beta-lactam beta-lactam antibiotics antibiotics glycopeptides glycopeptides aminoglycosides...

• BETA-LACTAMBETA-LACTAM ANTIBIOTICSANTIBIOTICS• GLYCOPEPTIDESGLYCOPEPTIDES• AMINOGLYCOSIDESAMINOGLYCOSIDES ((aminosidesaminosides))• TETRACYCLINESTETRACYCLINES

• BETA-LACTAMBETA-LACTAM ANTIBIOTICSANTIBIOTICS• GLYCOPEPTIDESGLYCOPEPTIDES• AMINOGLYCOSIDESAMINOGLYCOSIDES ((aminosidesaminosides))• TETRACYCLINESTETRACYCLINES

Assoc. Prof. I. Lambev (www.medpharm-sofia.eu)

Antiinfective agents are among the most dramaticexamples of the advances of modern medicine.Many infectious diseases once considered incurableMany infectious diseases once considered incurableand lethal now can be treated.and lethal now can be treated. The remarkably powerfuland specific activity of antimicrobial drugs is due to theirselective toxicity selective toxicity for targetsfor targets that are either uniqueto microorganisms or much more important in them than in animals or humansin animals or humans. Among these targets arebacterial and fungal cell wall-synthesizing enzymes, thebacterial ribosome, the enzymes required for nucleotidesynthesis and DNA replication, the mechanism of viralreplication, etc. The much older and less selectiveselectivecytotoxic drugscytotoxic drugs are the antiseptics and disinfectants.

AntiinfectiveAntiinfective agents agents may be classified may be classified according to according to their antimicrobial activity::1. Antibacterial drugs (antibiotics 1. Antibacterial drugs (antibiotics and synthetic drugs)and synthetic drugs)2. Antiviral drugs2. Antiviral drugs3. Antifungal drugs3. Antifungal drugs4. Antiprotozoal drugs4. Antiprotozoal drugs5. Anthelmintic drugs5. Anthelmintic drugs6. Insecticides for ectoparasites 6. Insecticides for ectoparasites 7. Antiseptics and 7. Antiseptics and Disenfectant (Not are drugs)Disenfectant (Not are drugs)8. Prepartaions for Disinsection (Not are drugs)8. Prepartaions for Disinsection (Not are drugs)9. Prepartaions for Deratisation (Not are drugs)9. Prepartaions for Deratisation (Not are drugs)10. Vaccines, Serums, and Immunoglobulins10. Vaccines, Serums, and Immunoglobulins

30S: Aminoglycosides30S: Aminoglycosides30S: Tetracyclines30S: Tetracyclines50S: Chloramphenicol 50S: Chloramphenicol 50S: Macrolides, Lincosamides50S: Macrolides, Lincosamides50S: Linezolide, Streptogramins50S: Linezolide, Streptogramins

RifampicinRifampicinPolymyxinsPolymyxins

ANTIBIOTICS – mechanism of actionANTIBIOTICS – mechanism of action

β-lactams, Glycopeptides β-lactams, Glycopeptides

Adverse Drug Reactions (ADRs)Antibacterial agents may cause:

●direct host toxicity (aminoglycosides)●toxic interactions with other drugs●interference with protective effects of normal host microflora (by suppressing obligate anaerobes, e.g selection or promotion of drug resistance)●tissue lesions at injection sites (tetracyclines)●impairment of host immune system (chloramphenicol)

●reduced phagocytosis (tetracyclines) ●inhibition of phagocytosis (aminoglycosides)●hypersensitivity reactions (penicillins, aminosides, sulfonamides)●hepatic microsomal enzyme induction (rifampicin) or inhibition (chloramphenicol, metronidazole) that interferes with their own metabolism as well as that of concurrent medications ●●residues in animal products for human consumption (all antibacterials).

NB:NB: withdrawal periods… withdrawal periods…

Because of the potential for some antibacterials to reduce protein production, incl. antibodies(e.g. aminoglycosides,amphenicols, lincosamides, macrolides,tetracyclines), concurrent antibacterial medications need to be selected carefullywhen immunizing animals, especiallywith killed vaccines.

Selection or promotion of resistance

Antibacterial agents do not cause bacteria tobecome resistant but their use preferentiallyselects resistant populations of bacteria. Some genes that code for resistance have beenidentified in bacterial cultures. The most clinicallyimportant for resistance are plasmids. They carrygenes that may benefit survival of theorganism (e.g. antibacterial resistance)transmitted from one bacterium to another.

