Antibacterials Part 1

Part 1: b-Lactam Antibiotics

Introduction

Mechanism of Action - interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage) by binding penicillin binding proteins, inhibition of transpeptidases, or activation of autolysis; bactericidal

Classes – penicillins, cephalosporins, penems and monobactams; all have a b -lactam ring

Penicillins

General – isolated from the mold Penicillium notatum

Mechanism of Action – interfere with last step of cell wall synthesis

Spectrum of Activity

Natural Penicillins:

Penicillin G – gram(+) and gram(-) cocci, gram(+) bacilli, spirochetes
Penicillin V – similar to Penicillin V; higher MLC than Penicillin G; more acid stable; oral infections

Penicillinase Resistant Penicillins: active against penicillinase-producing S. aureus; ineffective against gram(-) cocci

IV: Methicillin, naficillin, oxacillin

Oral: Cloxacillin, Dicloxacillin

Aminopenicillins (Extended Spectrum) – Ampicillin, Amoxicillin: similar spectrum as natural penicillins but are more effective against enterococci and gram(-) rods such as E. coli, Proteus mirabilis, Salmonella spp. and Shigella spp. (remained susceptible to b -lactamases)

Ampicillin – drug of choice against Listeria monocytogenes
Amoxicillin – often used prophylactically by dentists
Bacampicillin

Antipseudomonal Penicillins – enhanced gram(-) activity, but loss of some gram(+) activity

Carbenicillin
Ticarcillin
Piperacillin (most potent)
Indanylcarbenicllin

Extended Spectrum Penicillins - retain gram(+) potency with extend coverage of gram(-) bacteria including those covered by the amino and anti-Pseudomonal penicillins (Klebsiella spp. Acinetobacter, Morganella, Providencia, Enterobacter spp.)

Azlocillin
Mezlocillin
Piperacillin

b -lactamase inhibitors – compounds containing a b -lactam but devoid of antibacterial activity; extends antimicrobial activity except does not enhance piperacllin or ticacillin’s anti-Pseudomonal activity

Clavulanic acid – Amoxacillin + Clavulanate (Augmentin); Ticarcillin + Clavulanate (Timentin)
Sulbactam – Ampicillin + Sulbactam (Unasyn)
Tazobactam - Piperacillin + Tazobactam (Zosyn)

Metabolism and Disposition – vary markedly in biodisposition from drug to drug and with pt. age

Absorption from the GI tract – not well absorbed except for penicillin V and amoxicillin (most are given IV)

Protein Binding – varies Ampicillin/Amoxicillin – 17% to Cloxacilln and dicloxacillin > 95%

Metabolism – little metabolism

Elimination – Kidney – major route of elimination; filtered and excreted

Hepatic: naficillin, cloxacillin, dicloxacillin, ampicillin, carbenicillin, ticarcillin, mezlocillin and piperacillin demonstrate significant hepatic elimination
CSF – virtually all parenteral penicillins penetrate into the CSF when inflammation is present

Infant/Child Changes – longer half life in infants due to underdeveloped kidney

Available Formulations: Most are available in dry powder that can be reconstituted for injections (except penicillin V, cloxacillin, dicloxacillin and amoxicillin)

Recommended Dosing and Dosing Strategies

short elimination half-lives; requiring frequent administration or continuous infusion

for all b-lactam antibiotics, the drug concentration must remain above the minimal inhibitory concentration (MIC) for the drug to be effective

Adverse Effects – very safe; side effects are extremely varied in presentation

allergic reactions (IgE mediated anaphylaxis to delayed hypersensitivity including contact dermatitis) – penicillins can act as haptens and combine with proteins; the penicilloyl component is formed when the b -lactam ring is opened and it forms an amide linkage to proteins

anaphylactic reactions to penicillin occur in 0.2 % with death resulting in 0.001%; can use alternative antibiotics

desensitization may be used if no options are available

alterations in platelet function

interstitial nephritis – macular rash, eosinophilia, proteinuria, eosinophiluria and hematuria; reversible

hypokalemia with antipseudomonal and extended spectrum penicillins

Drug Interactions – few; probenecid competes with penicillins for renal tubular secretion; probenecid can be used to prolong the elimination half-life of penicillin or ampicillin

antipseudomonal penicillins and extended spectrum penicillins cause degradation of aminoglycosides
nafcillin interacts with both cyclosporin and warfarin

