CLINICAL ASPECTS OF CEPHALOSPORIN AND PENEM

GROUP OF ANTIBIOTICS

Beta lactam Antibiotics

• Penciillins • Cephalosporins• Penems(carbapenems) • Monobactams • common chemical properties • Mechanism of action of bacterial cell wall

synthesis inhibition, by binding to the penicillin-binding proteins (PBP) within the cell wall and resulting in subsequent cell lysis.

Cephalosporins• Wide-spectrum β-lactum bactericidal, chemical

properties being similar to the penicillins• Cephalosporium acremonium, containing the

common 7-aminocephalosporanic acid nucleus • Cephamycins : Streptomyces species or are synthetic

derivatives produced by substituting oxygen for sulfur (methoxy group) in cephalosporin nucleus.

• MOA: Bacterial cell wall synthesis inhibition, by binding to the penicillin-binding proteins (PBP) within the cell wall and resulting in subsequent lysis of the cell.

• The free base acid stable forms of cephalosporins are used for oral administration. Sodium salt derivatives are used for parenteral use.

ClassificationThree generations based primarily • spectrum of antibacterial activity • the basis of antimicrobial activity, including β-

lactamase stability and pharmacological properties Generationwise, from first to fourth the spectrum of activity against gram negative

organisms and the stability against β-lactamase increase usually with the same or reduced spectrum of activity against gram positive organisms and pharmacokinetic differences.

• Usually active against beta haemolytic streptococci and against beta lactamse producing staphylococci. Methicillin resistant Staphylococcus, Mycobacteria and Enterococci spp are resistant to all cephalosporins.

FIRST GENERATION G+ve G-ve betalactamase stability +++ + + ORAL PARENTERAL Cephalexin Cefazolin Cefadroxil Cephapirin Cefadrine Cefalonium

Cephradine Cefacetrile Cephaloglycin Cefatrizine Cephalothin Cephaloridine

*•

SECOND GENERATION G+ve G-ve beta lactamase stability ++ ++ + + ORAL PARENTERAL Cefamandole Cefaclor Cefotiam Cefuroxime axetil Ceforanide Cefprozil Cefonicid Cefuroxime Cefmetazole Cefacetrile Cefotiam Cefranide Loracarbef Cefoxitin* Cefotetan* * Cephamycins

THIRD GENERATION G+ve G-ve beta lactamase stability +/++ +++ ++ + ORAL PARENTERAL Cefsulodin Ceftiofur Ceforanide Cefotaxime Cefpodoxime proxetil Cefmenoxime Cefixime Ceftriaxone Ceftibuten Ceftizoxime Cefdinir Ceftazidime Cefmenoxime Cefovecin Cefditren pivoxil Cefoperazone Cefodizime Latamoxef (moxalactam)* Cefetamet* Cephamycins

FOURTH GENERATION G+ve G-ve beta lactamase stability ++/+++ ++++ + ++ + ORAL PARENTERAL Cefmetazole Cefepime Cefditoren Cefpirome Cefquinome

High activity against gram positive bacteria including β-lactamase producing S.aureus.

Generally susceptible to β-lactamases ; not as effective against anaerobes as penicillins.

Wide distribution in ECF , but poor penetration across biological membranes and physiological barriers

Oral absorption is poor and highly erratic in ruminants, thus being used only in preruminant calves

Rapid elimination in urine, with the half life less than one hour except for cefadroxil which has a longer half life in dogs

Cephalexin, cefadroxil : primarily for skin and soft tissue infections such as pyoderma caused by streptococci and Staph. aureus, and bacterial endocarditis caused by Streptococcus viridans and S .aureus.

Cefazolin and cephalexin are used to treat bone and joint infections in the treatment of open fractures, lymphadenitis, abscesses, pharyngitis etc.