Plasmids are cytoplasmic genetic elements which transfer drug resistance to previously susceptible bacteria.Acquired resistance is not a problem in all bacteria.For example, Gram-positive bacteria (with some exceptions, incl. Staphylococcus spp) are often unable to acquire resistance plasmids (and thus acquire resistance through mutation, a slower process), whereas resistance is an increasing problem in many Gram-negativepathogens such as the Enterobacteriaceae.

Enterobacteriaceae:• E. coli, Salmonella, Schigella• Yersinia pestis (plugue!)• Klebsiella• Enterobacter• Serratia• Citrobacter

The intestine is a major site of transfer of antibacterial resistance. This is important whenantibacterial agents are used in animals in contact with fecal material, an enormous reservoir of intestinal bacteria.Nosocomial infectionsNosocomial infectionsIn veterinary hospitals, nosocomial infection (infection acquired during hospitalization) by resistant bacteria is an emerging problem. Bacteriamost frequently implicated in veterinary hospitals areKlebsiella, Escherichia, Proteus and Pseudomonas spp.

Factors predisposing to nosocomial infections include age extremes (young or old), severity of disease,duration of hospitalization, use of invasive supportsystems, surgical implants, defective immune responses and prior antibacterial drug use.The drugs with greatest potential to suppress endogenous flora are those most active againstobligate anaerobic bacteria (amphenicols, lincosamides, beta-lactams) and those undergoing extensive enterohepatic recycling(chloramphenicol, lincosamides, tetracyclines). Cephalosporins are a major risk factor in humans.

HypersensitivityHypersensitivity reactions to antibacterial agents are reported less frequently in VM than in human patients, where they constitute 6–10% of all drug reactions. To induce an allergic response, drug molecules must be able to form covalent bonds with macromolecules such as proteins. Bonding with the protein carrier enables reaction with T lymphocytesand macrophages. The reactive moiety is usually adrug metabolite, e.g. the penicilloyl moietyof penicillins.

●Hypersensitivity reactions depend on the combination of antigen and antibody and are not dose related. The first episode cannot be anticipated, although atopic individuals have a greater tendency to develop drug allergies.●Hypersensitivity reactions have been reported most frequently in veterinary patients with cephalosporins,penicillins and sulfonamides.●Doberman pinschers have an increased risk of sulfonamide hypersensitivity, possibly due to delayed sulfonamide metabolism.

●The probability of an anaphylactoid reaction (i.e. direct histamine release that is not immunologically mediated) is increased with penicillin preparations containing methylcellulose as a stabilizer.Drug hypersensitivity may manifest in different ways.●Acute anaphylaxis is associated with IgE-triggered mast cell degranulation and characterized by oneor more of the following signs: hypotension, bronchospasm, angioedema, urticaria, erythema,pruritus, pharyngeal and/or laryngeal edema, vomiting and colic.

BETA-LACTAM ANTIBIOTICS(inhibitors of cell wall synthesis)

Their structure contains a beta-lactam ring.

The major subdivisions are:

(a) penicillins whose official names usually include or end in “cillin”(b) cephalosporins which are recognized by the inclusion of “cef” or “ceph” in their official names. (c) carbapenems (e.g. meropenem, imipenem)(d) monobactams (e.g. aztreonam)(e) beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam).

I. PENICILLINS A. FLEMING (1881–1955)•Penicillin G- P. notatum

(1929)(1929)

The fugus Penicillium chrysogenum

The cell wall completely surrounds the cytoplasmicmembrane, maintains cell shape and integrity, andprevents cell lysis from high osmotic pressure. Thecell wall is composed of a complex cross-linked polymer of polysaccharides and polypeptides,peptidoglycan (murein, mucopeptide). The polysaccharide contains alternating amino sugars, N-acetylglucosamine, and N-acetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine.

Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process offorming a cross-link with a nearby peptide. Cross-links give the cell wall its structural rigidity.Beta-lactam antibiotics covalently bind to the active site of PBPs. This inhibits thetranspeptidation reaction, halting peptidoglycan synthesis, and the cell dies. Beta-lactams kill bacterial cells onlywhen they are actively growing and synthesizing cell wall.

NARROW SPECTRUM PENICILLINS• Biosynthetic (natural) penicillins• Antistaphylococcal penicillins

BROAD SPECTRUM PENICILLINS• Aminopenicillins• Antipseudomonal penicillins

- Carboxypenicillins- Ureidopenicillins

1. NARROW SPECTRUM PENICILLINSa) Biosynthetic (natural) penicillins

Benzylpenicillin (Penicillin G® Na or K) – i.m.Phenoxymethylpenicillin (Penicillin-VK®) – p.o.Benzathine benzylpenicillin (effect 2 to 4 weeks)

b) Antistaphylococcal penicillins

Isoxazolyl penicillins- Cloxacillin, Dicloxacillin- Flucloxacillin, Oxacillin

Others: Methicillin, Nafcillin (crosses BBB)

