β-Lactam Antibiotics

β-Lactam Antibiotics

β-lactam antibiotics (beta-lactam antibiotics) are a class of broad-spectrum antibiotics, consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems.

What does beta lactam mean?

 A beta-lactam (β-lactam) ring is a four-membered lactam. (A lactam is a cyclic amide.) It is named as such because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.

How do beta lactam antibiotics kill bacteria?

 Beta-lactam antibiotics kill bacteria that are surrounded by a cell wall. Bacteriabuild cell walls by linking molecules together—beta-lactams block this process. Without support from a cell wall, pressure inside the cell becomes too much and the membrane bursts.

 Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta-lactam ring. Beta-lactam antibiotics include:

●Penicillins

●Cephalosporins●

Cephamycins●

Carbapenems

The penicillins

The penicillins are among the earliest classes of antibacterial drugs. Penicillins are divided into subclasses based on chemical structure (eg, penicillins, monobactams, and carbapenems), spectrum (narrow, broad, or extended), source (natural, semisynthetic, or synthetic), and susceptibility to β-lactamase destruction. Manipulation of some drugs has improved the spectrum, resistance to β-lactamase destruction, or clinical pharmacologic characteristics that enhance efficacy.

Narrow-spectrum β-Lactamase–sensitive Penicillins:

This group includes naturally occurring penicillin G (benzylpenicillin) in its various pharmaceutical forms and a few biosynthetic acid-stable penicillins intended for oral use (penicillin V [phenoxymethyl-penicillin] and phenethicillin). Penicillins in this class are active against many gram-positive but only a limited number of gram-negative bacteria. These drugs are also effective against anaerobic organisms. They are, however, susceptible to β-lactamase (penicillinase) hydrolysis.

Broad-spectrum β-Lactamase–sensitive Penicillins:

Penicillins in this class are derived semisynthetically and are active against many gram-positive and gram-negative bacteria. However, they are readily destroyed by the β-lactamases (produced by many bacteria). Many members of the group are acid stable and are administered either PO or parenterally. Of those used in veterinary medicine, aminopenicillins, eg, ampicillin and amoxicillin (which may also be produced naturally), are the best known. Several ampicillin precursors more completely absorbed from the GI tract also belong to this class (eg, hetacillin, pivampicillin, talampicillin).

A large number of gram-positive and gram-negative bacteria (but not β-lactamase–producing strains) are sensitive to the semisynthetic broad-spectrum penicillins (ampicillin and amoxicillin). Susceptible genera include Staphylococcus, Streptococcus, Trueperella, Clostridium, Escherichia, Klebsiella, Shigella, Salmonella, Proteus, and Pasteurella. Although bacterial resistance is widespread, the combination of β-lactamase inhibitors and broad-spectrum penicillins markedly enhances the spectrum and efficacy against both gram-positive and gram-negative pathogens. Clavulanate-potentiated amoxicillin is an excellent example of such a synergistic association.

Mecillinam is less active than ampicillin against gram-positive bacteria but is highly active against many intestinal organisms (except Proteus spp) that do not produce β-lactamases.

β-Lactamase–protected Penicillins:

Several naturally occurring and semisynthetic compounds can inhibit many of the β-lactamase enzymes produced by penicillin-resistant bacteria. When used in combination with broad- or extended-spectrum penicillins, there is a notable synergistic effect because the active penicillin is protected from enzymatic hydrolysis—and thus is fully active against a wide variety of previously resistant bacteria. Examples of this chemotherapeutic approach include clavulanate-potentiated amoxicillin and ticarcillin as well as sulbactam-potentiated ampicillin and tazobactam-potentiated piperacillin.

Narrow-spectrum β-Lactamase–resistant Penicillins:

This group, through substitution on the penicillin nucleus (6-aminopenicillanic acid), is refractory to a greater or lesser degree to the effects of various β-lactamase enzymes produced by resistant gram-positive organisms, particularly Staphylococcus aureus. However, penicillins in this class are not as active against many gram-positive bacteria as penicillin G and are inactive against almost all gram-negative bacteria. Acid-stable members of this group may be given orally and include isoxazolyl penicillins, such as oxacillin, cloxacillin, dicloxacillin, and flucloxacillin. Methicillin and nafcillin are available as parenteral preparations. Temocillin is a semisynthetic penicillin that is β-lactamase stable but also active against nearly all isolates of gram-negative bacteria except Pseudomonas spp.

The semisynthetic β-lactamase–resistant penicillins, such as oxacillin, cloxacillin, floxacillin, and nafcillin, have spectra similar to those noted above (although often at higher MIC) but also include many of the β-lactamase–producing strains of staphylococci (especially S aureus and S epidermidis).

Carbapenems:

Carbapenems are antibiotics used for the treatment of infections known or suspected to be caused by multidrug-resistant (MDR) bacteria. Their use is primarily in people who are hospitalized.

Like the penicillins and cephalosporins, they are members of the beta lactam class of antibiotics, which kill bacteria by binding to penicillin-binding proteins and inhibiting cell wall synthesis. They exhibit a broader spectrum of activity compared to cephalosporins and penicillins. Their effectiveness is less affected by many common mechanisms of antibiotic resistance than other beta lactams.active against many aerobic and anaerobic gram-positive and gram-negative organisms.