Clinical Indications – being used less frequently because of cephalosporins

drug of choice for Streptococcus pneumoniae and S. pyogenes, acute otitis media, rheumatic carditis and for infections in patients with sickle cell disease

Cephalosporins

General – produced by fungus Cephalosporanium acremonium

Cephalosporin P – activity only against gram(+)
Cehpalosporin N – activity against both gram(+) and gram(-)
Cephalosporin C – less potent but same spectrum of activity; undergoes hydrolysis to 7-aminocehpalosporanic acid which is the starting compound for the production of the four generation cephalosporin antibiotics
Most commonly prescribed anti-infectives in the world

Mechanism of Action – precise mechanism of action is unknown; bind penicillin binding proteins (PBP’s) which include transpeptidases, carboxypeptidases and endopeptidases that are required for the synthesis of bacterial cell wall

each cephalosporin has different affinities for PBP which determines its antibiotic effect

Spectrum of Activity

First Generation Cephalosporins – active against both gram(+) and gram(-)

Drugs: Cephalothin, Cephapririn, Cephradine, Cephalexin, Cefazolin, Cefadroxil

acid stable and resistant to b -lactamase hydrolysis

Second Generation Cephalosporins – similar activity against gram(+) bacteria with extended coverage of gram(-)

Drugs: Cefamandole, Cefaclor, Cefuroxime, Cefoxitin, Cefotetan, Cefmetazole, Cefonicid

Cephamycin Group (Cefaclor) – similar to 2^nd generation cephalosporins; contain a methoxy group at the 7 position of the b -lactam

Covered streptococcus pneumoniae, S. pyogenes, H. influenzae, Moraxella catarrhalis, S. aureus and E. coli

Do not enter the CNS enough to prevent or treat bacterial meningitis

Third Generation Cephalosporins

Drugs: Cefixime, Cefoperazone, Cefotaxime, Ceftazidime, Ceftizoxime, Ceftriaxone

most widely used drugs for the empiric treatment of infant and children with moderate to severe infections

increased gram(-) spectrum due to aminothiazole moiety to the amide group at the 7 position of the b -lactam ring

decreased gram(+) activity

enter CSF and can be used to treat bacterial meningitis

Ceftazidime – only antipseudomonal 3^rd generation cephalosporin – can be used to treat pseudomonas aeruginosa meningitis

Fourth Generation Cephalosporins

Drugs: Cefepime
Both gram(+) and gram(-) – potent against Pseudomonas aeruginosa

Advancements in Cephalosporins

Orally available Cephalosporins: Cefixime, Cefpodoxime proxetil and Ceftibuten (soon to be released)
cefixime and ceftibuten are ineffective against staphylococci; cefpodoxime has limited antistaphylococcal activity

Disposition

vary markedly in biodisposition both from drug to drug and with patient age (similar to penicillins)

Absorption – 1^st and 2^nd generation oral cephalosporins are well absorbed from the GI tract; 3^rd generation cephalosporins show moderate to poor bioavailability, but do achieve adequate systemic concentrations to treat infections of the upper and lower respiratory tract as well as urinary tract infections

Protein Binding: varying degrees; 10% for cephalexin to > 90% for cefoperazone

Ceftriazone – highly protein bound and therefore has a long elimination half-life; given as a single daily dose that saturates the protein binding sites and produces an initial bolus of free drug and is followed as a continual release as it is released from protein; analogous to administering a continuous IV infusion of the drug

Penetration into the CSF: only 3^rd and 4^th generation drugs penetrate into the CSF effectively

demonstrate a delayed CSF sterilization in children and not used for bacterial meningitis