Antibacterial spectrum of narrow-spectrumbiosynthetic penicillins: ●Narrow-spectrum penicillins are active against Gram-positive aerobes and obligate anaerobes.●They are ineffective against most Gram-negative aerobes and Penicillase-producing Staphylococcus.Antibacterial spectrum of antistaphylococcal penicillins:● Staphylococcus spp (without MRSAwithout MRSA)

Clinical applicationsNarrow-spectrum biosynthetic penicillins: are still the drugs of choice in small animalsin small animals include clostridial diseases, listeriosis, actinomycosis, anaerobic infections (abscess, fight wound, pyothorax) and β-hemolytic streptococcalinfections.Antistaphylococcal penicillins:●Staphylococcal skin infections in dogs●Surgical prophylaxis, especially for orthopedic procedures●Treatment of osteomyelitis, discospondylitis

Penicilline G Sodium®®:

20 000 – 40 000 /IU/kg/BW q.6–8 h i.v., i.m., s.c.

Penicillin-VK® ® (Potassium): 10 mg/kg/BW q.8 h p.o.

Cloxacillin,Dicloxacillin,Flucloxacillin:10 – 40 mg/kg q.8 h p.o.

500 mg

Flucloxacillin

2. BROAD-SPECTRUM PENICILLINS

a) Aminopenicillins

The aminopenicillins have identical spectrumand activity, but amoxicillin is better absorbedorally (70–90%). They are effective against streptococci, enterococci, and some Gram-negative organisms (incl. H. pylori)but have variable activity against staphylococci and are ineffective against P. aeruginosa.

Amoxicillin and Ampicillin

Barry J. Marshall (2005)J. Robin Warren (2005)

Clinical applications of aminopenicillins●Soft tissue non-staphylococcal infections in dogs and cats.●Cat abscesses.●Uncomplicated urinary tract infections, but amoxicillin-clavulanate might be a better choice.●Some enteric infections.●Amoxicillin in combination with metronidazole and omeprazole has been used for treatment of Helicobacter gastritis.

Amoxicillin:Amoxicillin:10 – 20 mg/kg/BW10 – 20 mg/kg/BW

q. 8–12 h q. 8–12 h i.v., i.m., s.c. p.o.i.v., i.m., s.c. p.o.

Cat abscesses

AMOXICILLINAMOXICILLIN

•Carboxypenicillins- Carbenicillin (out…)- Ticarcillin

•Ureidopenicillins- Azlocillin- Mezlocillin- Piperacillin

b) Antipseudomonal penicillinsThese drugs retain activity against streptococci andpossess additional effects against Gram-negativeorganisms, including various Enterobacteriaceae(E. coli, Salmonella, Schigella, Proteus)and Pseudomonas.

Clinical applications in VM●For topical treatment of otitis externa due to P. aeruginosa resistant to other drugs.●For systemic treatment infections by Pseudomonas spp, usually in combination with an aminosides to delay the emergence of resistance.●When combined with clavulanate, ticarcillin is effective against many β-lactamase producing strains of otherwise resistant Gram-negative bacteria and Staphylococcus.

Known drug interactions

●Penicillins are often said to be synergistic with aminoglycosides against many Gram-positive microorganisms, incl. Staphylococcus aureus.●Narrow-spectrum penicillins such as penicillin G are synergistic with drugs that bind β-lactamase enzymes, including cloxacillin, clavulanate and some cephalosporins.

Antibacterial drugsAntibacterial drugs have been have beenclassified broadly into:classified broadly into:

1.1. BacteriostaticBacteriostatic,, i.e. those that act primarily i.e. those that act primarily by arresting bacterial multiplication, such asby arresting bacterial multiplication, such astetracyclines, amphenicols, macrolides,tetracyclines, amphenicols, macrolides,lincosamides, sulfonamides, trimetrhoprime.lincosamides, sulfonamides, trimetrhoprime.2.2. BactericidalBactericidal, i.e. those which act primarily, i.e. those which act primarilyby killing bacteria, such as beta-lactams, by killing bacteria, such as beta-lactams, glycopeptides, aminoglycosides, isoniazid,glycopeptides, aminoglycosides, isoniazid,rifampicin, fluoroquinolones, metronidazole.rifampicin, fluoroquinolones, metronidazole.

Adverse effectsThe main hazard with the penicillins is allergic reaction.These include itching, rashes (eczematous or urticarial),fever, and angioedema. Rarely (about 1 in 10 000) thereis anaphylactic shock which can be fatal (about 1 in100 000 treatment courses). Allergies areleast likely when penicillins are given orally and mostlikely with local application. Metabolic opening of theβ-lactam ring creates a highly reactive penicilloyl groupwhich polymerizes and binds with tissue proteins to formthe major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can bedetected in the plasma of susceptible patients.

