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Case: Antibacterial agents. Class

The basic principles for the selection of antibacterial therapy include consideration of factors such as the likelihood that the infection is bacterial and the identification of the likely infecting organism to support a rational selection of an antibiotic. Consideration of host and drug factors that could influence antibiotic selection include identification of the site of infection, which will influence the selection of the antibiotic and its route of administration; recognition of concomitant diseases such as AIDS; recognition of the likelihood of drug allergies; recognition of hepatic or renal dysfunction that could alter antibiotic clearance; and recognition of drug toxicity, drug-drug interactions, drug resistance, the patient's age or pregnancy or maternal status; and drug cost.

Antibacterial agents, which target specific components of microorganisms that are unique or more essential to their function than they are to humans, are classified according to their mechanisms of action. The component targets include enzymes necessary for bacterial cell-wall synthesis, the bacterial ribosome, and enzymes necessary for nucleotide synthesis and deoxyri-bonucleic acid (DNA) replication.

Resistance of pathogens to antibacterial and other chemotherapeutic agents may be the result of a natural resistance or may be acquired. In either case, it occurs through mutation, adaptation, or gene transfer. The mechanism of resistance for any antibacterial agent varies, but is a result of either changes in uptake of drug into, or its removal from, the bacterial cell, or to changes in the bacterial cell target site of the drug from a gene mutation. Multiple drug resistance is also a major impediment to antibacterial therapy and may be chromosomal or plasmid mediated, where genetic elements from resistant bacteria that code for enzymes that inactivate antibacterial agents are transferred to nonresistant bacteria. The emergence of drug resistance is to a large degree the result of the widespread and often unnecessary or inappropriate use of antibiotics in humans.

The penicillins (see above) include natural penicillins, penicillins that are resistant to staphylococcal β-lactamase, and extended-spectrum penicillins (Table Partial listing of penicillins).

Table: Partial listing of penicillins

Natural

Penicillin G (prototype)

Penicillin V

Extended-Spectrum

Aminopenicillins

Ampicillin

Amoxicillin

Ureidopenicillins

Mezlocillin

Piperacillin

Carboxypenicillin

Ticarcillin

β-Lactamase Resistant

Nafcillin

Oxacillin

Cloxacillin

Dicloxacillin

The cephalosporins are classified as first to fourth generation, according to their antibacterial spectrum (Table Selected listing of cephalosporins).

Table: Selected listing of cephalosporins

Representative Cephalosporins (Route) Notes
First generation

  • Cefazolin (IV)
  • Cephalexin (PO)
  • Cefadroxil (PO)
Active against gram-positive cocci, including staphylococci, pneumococci, and streptococci. They are particularly good for soft tissue and skin infection
Second generation

  • Cefuroxime (IV) oral form is cefuroxime axetil
  • Cefotoxin (IV)
  • Cefotetan (IV)
These agents have marked differences in their spectrum of activity. In general, they are active against certain aerobic gram-negative bacteria in addition to activity against many gram-positive organisms sensitive to first-generation cephalosporins. Certain agents are active against Haemophilus influenza (e.g., cefuroxime), whereas others are active against Bacteroides fragilis (e.g., cefotoxin)
Third generation

  • Cefotaxime (IV)
  • Ceftazidime (IV)
  • Ceftriaxone (IV)
Expanded aerobic gram-negative spectrum. Cross the blood-brain barrier. Useful to treat bacterial strains resistant to other drugs
Fourth generation

  • Cefepime (IV)
Generally similar activity to third-generation cephalosporins but more resistance to β-lactamases

Table Partial listing of antimicrobial agents lists these and other selected antimicrobial agents. Aztreonam, which is relatively β-lactamase resistant, is the only available monobactam.