Imipenem and meropenem are among the most active drugs against a wide variety of bacteria. Imipenem is derived from a compound produced by Streptomyces cattleya. Aztreonam is a related (monobactam) compound but differs from other β-lactams in that it has a second ring that is not fused to the β-lactam ring.

Imipenem, the first clinically used carbapenem, was developed at Merck and Co. It was approved for use in the United States in 1985. Imipenem is hydrolyzed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic intermediate, and thus is co-formulated with the dehydropeptidase inhibitor cilastatin. Imipenem is available in both intravenous and intramuscular formulations.

Meropenem is stable to mammalian dehydropeptidases and does not require co-administration of cilastatin. It was approved for use in the United States in 1996. In most indications it is somewhat more convenient to administer than imipenem, 3 times a day rather than 4. Doses of less than one gram may be administered as an IV bolus, whereas imipenem is usually administered as a 20-minute to one hour infusion. Meropenem is somewhat less potent than imipenem against gram-positive pathogens, and somewhat more potent against gram-negative infections. Unlike imipenem, which produced an unacceptable rate of seizures in a phase 2 trial, meropenem is effective for the treatment of bacterial meningitis. A systematic review performed by an employee of the company that markets meropenem concluded that it provides a higher bacterial response and lower adverse event rates than imipenem in people with severe infections, but no difference in mortality rate.

Ertapenem is administered once daily as an intravenous infusion or intramuscular injection. It lacks useful activity against the P. aeruginosa and Acetinobacter species, both of which are important causes of hospital-acquired infections.

Doripenem has a spectrum of activity very similar to that of meropenem. Its greater stability in solution allows the use of prolonged infusions and it is somewhat less likely to produce seizures than other carbapenems.



The Cephalosporins and Cephamycin  

The cephalosporins, and the closely related cephamycins, are similar to penicillins in several respects, sharing pharmacologic group features.
Cephalosporins include cephamycins, the latter of which differ from other cephalosporins in that they contain a 7-alpha-methoxy group, which imparts resistance to extended-spectrum β-lactamases.. The early cephalosporins differed mainly with respect to pharmacokinetic characteristics. Whereas penicillins were classified based on source (natural versus semisynthetic) and spectra, cephalosporins are classified by generations (1–4). Later generations are more resistant to β-lactam destruction and are often characterized by extended but variable spectra.

First-generation Cephalosporins:

     This group includes cephalothin (no longer marketed in the USA), cephaloridine, cephapirin, cefazolin, cephalexin, cephradine, and cefadroxil. Cephalosporins in this group are usually quite active against many gram-positive bacteria but are only moderately active against gram-negative organisms. They are ineffective against enterococci. Susceptible gram-negative bacteria include Escherichiacoli and Proteus, Klebsiella, Salmonella, Shigella, and Enterobacter spp. Cefazolin is more effective against E coli than cephalexin, the latter of which is minimally susceptible. Although generally less susceptible to β-lactamase destruction than penicillins, they are susceptible to cephalosporinases. They are not as effective against anaerobes as are the penicillins.

Second-generation Cephalosporins:

     This group includes cefamandole, cefoxitin (a cephamycin), cefotiam, cefachlor, cefuroxime, and ceforanide. These agents are generally active against both gram-positive and gram-negative bacteria. Moreover, they are relatively resistant to β-lactamases compared with first-generation drugs. They are ineffective against enterococci, Pseudomonas aeruginosa (with the frequent exception of cefoxitin), Actinobacter spp, and many obligate anaerobes (again, cefoxitin is an exception).

Third- and Fourth-generation Cephalosporins:

     The third-generation cephalosporins include ceftiofur, ceftriaxone, cefsulodin, cefotaxime, cefoperazone, moxalactam (not a true cephalosporin), and several others, including cefpodoxime and cefovecin, approved for use in dogs and for use in dogs and cats, respectively. Cefepime is a fourth-generation cephalosporin. The spectrum of third- and fourth-generation cephalosporins varies and should be confirmed based on culture and susceptibility testing before use. The spectrum of veterinary third-generation cephalosporins should not be considered extended in that efficacy often does not include Pseudomonas or other problematic coliforms. Ceftiofur has been specifically approved for use in cattle with bronchopneumonia, especially if caused by Mannheimia haemolytica or Pasteurella multocida. Although it is approved for use in dogs to treat urinary tract infections (injectable), other more convenient drugs are generally used. Cefpodoxime and cefovecin are particularly effective against Staphylococcus pseudintermedius, while retaining fair efficacy toward gram-negative organisms such as E coli, Klebsiella, and Proteus. Some drugs approved for use in people have only moderate activity against gram-positive bacteria (again, enterococci are resistant) but have extensive activity against a wide variety of gram-negative bacteria, including Pseudomonas spp, Proteus vulgaris, Enterobacter spp, and Citrobacter spp (eg, cefotaxime, ceftazidime). Third- and fourth-generation cephalosporins were designed to be increasingly resistant to β-lactamases. However, differences in chemical structure have been overcome by the formation of extended-spectrum β-lactamases that target third- and fourth-generation drugs (but not, as a general rule, cephamycins). Ceftiofur is a third-generation cephalosporin with a gram-negative spectrum that is more similar to that of first-generation cephalosporins.