Amoxicillin:rash 11 hours afteradministration

There is cross-allergy between all the variousforms of penicillin, probably due in part to theircommon structure, and in part to the degradationproducts common to them all. Partial cross-allergy exists between penicillinsand cephalosporins (a maximum of 10%) which is of particular concern when the reaction to eithergroup of antimicrobials has been angioedema or anaphylactic shock. Carbapenems and the monobactams have a much lower risk of cross-reactivity.

When the history of allergy is not clear and it isnecessary to prescribe a penicillin, the presence of IgE antibodies in serumis a useful indicator of reactions mediated bythese antibodies, i.e. immediate (type 1) reactions.Additionally, an intradermal test for allergy maybe performed; appearance of wheal reaction indicates a positive response. Only about 10% of patients with a historyof “penicillin allergy” respond positively.

Other (nonallergic) ADRs include diarrhoea due to alteration in normal intestinal flora which may progress toClostridium difficile-associated diarrhoea. Neutropeniais a risk if penicillins or other β-lactam antibiotics areused in high dose and usually for a period of longer than10 days. Rarely penicillins cause anaemia, sometimeshemolytic, and thrombocytopenia or interstitialnephritis. Penicillins are presented as their sodiumor potassium salts. Extremely high plasma penicillinconcentrations cause convulsions. Co-amoxiclav, flucloxacillin, or oxacillin given in high doses for prolonged periods in the elderly may causehepatic toxicity.

Antibacterial drugsAntibacterial drugs have been have beenclassified broadly into:classified broadly into:

1.1. BacteriostaticBacteriostatic,, i.e. those that act primarily i.e. those that act primarily by arresting bacterial multiplication, such asby arresting bacterial multiplication, such astetracyclines, amphenicols, macrolides,tetracyclines, amphenicols, macrolides,lincosamides, sulfonamides, trimetrhoprime.lincosamides, sulfonamides, trimetrhoprime.2.2. BactericidalBactericidal, i.e. those which act primarily, i.e. those which act primarilyby killing bacteria, such as beta-lactams, by killing bacteria, such as beta-lactams, glycopeptides, aminoglycosides, isoniazid,glycopeptides, aminoglycosides, isoniazid,rifampicin, fluoroquinolones, metronidazole.rifampicin, fluoroquinolones, metronidazole.

Adverse effectsThe main hazard with the penicillins is allergic reaction.These include itching, rashes (eczematous or urticarial),fever, and angioedema. Rarely (about 1 in 10 000) thereis anaphylactic shock which can be fatal (about 1 in100 000 treatment courses). Allergies areleast likely when penicillins are given orally and mostlikely with local application. Metabolic opening of theβ-lactam ring creates a highly reactive penicilloyl groupwhich polymerizes and binds with tissue proteins to formthe major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can bedetected in the plasma of susceptible patients.

Amoxicillin:rash 11 hours afteradministration

There is cross-allergy between all the variousforms of penicillin, probably due in part to theircommon structure, and in part to the degradationproducts common to them all. Partial cross-allergy exists between penicillinsand cephalosporins (a maximum of 10%) which is of particular concern when the reaction to eithergroup of antimicrobials has been angioedema or anaphylactic shock. Carbapenems and the monobactams have a much lower risk of cross-reactivity.

When the history of allergy is not clear and it isnecessary to prescribe a penicillin, the presence of of IgE antibodies in serumis a useful indicator of reactions mediated bythese antibodies, i.e. immediate (type 1) reactions.Additionally, an intradermal test for allergy maybe performed; appearance of wheal reaction indicates a positive response. Only about 10% of patients with a historyof “penicillin allergy” respond positively.

Other (nonallergic) ADRs include diarrhoea due to alteration in normal intestinal flora which may progress toClostridium difficile-associated diarrhoea. Neutropeniais a risk if penicillins or other β-lactam antibiotics areused in high dose and usually for a period of longer than10 days. Rarely penicillins cause anaemia, sometimeshemolytic, and thrombocytopenia or interstitialnephritis. Penicillins are presented as their sodiumor potassium salts. Extremely high plasma penicillinconcentrations cause convulsions. Co-amoxiclav, flucloxacillin, or oxacillin given in high doses for prolonged periods in the elderly may causehepatic toxicity.

II. CEPHALOSPORINS

The nucleus of the cephalosporins, 7-aminocephalo-sporanic acid, bears a close resemblance to 6-amino-penicillanic acid. The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R1 and R2 groups has yielded hundredsof potent compounds of low toxicity. Cephalosporinscan be classified into four major generations, depending mainly on the their antibacterial spectrum and some pharmacokinetic properties.