FIRST GENERATION

SECOND GENERATION

Generally reserved for infections, are resistant to first Same or slightly less efficacious than first-generation against

gram-positive pathogens; primarily against S. aureus and S. intermedius

Greater spectrum of activity against Gram-negative organisms such as H.influenze, Enterobacter aerogenes and Neisseria sp.

Ineffective against P. aeruginosa, Enterococcus Actinobacter species and anaerobes, except ;

Cefoxitin and Cefotetan, which are technically cephamycins, are effective against anaerobic gram negative organisms, including Bacteroides fragilis, but not active against Pseudomonas.

Relatively resistant to β-lactamases, with poor penetration of the blood-brain barrier.

Pharmacokinetic properties are similar to those of the first generation cephalosporins.

Cefuroxime axetil the only 2nd gen, to penetrate into cerebrospinal fluid

IM Injections are painful, and may cause thrombophlebitis on IV administeation.

The broad antibacterial activity may lead to gastrointestinal disturbances and superinfection by resistant microorganisms including yeasts.

Cefoxitin, valued particularly for its broad activity against anaerobes and enterobacteriaceae, is used in the treatment of severe mixed infections with anaerobes in conditions like aspiration pneumonia, bite infections , ruptured intestine gangrene, peritonitis and pleuritis.

Cefuroxime is effective for short lasting dry cow therapy and clinical mastitis, has been also given orally to treat otitis media and upper respiratory tract infections

THIRD GENERATION

High antibacterial activity and broad resistance to β-lactamases, though, are less effective than 1st and 2nd generation gainst gram positive bacteria

Not first choice antimicrobial agents in animals , and used only where other alternatives are not available.

Used to treat bone and joint infections, pneumonia, enteritis, endocarditis, rhinosinusitis and cystitis.

Most effective of the cephalosporins against antibiotic-resistant gram-negative aerobes, effective against Proteus vulgaris, Enterobacter species, Citrobacter species, Haemophilus species, Neisseria species and Moraxella species

Moderate activity against Gram-positive bacteria and are inferior in activity against Staphylococci

Ceftriaxone ceftizoxime, cefotaxime and ceftazidime

Reach effective antibacterial concentration in the CNS; effective in therapy for susceptible pathogens in bacterial meningitis

Gastrointestinal disturbances snd superinfection by the resistant organisms, including yeasts, can occur due to BS action

The excretion - largely through urine, though Ceftriaxone and latamoxef are excreted in bile , making them to be used cautiously if at all / avoided in horses

Ceftriaxone : needs once daily dosing. The Biliary elimination occurring with ceftriaxone and latamoxef

makes them to be avoided or used cautiously in species with expanded large intestines( adult horse)

Cefpodoxime stable & effective against beta-lactamase producing bacteria; has

been used in skin infections in dogs with no adverse effect Ceftazidime and Cefoperazone, : H ighly active against

Pseudomonas.aeruginosa among all cephalosporins, compared to Ceftriaxone and Ceftizoxime, which also have antipseudomonal activity to some extent.

Ceftazidime may be reconstituted with1%lignocaine for IM injection to reduce pain

Cefixime : advocated as an oral follow up to a group 4 parenteral cepohalosporin

Cefoperazone : contraindicated in the herbivore aspecies with an expanded bowel. It has been used for treating coliform mastitis

CEFOVECIN Newer one, differs from other as it stays in the dog’s or cat’s body

for a very long time after it has been injected. Single SC injection effect lasts for up to 14 days. Depending on the

infection concerned, the injection can be repeated if necessary (upto three times)

Used in dogs and cats to treat skin and soft tissue infections; such as wounds, abscesses and pyoderma and also urinary tract infections.

Not to be used in dogs or cats of less than 8 weeks old, or in dogs or cats with severe kidney problems (renal dysfunction).

As no studies have been made in breeding animals and it has an exceptionally long duration in the body, it should not be used in pregnant or lactating dogs or cats and treated animals should not be used for breeding for 12 weeks after the last injection .