Metabolism: few undergo significant metabolism

3^rd generation undergo biliary excretion and useful in treatment of hepatobiliary infections
most excretion is renal and confined to filtration; few cephalosporins undergo tubular secretion

infants have longer elimination half-life due to underdeveloped kidney function
Ceftriaxone is not recommended in infants in the first month because it may displace bilirubin from protein
kidney disease can also alter excretion and will necessitate dosing modifications

Available Formulations: dry powder that is reconstituted for injection, tablets and capsules

liquid suspensions taste better than penicillin preparations and easier to give to kids

Recommended dosing and dosing strategies – must follow strict dose guidelines to provide effective dose without side effects

most parental cephalosporins require two or three doses per day; Ceftrixone only requires a single daily dose

oral cephalosprin preparations vary greatly in dosing frequency; Cefadroxil (1^st), cefprozil (2^nd) and all three of the oral 3^rd generation drugs only need a single dose

Side Effects – safest class of antibiotic and perhaps the safest class of drugs available in medicine

gastrointestinal effects are most common – nausea, bloating and diarrhea
allergic reactions; less common than the penicillins
serum sickness with cefaclor
Coombs reaction, bone marrow suppression, throbocytosis, acute tubular necrosis, transaminase elevations
Ceftriaxone – biliary sludge in the gallbladder
Cefamandole, cefonicid, cefoperazone, cefotetan, maxolactam – disulfiram reaction (maxolactam can cause hypoprothrombinemia)

Drug Interactions – few; ceftriaxone can replace protein bound warfarin and phenytoin

Clinical Indications – important in pediatric therapy

respiratory and urinary tract infections in the outpatient setting – 2^nd and 3^rd generation (amoxicillin is drug of choice)
skin infections – 2^nd generation
infections of infants and children with moderate to severe infections – often use ampicillin + cefotaxime in newborn
after the first month of life, ceftriaxone or cefuroxime can be used in children with hospital acquired infections
ceftrazidime is used for emperic therapy in critically ill children
ceftriaxone is now used on a outpatient basis in pediatric patients

Monobactams Aztreonam – monocyclic b -lactam

Mechanism of Action – interferes with cell wall synthesis by binding to penicillin binding proteins; similar to other b -lactam antibiotics; bactericidal

Spectrum – limited to aerobic gram(-) bacteria; resembles the aminoglycoside antibiotics

resistant to degradation to most plasmid and chromosomally mediated b -lactamases

often used with aminoglycosides or expanded spectrum cephalosporins

Metabolism and Disposition – poorly absorbed into systemic circulation and therefore given parenterally by IM or IV

well distributed into most body fluids and tissues; enters the CSF in effective concentrations
30-50% is bound to plasma proteins eliminated by both hepatic and renal mechanisms; 70% is eliminated unchanged in the urine by filtration and tubular secretion
similar pharmacokinetics in older infants and children to adults

Clinical Indications – not 1st line therapy for any pediatric infections; use when aminoglycosides are contraindicated due to similar spectrum to aminoglycosides and without nephrotoxicity, can be used as an aminoglycoside substitute

Adverse Effects – similar to penicillin and cephalosporins

local injection site reactions; rash, diarrhea, N/V; 7% pts show adverse reactions
weakly immunogenic and does not appear to precipitate allergic reactions in pts allergic to penicillin

Drug Interactions – probenecid competes with its tubular secretion and may decrease secretion by 50% – does not appreciably alter total body elimination or plasma drug concentrations

Available Formulations – IM or IV

Dosing – infused over 3-20 minutes; must alter dose for renal disease and neonates

Penem Antibiotics: Imipene and Meropenem

Mechanism of Action – b-lactam which binds to all the penicillin binding proteins with greatest affinity for PBP’s 1 and 2