7-Aminocephalosporanic acid nucleus

Ceftriaxon

Cephalosporins are similar to penicillins, but morestable to many bacterial beta-lactamases and therefore have a broader spectrum of activity. However, strains of strains of E. coliE. coli and and KlebsiellaKlebsiella species speciesexpressing extended-spectrum beta-lactamases that can hydrolyze most cephalosporins are becoming a problem!!

Klebsiella pneumoniaeKlebsiella pneumoniae

1. First-generation cephalosporins ●cefadroxil, cefalonium, cefazolin, ●cefalotin, cefapirin, cefradineThese drugs are very active against Gram-positivecocci (pneumococci, streptococci, andStaphylococci). Cephalosporins are not activeagainst MRSA. E. coli, K. pneumoniae, and P. mirabilis are often sensitive. Anaerobic cocciare usually sensitive except Bacteroides fragilis.

They do not cross BBB.

Clinical applications

First-generation●Osteomyelitis●Skin infections caused by StaphylococcusStaphylococcus (but not MRSA)(but not MRSA)●Soft tissue infections due to susceptible organisms●Urinary tract infections (but not prostatis)●Discospondylitis●Bacterial conjunctivitis (cefalonium)

CefaloniumCefalonium (Cepravin™): 250 mg (Cepravin™): 250 mgCarton – 8Carton – 8 cowscows: : 32 syringes)32 syringes)• Long-acting cephalosporinLong-acting cephalosporin• Cure existing infections at dry offCure existing infections at dry off• Protect against Protect against mastitismastitis and reduce and reduce new infections at calvingnew infections at calving

Indications:In conjunction with teat spraying and proper management of thecow during the drying off period, the careful administration ofCepravin Dry Cow at drying off reduces new infections in thedry period and treats subclinical mastitis.Dosage1 syringe per quarter (3 monts) immediately after final milkingWithholding Period Milk: Treatment to be at least 49 days before calving.Milk from the first 8 milkings after calving must be discarded. Meat: 30 days

CeCeffaloniumalonium (Cepravin (Cepravin™™)):: 250 250 mgmg in spray in spray syringes (jeringas – spanish): syringes (jeringas – spanish): intrammaryintrammary

2. Second-generation cephalosporins •cefalexin, cefamandole,•cefuroxime, cefoxitin

They are active against organisms inhibited by first-gene-ration drugs, but in addition they have extended Gram-negative coverage. Klebsiellae (incl. those resistant to cefalotin) are usually sensitive. Cefamandole, cefuroxime, and cefaclor are active against H. influenzaebut not against serratia or B. fragilis. In contrast, cefoxitin,and cefotetan are active against B. fragilis and some serratia strains but are less active against H. influenzae.

Cefalexin p.o.•Cats: 22 – 50 mg/kg q.8–12 h•Dogs: 20 – 40 mg/kg q.8–12 h

Clinical applications

Second-generation●Orally active cephalosporins in dogs and cats.●In veterinary institutions the human-approved formulation cefuroxime is used for surgical prophylaxis for orthopedic surgery.

CefuroximeCefuroximeZinacef™:Zinacef™:

20–50 mg/kg/BW20–50 mg/kg/BWq.8–12 hq.8–12 h

i.v., i.m., s.c.i.v., i.m., s.c.

Cefoxitin10–30 mg/kg

q.6–8 hi.v., i.m., s.c.

3. Third-generation cephalosporins •cefoperazone, cefpodoxime, cefotaxime,•cefovecin, ceftriaxone

Compared with second-generation agents, thesedrugs have extanded Gram-negative coverage, and some are able to cross the BBB. Third-generation drugs are active against Citrobacter,Serratia marcescens, and Providencia. They arealso effective against β-lactamase-producing strains of Haemophilus and Neisseria.

Clinical applications

●Third-generation cephalosporins should bereserved in small animal practice for seriousinfections caused by Gram-negative aerobic and facultatively anaerobic bacteria, especiallyEnterobactericaceae.●They may also be indicated for the treatmentof urinary tract infections.

CeftriaxoneCeftriaxone15 – 50 mg/kg15 – 50 mg/kgq.12–24 h i.v.q.12–24 h i.v.

Cefpodoxime5 – 10 mg/kg

q.12–24 h

Neisseria Neisseria mmeningitidis eningitidis

●Ceftriaxone and cefotaximeare approved for thetreatment of meningitis, including meningitismeningitiscaused by pneumococci, meningococci, H. influenzae, and susceptible enteric Gram-negative rods, but not by L. monocytogenes.