CEFTIOFUR New generation cephalosporin Broader gram-positive activity, including good activity against

Streptococci, less against Pseudomonas than other 3rd-generation o Found in endometrial tissue within four to eight hours in cows Long elimination half life; allowing once daily dosing. Ceftiofur crystalline freee acid, ceftiofur hydrochloride and

ceftiofur sodium salts. formulations The crystalline free acid is an injectable suspension for cattle and

pigs at 200mg/ml and 100mg/ml ceftiofur equivalent concentration respectively, which can be administered IM and subcutaneously.

Site: in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head ( base of the ear), avoiding all the blood vessels in cattle; .

In swine, post auricular region of the neck IM; volume of injection at each site being a maximum of 2ml

Indicated for treatment of bronchopneumonia in cattle, especially when caused by Pasteurella hemolytica or P.aeruginosa.

Ceftiofur sodium (50mg/ml powder vials for inj) and ceftiofur hydrochloride (50mg/ml sterile suspension) are the formulations approved for use in dogs, horses, catlle,sheep, goats and swines.

Administered intramammary for coliform mastitis,approved for treatment of UTI in dogs.

Cutaneous drug reaction characterised by hair loss and pruritus in cows.

Pain at the injection site and decreased feed consumption being the most commonly observed adverse effect

FOURTH GENERATION Extended spectrum of activity than third generation agents,

against both gram positive and gram negative organisms. High activity against Enterobacteriaceae, moderate activity

against P.aeruginosa and enhanced activity against staphylococci Increased stability against hydrolysis by beta-lactamases Excellent penetration ability in to CSF Pocess chemical characteristics that may lead to reduced

development of resistance by Gram-negative organisms. However, they are not indicated for enteric pathogens causing food-borne disease

Cefepime and cefpirome - only in humans Cefquinome, an extended spectrum beta-lactam, is used only in

veterinary medicine; is safe and well tolerated. Parenteral (IM and IMM) for bovine respiratory disease (BRD)

and intrmammarily for mastitis.

Pharmacokinetics

Absorption Good on PO administration especially in in

monogastric animals The absorption of most of the cephalosporins is

unaffected by the presence of food, except for cephradine for which it may be delayed

Distribution: Very well into most of the body tissues and fluids.

including bone, pleural fluid, pericardial fluid and synovial fluid and urine.

Higher levels are found in inflamed than in normal bone. Very high levels are found in the urine

Penetrate poorly into prostatic tissue and aqueous humor

• Most of the cephalosporins have poor penetration of the BBB, except some third-generation antibiotics like cefotaxime, ceftriaxone ceftizoxime and ceftazidime

• No adverse teratogenic or fetotoxic effects, except a slight decrease in fetal weight , (lab animals).

• The distribution of ceftiofur into milk is insufficient to produce therapeutic concentrations:

• The survival rate of cattle with severe coliform mastitis can be increased with systemic ceftiofur administration, a result attributed to controlling the effects of bacteremia .

Biotransformation Not clinically significant. : desacetyl and de-

esterization derivatives.The metabolites of many may retain some antibacterial activity.

Elimination Renal tubular secretion and/or glomerular

filtration. Thus doses to be adjusted in case of severe renal failure/insufficiency to guard against accumulation and toxicity.

Cefoperazone, Cefamandole and Ceftriaxone are eliminated through bile into the feces; and are frequently used in patients with renal insufficiency

Side/Adverse Effects Gastrointestinal disturbances Hypersensitivity reaction Bleeding disorders: with Cefotetan,

Ceftazidime, Cefamandole and Cefoperazone.ssociated with an increased risk of bleeding due to a decrease in prothrombin activity and anti vitamin K effects. Prophylactic vitamin K therapy is recommended when used for prolonged periods in malnourished or seriously ill patients.