Table: Partial listing of antimicrobial agents

Antibacterial Agents Mechanism Of Action Adverse Effects
β-Lactam antibiotics

Penicillins

Cephalosporins

Monobac tarns

  • Aztreonam (p)

Carbapenems

  • Imipenem (p)
  • Meropenem (p)
  • Ertapenem (p)

Vancomycin (o,p)

Inhibit synthesis of the bacterial cell wall P-Lactam antibiotics: hypersensitivity with rare potential for anaphylactic shock

Cephalosporins: may cause local irritation and pain from IM injection. Those with a methylthiotetrazole group, e.g., cefotetan, may cause hypoprothrombinemia and bleeding disorders

Aztreonam: occasionally may cause skin rashes

Carbapenems: may cause GI (gastrointestinal) discomfort and skin rashes and seizures in patients with renal dysfunction (particularly imipenem)

Vancomycin: relatively non-toxic. Fever, chills, and infusion-related flushing ("red-man" syndrome) are encountered. Ototoxicity is a rare effect

Chloramphenicol Tetracyclines

  • Tetracycline (o,p)
  • Oxytetracycline (o,p)
  • Doxycycline (o,p)
  • Methacycline (o)
  • Minocycline (o,p)

Macrolides

  • Erythromycin (o,p)
  • Clarithromycin (o)
  • Azithromycin (o)

Ketolides

  • Telithromycin (o)

Oxazolidinones

  • Linezolid (o,p)

Aminoglycosides

  • Streptomycin (p)
  • Neomycin (o)
  • Amikacin (p)
  • Gentamicin (p)
  • Tobramycin (p,i)

Spectinomycin (p)

Lincomycins

  • Clindamycin (o,p)
Bind to bacterial ribosomes to inhibit protein synthesis Chloramphenicol: GI disturbances, reversible suppression of bone marrow, rarely aplastic anemia

Tetracyclines: GI disturbances and bacterial overgrowth, teeth and bone deformation in children

Erythromycin and clarithromycin: severe GI disturbances, hypersensitivity, hepatic P450 inhibition

Telithromycin: hepatic P450 inhibition

Linezolid: reversible thrombocytopenia

Aminoglycosides: ototoxicity and nephrotoxicity

Clindamycin: GI disturbances, hepatic dysfunction, potentially fatal colitis

Sulfonamides

  • Sulfadiazine (o)
  • Sulfamethizole (o)
  • Sulfamethoxazole (o)
  • Sulfanilamide (t)
  • Sulfisoxazole (t,o)

Trimethoprim

Sulfonamides: structural analogs of p-aminobenzoic acid that inhibit bacterial dihydropteroate synthase to block folic acid synthesis and cell growth

Trimethoprim: selectively inhibits dihydrofolic acid reductase to block folic acid synthesis and cell growth. Acts synergistically with sulfamethoxazole with which it is often coadministered

Sulfonamides:

hypersensitivity urinary tract dysfunction, hemolytic or aplastic anemia, potentially fatal Stevens-Johnson syndrome

Trimethoprim: blood dyscrasias

Fluoroquinolones (selected)

  • Ciprofloxacin (t,o,p)
  • Levofloxacin (t,o,p)
  • Ofloxacin (t,o,p)
  • Gatifloxacin (o,p)
  • Moxifloxacin (o,p)
Inhibit activity of bacterial topoisomerase (DNA gyrase) that is necessary for replication GI disturbances, reversible arthropathy, arrhythmias

t = topical, o = oral, p = parenteral, i = inhalation.

It is nonallergenic and is active only against aerobic gram-negative bacilli (e.g., pseudomonas, serratia). The carbapenems (imipenem, meropenem, and ertapenem), which are resistant to most β-lactamases, have a wide spectrum of activity against gram-positive and gram-negative rods and anaerobes. To prevent its metabolism, imipenem is administered with an inhibitor of renal tubule dehydropeptidase, cilastatin.

Vancomycin, which is unaffected by β-lactamases, inhibits bacterial cell-wall synthesis by covalent binding to the terminal two D-alanine residues of nascent peptidoglycan pentapeptide to prevent their elongation and cross-linking, thus increasing the susceptibility of the cell to lysis. It is active against gram-positive bacteria.

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