●Ceftazidime andCeftazidime andcefoperazonecefoperazone are are the only two drugsthe only two drugswith useful activitywith useful activityagainst against P. aeruginosaP. aeruginosa..

●Cefovecin is registered in some markets for use in canine skin and soft tissue infections associated with Staph. intermedius, β-hemolytic streptococci, Escherichia and Pasteurella multocida; canine urinary tract infections associated with Escherichia and Proteus spp; feline skin and soft tissue infections associated with Pasteurella multo-cida, Fusobacterium spp, Bacteroides spp, Prevotella oralis, β-hemolytic streptococci and Staphylococcus intermedius; and felineurinary tract infections associated withEscherichia.

4. Fourth-generation cephalosporins•cefepime, cefpirome

●Are used in human medicine for treatment of nosocomial or community-acquired lower respiratory tract infections, bacterial meningitis and urinary tract infections.

III. CARBAPENEMS

•Doripenem•Ertapenem•Meropenem•Tienam (imipenem/cilastatin)

Imipenem has a wide spectrum with goodactivity against many Gram-negative rods, including P. aeruginosa, Gram-positiveorganisms, and anaerobes. It is resistant to most β-lactamases. Imipenem is inactivated by dehydropeptidasesin renal tubules, resulting in low urinary concentrations. It is administered together with an inhibitor of renal dehydropeptidase(Cilastatin) for clinical use.

● The most common ADRs of carbapenemsare nausea, vomiting, diarrhea, skin rashes,and reactions at the infusion sites. Excessivelevels of imipenem in patients with renal failure may lead to seizures. ● Meropenem and ertapenem are less likely tocause seizures than imipenem. Patients allergicto penicillins may be allergic to carbapenems.

Clinical applications of carabapenems in VM●For serious and multiresistant bacterial infections.Known drug interactions●Additive or synergistic antibacterial effects may occuragainst some bacteria when imipenem is used with anaminoglycoside.●Antagonism of antibacterial effects may occur if usedwith other β-lactams.●Synergy may occur against Nocardia when used in combination with Co-Trimoxazole.●Chloramphenicol may antagonize the antibacterial efficacy of imipenem.

IV. MONOBACTAMS

•Aztreonam

Monobactams are drugs with a monocyclic β-lactamring. They are relatively resistant to beta-lactamases and active against Gram-negative rods (including Pseudomonas and Serratia). They have no activityagainst Gram-positive bacteria or anaerobes.Aztreonam is given i.v. Penicillin-allergic patients tolerate aztreonam.

V. BETA-LACTAMASE INHIBITORS

•Clavulanic acid•Sulbactam•Tazobactam

( ̶ )

Ampicillin, amoxicillin, ticarcillin, and piperacillin are also available in combinationwith one of several beta-lactamase inhibitors:clavulanic acid, sulbactam, or tazobactam. The addition of a beta-lactamase inhibitor extends the activity of these penicillins to includebeta-lactamase-producing strains of S. aureus,(without MRSA), E. coli, K. pneumoniae, P. aeruginosa, Proteus, H. influenzae).

•CO-AMOXICLAV CO-AMOXICLAV (amoxicillin + clavulanic acid)(amoxicillin + clavulanic acid)

AugmentinAugmentin

•SULTAMICILLINSULTAMICILLIN (ampicillin (ampicillin ++ sulbactam) sulbactam)

•PIPERACILLIN + TAZOBACTAMPIPERACILLIN + TAZOBACTAMTazocinTazocin

•CEFOPERAZONE + SULBACTAMCEFOPERAZONE + SULBACTAMSulperazonSulperazon

●Amoxicillin-clavulanate has many applications insmall animal practice because of its broad spectrumand excellent activity against Staphylococcus. It isoften the drug of first choice for infections in skin, soft tissue and urinary tract and for surgical prophylaxis.●A combination of ampicillin and sulbactam (another β-lactamase inhibitor) is available in some countries and has similar uses.●The indication for ticarcillin-clavulanate is usuallyfor systemic treatment of susceptible P. aeruginosainfections resistant to other antibacterials.

Antibacterial spectrumfor amoxicillin-clavulanate

Co-Amoxiclave (BAN):Amoxicillin & Clavulanate

• Augmentin®®

• Clavulox®®

* MRSA

Amoxicillin & Clavulanate(Augmentin®®, Clavulox®®)12.5–25 mg/kg q.8–12 h

p.o., i.m., s.c.

Antibacterial spectrum for ticarcillin-clavulanate

* MRSA are resistant

GLYCOPEPTIDESGLYCOPEPTIDES

Glycopeptides inhibit synthesis of cell wallpeptidoglycan and inhibit bacterial cell membranepermeability: Teicoplanin, Vancomycin, Aviparcin and Bacitracin.Bacitracin has activity against Gram-positive organisms but is markedly nephrotoxic. It is restricted to topical and ophthalmic use in combination with polymyxin and/or neomycin(e.g. Bivacin®, Topocin®, etc.).