Hepatic dysfunction: cefotaxime, cephalothin, and cephapirin

Renal insufficiency : Nephrotoxicity in patients with renal insufficiency , receiving the full dosage of cephalosporin; and thus dosage should be adjusted

Pain at the injection site: Abscesses , severe local tissue reactions with IM injections ; Thrombophlebitis after IV administration

• Other effects: Some other adverse effects noticed in humans include eosinophilia, hearing loss ( cefuroxime) seizures, especially with high doses and in patients with

Dogs Ceftiofur- Anemia, Hyperprothrombinemia,

Thrombocytopenia, Platelet dysfunction All cephalosporins: anorexia, diarrhoea , vomiting (oral),

thrombophlebitis,abscess.

Horse cefpodoxime proxetil, cefotaxime : Colic diarrhea cefoxitin : Laminitis cefazolin: hypersensitivity

Cattle Ceftiofur : Ear swelling , may develop a transiently

drooping ear, medication leakage or bleeding from the site just after injection

Incompatibilities The admixture of any cephalosporin with other

medications in the same syrienge is not recommended, as it . may result in substantial mutual inactivation; they should not be mixed in the same syrienge, intravenous bag or bottle.

Laboratory value alterations False-positive or false negative glucosuria

( cephalexin) Increased urine ketone values Elevated serum and urine creatinine levels False-positive Proteinuria (cefamandole) Prolonged Prothrombin time

INTERACTIONS Food Desirable to administer along with food. Aminoglycosides synergistic activity when combined with an

aminoglycoside. Antacids and H2-receptor antagonists Decrease the absorption of cephalosporins and thus

should not be taken within 2 hous of taking these antacids Anticoagulants Coumarin- or indandione-derivative, or Heparin or

Thrombolytic agents , concurrent use may increase the bleeding risk associated with cephalosporins and Dosage adjustments of anticoagulants may be necessary during and after therapy with cephalosporins

Nephrotoxic medications

Increased incidence of nephrotoxicity when used concurrently other nephrotoxic medications, such as loop diuretics, aminoglycosides(cephalothin) especially in patients with pre-existing renal function impairment

Platelet aggregation inhibitors

Hypoprothrombinemia induced by large doses of salicylates and the gastrointestinal ulcerative or hemorrhagic potential of nonsteroidal anti-inflammatory drugs [NSAIDs], salicylates, or sulfinpyrazone may increase the risk of hemorrhage if used concurrently with cephalosporins

CARBAPENEMS

• New class of drugs which are structurally similar to the penicillins.

• Widest activity of any antibiotics

• Highly active against a wide variety of gram positive and gram negative bacteria (both aerobic and anaerobic)

• Imipenem

• Faropenem

• Meropenem

CARBAPENEMS…contd

Imipenem

• Stability against most of the β-lactamases

• Ability to penetrate porin channels that usually exclude other drugs.

• More rapidly bactericidal

• Less likely to induce release of endotoxin in an animal from gram-negative sepsis.

• GI disturbances: nausea and vomiting., seizures,hypersalivation and vocalization in dogs

Imipenem…contd

• Rapidly hydrolyzed by the enzyme, dihydropeptidase, found in the brush border of the proximal renal tubule.

• Always administered with cilastatin, (an inhibitor of dihydropeptidase) to decrease renal tubular metabolism.

• Disadvantages : induction of resistance and high cost.

• Dose: dogs and cats- 5-10mg/kg, IV or deep IM, q 8 h; horse : 10-20mg/kg, IV, q 6 h

Meropenem

• As effective as cefotaxime or ceftriaxione in bacterial meningitis

• Lower incidence of adverse effects to the CNS, such as seizures.

• Dose in dog is 2-5mg/kg, slow IV (with IV fluids) , q 6 h; 5 -10mg/kg, deep IM q8 h or 8-12 mg/kg SC, q 8 -12 h.

• Synergistic with aminoglycosides against P.aeruginosa used for intra-abdominal infections, severe lower respiratory tract infections, septicemia and life threatening soft tissue infections