Spectrum of Activity – broad spectrum activity against aerobic and anaerobic gram(+) and gram(-) pathogens

highly resistant to degradation by both plasmid and chromosomally mediated b-lactamases

induce b -lactamases which may limit antibiotic activity

bacterial resistance usually occurs by alterations in the PBPs

Metabolism and Disposition – imipenen and meropenem are not absorbed by oral administration; only used parenterally

well distributed in most body fluids and tissues including the CSF in pts with meningitis
20% protein bound
excreted by the kidney mostly via filtration

imipenem is degraded by dihydropeptidase I in the proximal tubular brush border producing a toxic metabolite; cilastatin is a dihydropeptidase inhibitor and is administered with imipenem; meropenem is resistant to degradation by dihydropeptidase

Elimination

elimination half-life of imipenem: neonates: 1.5-3 hrs; infants + children: 1-1.4 hrs; adults: 0.8-1.3 hrs
elimination half-life of meropenem: infants and children: 1.1-1.4 hrs; adults: 0.8-1.2 hrs

Available Formulations – imipenem/cilastatin: IM or IV

Adverse Effects – similar to other b -lactam antibiotics

Imipenem: GI complaints (N/V, diarrhea), skin rash, reversible neutropenia; seizures
Meropenem has similar but less severe side effects

Drug interactions – none identified

Clinical Indications – very broad spectrum; different PBP targets than the penicillins and cephalosporins and it is recommended that they are not used as a first line drug and reserve their use for when other drugs fail

treatment of serious infections in hospitalized pts; alternative therapy for gram(-) sepsis in immune compromised patients; nosocomial infections in critically ill children; and for alternatives after other drugs have failed
safe and effective in pediatric patients with community acquired respiratory tract infections, skin and soft tissue infections, uncomplicated UTIs and intra-abdominal infections

Recommended Dosing – decrease dose in pts with renal disease

Summary of b-Lactams

Drug Class	Route	Drug	Spectrum
Natural Penicillins	Oral	Penicillin G and V	Gram(+) except enterococci; Neisseria gonorrhea and Neisseria meningitides
Amino Penicillins	Oral	Ampicillin, Amoxicillin	Broader gram(-) coverage than natural penicillins; covers the enterococci
Penicillin Resistant Penicillins (PRP)	IV	Methicillin, Naficillin, Oxacillin	Skin infections when S. Aureus is possible
PRP	Oral	Cloxacillin, Dicloxacillin, Oxacillin	Same as above
Antipseudomonal		Carbenicillin, Ticarcillin, Piperacillin, Mezlocillin	Pseudomonas aeruginosa; anaerobics
Combination Penicillins with b -lactamase inhibitors		Amoxicillin + clavulanic acid (Augmentin) Ticarcillin + clavulanic acid (Timentin) Ampicillin + Sulbactam (Unasyn) Piperacillin + Tazobactam (Zosyn)	Very broad coverage; anaerobic coverage; Timentin + Zosyn cover Pseudomonas
Cephalosporins
First Generation	Oral: Cephalexin, Cefadroxil; IV: cephalothin, Cephapirin, Cefazolin	Cephalothin, Cephapirin, Cephradine, Cephalexin, Cefazolin, Cefadroxil	Gram(+) and PEcK (Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae)
Second Generation	Oral: Cefaclor, Cefprozil IV: the rest	Cefamandole, Cefaclor Cefuroxime, Cefoxitin Cefotetan, Cefmetazole, Cefonicid, Cefprozil loracarbef	Gram(+) and HEN PEcK (Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + PEcK)
Third Generation	Oral: Cefixime, Ceftibuten, Cefpodoxime, Cefetamet IV: the rest	Ceftriaxone, Ceftazidime, Cefotaxime, Ceftizoxime, Cefixime, Cefoperazone, Cefpodoxime, Ceftibuten	Expanded gram(-)coverage
Fourth Generation		Cefepime	Similar to 3^rd generation with expanded gram(+) coverage and Pseudomonas
Monobactam	IM or IV	Aztreonam	Gram(-) aerobic
Carbapenem	IV or IM	Imipenem + cilastin, Meropenem	Gram(+); gram(-) (including Pseudomonas); Anaerobes