●The most common indication of Vancomycinwould be MRSA infections or multidrug-resistantEnterococcus.●Teicoplanin is administered IM but can also be given by rapid IV injection.●Vancomycin and Teicoplanin are not absorbedorally. They are drug of choice for the oral treatmentof bowel inflammations occurring as a complication ofantibiotic therapy (pseudomembranous enterocolitiscaused by Clostridium difficile) in human.

Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine(in other aminoglycosides), to which various amino sugars are attached by glycosidic linkages. They are water-soluble, stable in solution, and more active at alkaline than at acid pH. Aminoglycosides have polar groups in theirmolecules and do not absorb in GIT.

AMINOGLYCOSIDESAMINOGLYCOSIDES

Streptomycin

Streptomycin. Its antibacterial activityis due to its binding to the 30S subunit of thebacterial ribosome and inhibiting of proteinsynthesis. It has a wide spectrum of antibacterial activity but is primarily used totreat mycobacterial infections (i.m.).•The main problems are eighth nerve toxicity (vestibulotoxicity more than deafness), nephrotoxicity, allergic reactions.

Gentamicin Tobramycin

Mechanisms of action

Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins and inhibitprotein synthesis in at least three ways:(1) interference with the initiation complex of peptide formation; (2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide, resulting in a nonfunctional or toxic protein; (3) breakup of polysomes into nonfunctional monosomes.

Aminoglycosides act bactericidalon dividing and non-dividing extracelular microorganisms.

They are in general active against staphylococci and aerobic Gram-negative organisms including P. aeruginosa and almost all the Enterobacteriaceae.

Aminoglycosides are mostly used against Gram-negative enteric bacteria almost always used incombination with a β-lactams to extend coverageto include potential Gram-positive pathogens andto take advantage of the synergism between these two classes of drugs. Penicillin-aminoglycoside combinations also areused to achieve bactericidal activity in the treatmentof enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal andstaphylococcal endocarditis.

Amikacin Gentamicin

– sol. 80 mg/2 ml (80 mg/8 h i.m.)

Kanamycin Neomycin - Bivacin – spray derm. fl 150 ml (neomycin/bacitracin), Nemybacin®

- Topocin – pulvis adspersorius (neomycin/bacitracin)

NetilmicinStreptomycinTobramycin. Inhaled Tobramycin (Tobi®)is used to treat mucoviscidosis in humans.

Gentamicin (Spelt with an “i”)●Probably now the most commonly used aminosidefor severe infections caused by Gram (–) aerobicbacteria in dogs with oft-treated ear infections Tobramycin: More active against Pseudomonas than gentamicin.Amikacin is particularly important in treating serious Pseudomonas and other Gram (–)infections in immunosuppressed patients. It can beadministered for 2–3 weeks at recommended doseswith less risk of nephrotoxicity than with gentamicin.

Gentamicin:6 mg/kg q.24 hi.m., i.v., s.c.

Tobramycin:1–2 mg/kg q. 8 h

i.m., i.v., s.c.

ADRs:Ototoxicity and nephrotoxicity are more likely tobe encountered when therapy is continued for morethan 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Concurrent use with loop diuretics (e.g. furosemide, ethacrynicacid) or other nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate nephro-toxicity. Ototoxicity can manifest as auditorydamage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage, evident by vertigo, ataxia, and loss of balance.

•Streptomycin and gentamicin are the most vestibulotoxic agents. •Neomycin, kanamycin, and amikacin are the most cochlear toxic agents. •Neomycin, tobramycin, and gentamicin are the most nephrotoxic agents. •In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate (given promptly i.v.) or neostigmine. •Hypersensitivity occurs infrequently.

Mechanisms of resistance●mutation of the organisms, resulting in altered ribosomes that no longer bind the drug●reduced permeability of the bacteria to the drug●inactivation of the drug by bacterial enzymes.

Pharmacokinetics●Aminoglycosides are not significantly absorbed from the gut, so must be given parenterally to treat systemic infections.●All have poor tissue penetration (including CNS and eye) as they are highly hydrophilic.

●They are eliminated almost exclusively by glomerular filtration.●Half-lives are short in plasma (40–60 min) butmuch longer (>30 h) for tissue-bound drug. ●Aminosides have a prolonged postantibiotic effect. Once-daily dosing is now recom-mended to reduce toxicity.●The bactericidal action of aminosides is enhancedin an alkaline medium and may be reduced by acidity secondary to tissue damage.●All aminoside bind to and are inactivated by pus.

