produce seizures in dogs on phenobarbital for epilepsy Metronidazole (flagyl) Mechanism of action: Metronidazol reduced by anaerobic bacteria and protozoa to produce a cytotoxic metabolite which disrupts DNA bactericidal against obligate anaerobes bacteria and protozoa Therapeutic uses: Treat infections caused by anaerobic pathogens, especially brain abscesses and pelvic, genitourinary tract, and respiratory infections in dogs, cats, and horses. Treat protozoal infections such as giardiasis, Entamobea and trichomoniasis in dogs and cats. Adverse effects: High or prolonged dosage may produce neurotoxicity with signs that include nystagmus, ataxia, and seizures. It is banned in food producing animals and pregnant animals because it has carcinogenic effect on laboratory animals Rifampin Mechanism of action: inhibits RNA polymerase and prevents RNA synthesis It is bactericidal for mycobacteria and Gram(+) pathogens. Therapeutic uses. combined with erythromycin to treat Rhodococcus equi in foals. used in combination with other antifungal agents to treat fungal infections such as aspergillosis or histoplasmosis in dogs and cats Pharmacokinetics: absorbed orally and rapidly distributed to cells and tissues. Administered orally in foals, dogs, and cats. Adverse effects: Hepatotoxicity may occur in animals with preexisting liver disease produce red-orange color urine, sweat, saliva but is not harmful. Nitrofurans Mechanism of action: It is reduced by bacteria to produce reactive intermediate that induce DNA fragmentation and may also block mRNA translation. Broad spectrum and Bacteriostatic. Therapeutic uses: Orally to treat lower urinary tract infection in dogs and cats Topically as an antibacterial ointment Powder as wound dressings in all species. Pharmacokinetics: Nitrofurantoin is absorbed orally and rapidly excreted by glomerular filtration and active secretion. Adverse effects: Nitrofurans not used in food-producing animals because of its potential carcinogenic effect on laboratory animals. Novobiocin: Mechanism of action: Blocks DNA gyrase which inhibit supercoiling of bacterial DNA It is bacteriostatic for Gram(+) cocci Therapeutic uses: Used for wound treatment and the treatment of mastitis particularly Staphylococcus infections. Pharmacokinetics: absorbed orally Tissue penetration is relatively poor. Administration: intramammary infusion usually combined with procaine penicillin to limit the development of resistance. Adverse effects: Novobiocin does not produce systemic toxicity SULFONAMIDES  Mechanism of Action: P-aminobezoic acid Folate are essential for the synthesis of purines (DNA synthesis precursor) Inhibited by dihydropteroate Sulfonamides synthetase In the absence of folate, cells cannot divide. Dihydrofolic acid Mammalian cells obtain preformed folate from the diet. Inhibited by Dihydrofolic acid Trimethoprim Reductase Bacteria are impermeable to folic acid and, therefore, rely on their ability to synthesize Teterahydrofolic acid folate de novo. Sulfanilamide competitively inhibits bacterial dihydropteroate synthetase. This enzyme uses DNA synthesis precursors para-aminobenzoic acid (PABA) for synthesis of Purines and pyrimidine folic acid. Without this reaction bacteria cannot replicate. (cell growth)  Therapeutic uses: Sulfachlorpyridazine: treat respiratory and enteric infections, especially colibacillosis in non-ruminants and in calves. Sulfamethoxazole: treat urinary tract infections in small animals. rapidly excreted and is very soluble and thus it reach high concentrations in urine with minimal danger of renal crystalluria. Sulfacetamide: used in ophthalmic preparations. Sulfasalazine: treat colitis and inflammatory bowel disease in dogs and cats. Potentiated sulfonamides: Is combinations of sulfonamide with trimethoprim or ormetoprim. Give synergistic action via sequential blockade of folate synthesis Trimethoprim and ormetoprim inhibit dihydrofolate reductase in bacteria (but not mammalian cells)  Potentiated sulfonamides have a broader spectrum of action and a reduced rate of development of bacterial resistance. Preparations include sulfadiazine plus trimethoprim sulfamethoxazole plus trimethoprim sulfadimethoxine plus ormetoprim. Pharmacokinetics well absorbed orally and widely distributed to tissues. Metabolized by acetylation and glucuronide conjugation unchanged drug and metabolites is excreted by glomerular filtration Sulfa drugs are bound to albumin and extent of binding depends on the ionization constant (pKa) of the drug. Administration: Administered orally or by injection Bacterial resistance: Bacteria that can obtain folate from their environment are naturally resistant to these drugs. Bacteria develop resistance by mechanisms of Increased PABA production decreased binding of sulfonamide to dihydropteroate synthase bacterial metabolism of sulfonamide. spectrum of action of the potentiated sulfonamides is broader combination is bactericidal rather than bacteriostatic. Adverse effects: Renal crystalluria: precipitation of sulfonamides in neutral or acidic urine may occur with large or prolonged doses and inadequate water intake hydration and alkalinization of urine can prevent the problem Therapeutic regimens generally do not extend beyond 5 days to reduce renal crystalluria. Keratoconjunctivitis may be observed in dogs treated with sulfadiazine Hematopoietic disturbances Thrombocytopenia anemia Sulfonamides should not be used in animals with preexisting bleeding disorders.