Spectinomycin is structurallyrelated to aminoglycosides.

●Has limited clinical application because resistance develops readily.●Is marketed in combination with lincomycin, which marginally enhances activity against Mycoplasma.

TETRACYCLINESTETRACYCLINES

Tetracyclines enter microorganisms in part by passivediffusion and in part by an energy-dependent processof active transport. Susceptible cells concentrate the drug intracellularly. Once inside the cell, tetracyclinesbind reversibly to the 30S subunit of the bacterialribosome, blocking the binding of aminoacyl-tRNAto the acceptor site on the mRNA-ribosome complex.This prevents addition of amino acids to the growingpeptide. Tetracyclines arebroad-spectrum bacteriostaticantibiotics that inhibitprotein synthesis.

●Tetracyclines have activity against many Gram (+) and Gram (–) aerobic bacteria but acquired resistance limits their activity against many species, such as Staphylococcus, Enterococcus, Enterobacteriaceae (including Enterobacter, Escherichia, Proteus and Salmonella, Shigella).●Atypical bacterial species (Rickettsia, Borrelia, Chlamydia and Mycoplasma) are generally susceptible, though some Mycoplasma (M. bovis) are resistant.

●In VM tetracyclines are used most frequentlyfor atypical bacterial diseases due to Chlamydia (in cats), Borrelia, Rickettsia and Mycoplasma.●Tetracyclines are the drugs of choice forEhrlichia canis and Rickettsia infections.●Brucellosis is commonly treated with tetracyclinesin combination with rifampicin or streptomycin.●Tetracyclines have antiinflammatory properties that are independent of their antibacterial action, particularly in the case of doxycycline andminocycline.

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Doxycycline:Doxycycline: 5–10 mg/kg/12 h p.o. or i.v. 5–10 mg/kg/12 h p.o. or i.v.

In humans also against :- Plasmodium falciparum- Yersinia pestis (plague!)

Minocycline:Minocycline: 5–15 mg/kg/12 h p.o. 5–15 mg/kg/12 h p.o.

Oxytetracycline:Oxytetracycline: 20 mg/kg/8 h p.o. 20 mg/kg/8 h p.o.

PharmacokineticsAbsorption after oral administration is approximately60–70% for tetracycline, oxytetracycline, andmethacycline; and 95–100% for doxycycline and minocycline. A portion of an orally administered doseof tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestineand is impaired by food and same cations (Ca2+, Mg2+,Fe2+, Fe3+ or Al3+), by dairy products, antacids and byalkaline pH.

Tetracyclines are 40–80% bound by serum proteins.They are distributed widely to tissues and body fluidsexcept for CSF. Minocycline reaches very highconcentrations in tears and saliva, which makes ituseful for eradication of the meningococcal carrierstate. Tetracyclines cross the placenta to reachthe fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to and damage – growing bones and teeth. Carbamazepine,phenytoin, barbiturates, and chronic alcohol ingestionmay shorten the half-life of doxycycline by 50% byinduction of hepatic enzymes that metabolize the drug.

Tetracyclines are excreted mainly in bile and urine.Concentrations in bile exceed those in serum tenfold.From 10 to 50% of various tetracyclines is excreted into the urine, mainly by glomerular filtration. From 10% to 40% of the drug is excreted in feces. Doxycycline, in contrast to othertetracyclines, is eliminated by nonrenal mechanisms, do not accumulate significantly and require no dosage adjustment in renal failure.Tetracyclines and macrolides have a good intracellular distribution.

A newly approved tetracycline analog, tigecycline,is a semisynthetic derivative of minocycline. It is poorly absorbed orally and must be administeredintravenously (t1/2 36 h).

ADRsof tetracyclines

Nausea, vomiting, and diarrhea are the most commonreasons for tetracycline medication. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with foodor carboxymethylcellulose, reducing drugdosage, or discontinuing the drug.

Brown staining of the teeth

Tetracyclines modify the normal flora and overgrowthof pseudomonas, proteus, staphylococci, resistantcoliforms, clostridia, and candida. This can result inintestinal disturbances, anal pruritus, vaginal or oralcandidiasis, or enterocolitis with shock and death.Tetracyclines are readily bound to calcium depositedin newly formed bone or teeth. When a tetracycline is given during pregnancy, it canbe deposited in the fetal teeth, leading to fluorescence,discoloration, and enamel dysplasia; it can be depositedin bone, where it may cause deformity or growthinhibition.

The main mechanisms of resistance to tetracyclines and its analogs are:

(1) impaired influx or increased efflux by an active transport protein pump; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; (3) enzymatic inactivation.