The beta-lactam group of antibiotics all contain a 3-carbon, 1-nitrogen ring that is highly reactive. Its primary mode of action is to interfere with proteins involved in synthesis of the cell wall, leading to lysis and cell death. More than half of all antimicrobial drugs are beta-lactams, with the penicillins and cephalosporins being the most prominent representatives.
Penicillin and Its Relatives
The penicillin family of antibiotics, named for the parent compound, is a large, diverse group of compounds, most of which end in the suffix -cillin. Although penicillins could be completely synthesized in the laboratory from simple raw materials, it is more practical and economical to obtain natural penicillin through microbial fermentation. The major source of the drug is a unique strain of Penicillium chrysogenum that has been manipulated experimentally to synthesize 1,000 times more penicillin than the original strain. The natural product can then be used either in unmodified form or to make semisynthetic derivatives. All penicillins consist of three parts: a beta-lactam ring, a thiazolidine ring, and a variable side chain that dictates its microbicidal activity (figure 1).
Fig1. Chemical structure and functions of semisynthetic penicillins. All penicillins start with a central molecule called a nucleus that forms the basic framework. The nucleus is an inactive penicillin derivative—aminopenicillanic acid—which has a bonding site on the nitrogen on the beta-lactam ring for addition of a side chain or R group. This “fine tunes” the end product to create finished molecules with a specialized desired action. Here we see penicillins that have resistance to penicillinase (methicillin, oxacillin, nafcillin), a broader activity spectrum (ampicillin), and acid resistance (penicillin V).
Penicillin G was the first antibiotic and is the parent compound for all “-cillin” drugs. It is narrow spectrum and cannot be given by mouth. It is often considered the drug of choice for infections by sensitive gram-positive bacteria (streptococci) and some gram- negative bacteria (meningococci). A close relative, penicillin V, has similar uses but has been modified to be stable in the stomach acid and so can be taken orally. The narrow-spectrum penicillins dicloxacillin and nafcillin are often given in place of penicillin G or V. So many pathogens have become resistant to methicillin that it has largely been replaced by newer varieties.
Other semisynthetic penicillins such as ampicillin and amoxicillin have been chemically altered with side chains that help them move across the outer membrane of gram-negative cell walls. This increases their spectrum and makes them useful in treating many types of gram negative infections. Ticarcillin and piperacillin have such an extended spectrum that they can be substituted for combinations of antibiotics.
Many bacteria produce enzymes that are capable of severing the beta-lactam ring of some penicillins, thereby destroying the mode of action. The enzymes are referred to as penicillinases or beta-lactamases, and they confer resistance on the bacteria that possess them. One way to bypass this problem was to develop penicillinase-resistant penicillins such as nafcillin and cloxacillin for treating infections caused by penicillinase-producing bacteria. Another strategy for reducing drug resistance has been to pair a beta-lactamase inhibitor with the penicillin to increase the longevity of the antibiotic in the presence of resistant bacteria. For example, clavulanic acid is often added to broad-spectrum penicillins to augment their effectiveness. Clavamox is a combination of amoxicillin and clavulanate marketed under the trade name Augmentin. Zosyn, a similar combination of the beta-lactamase inhibitor tazobactam and piperacillin, is used for a wide variety of systemic infections. These combined medications show an extended spectrum because of the synergy of the two drugs working together.
All of the “-cillin” drugs are relatively mild and well tolerated because of their specific mode of action on cell walls (which humans lack). The primary problems in therapy include resistant strains of pathogens and allergy (which is altogether different from toxicity). Showing an allergy to any of the penicillin drugs will require avoidance of all of them, regardless of the type.
The Cephalosporin Group of Drugs
The cephalosporin antibiotics currently account for one-third of all antibiotics administered. Cephalosporins are similar to penicillins; they have a beta-lactam structure that can be synthetically altered (figure 2) and have a similar mode of action. The generic names of these compounds are often recognized by the presence of the root cef, ceph, or kef in their names.
Fig2. The structure of cephalosporins. Like penicillin, their main nucleus consists of a beta-lactam ring (red) and a second ring (yellow). However, unlike penicillins, they have two sites for placement of R groups (at positions 3 and 7). This makes possible several generations of molecules with greater versatility in function and complexity in structure.
The cephalosporins are versatile. They are relatively broad spectrum, resistant to most penicillinases, and cause fewer allergic reactions than penicillins. Although some cephalosporins are given orally, many are poorly absorbed from the intestine and must be administered parenterally, by injection into a muscle or a vein.
Four generations of cephalosporins exist, with each group being more effective against gram-negative organisms than the generation before it. In addition, succeeding generations typically have improved dosing schedules and fewer side effects. First-generation cephalosporins (cephalothin and cefazolin) are most effective against gram- positive cocci and a few gram-negative bacteria. Second-generation forms (cefaclor and cefonicid) are more effective than the first- generation forms in treating infections by gram-negative bacteria such as Enterobacter, Proteus, and Haemophilus. Third-generation cephalosporins, such as cephalexin (Keflex) and ceftriaxone (Rocephin), are broad spectrum with especially well-developed activity against enteric bacteria that produce beta-lactamases. Fourth-generation drugs, such as cefepime, have the widest range of antimicrobial proper ties. They are effective with both gram-negative and gram-positive bacterial infections and are rapidly microbicidal.
Some recent additions to this drug family are two combination drugs that pair a broad-spectrum cephalosporin with a beta lactamase inhibitor. Zerbaxa is a combination of ceftolozene with tazobactam for treating resistant urinary tract and abdominal infections. Avycaz, which combines ceftizadime and avibactam, is being limited to the most life-threatening cases of kidney and abdominal infections.
Carbapenems and Monobactams Other beta-lactam drugs are the carbapenems or “penems” and aztreonam. Imipenem and ertapenem are broad-spectrum antibiotics with a mode of action similar to penicillin but with greater resistance to beta-lactamases. They are active in very low concentrations and can be taken by mouth with few side effects except for allergies. Starting in 2001, some carbapenem-resistant strains of gram-negative enteric bacteria began to emerge in hospital outbreaks. These pathogens, termed CRE (carbapenem-resistant Enterobacteriaceae), have continued to increase in numbers and are currently causing concern in some clinical set tings.
Aztreonam, a monobactam, is a narrow spectrum antibiotic for treating pneumonia, septicemia, and urinary tract infections by gram-negative aerobic bacilli. Aztreonam is especially useful when treating persons who are allergic to penicillin, because it is chemically different and does not cross-react with antibodies made to penicillin.
Miscellaneous Cell Wall Inhibitors (Non Beta-Lactam) Vancomycin is a narrow spectrum antibiotic most effective in treating staphylococcal infections in cases of penicillin and methicillin resistance or in patients with an allergy to penicillins. It has also been chosen to treat Clostridium infections in children and endocarditis (infection of the lining of the heart) caused by Enterococcus faecalis. Because it is very toxic and hard to administer, vancomycin is usually restricted to the most serious, life-threatening conditions. Two relatives of vancomycin—Dalbavancin and Orbactive—were recently introduced as alternative choices for skin and structure infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA).
Bacitracin is a narrow-spectrum peptide antibiotic produced by a strain of Bacillus subtilis. Its primary effect is to block the elongation of the peptidoglycan in gram-positive bacteria. Since it was first isolated, its greatest claim to fame has been as a major ingredient in a common drugstore antibiotic ointment (Neosporin) for combating superficial skin infections by streptococci and staphylococci. For this purpose, bacitracin is usually combined with neomycin (an aminoglycoside) and polymyxin.
Isoniazid (INH) works by interfering with the synthesis of my colic acid, a necessary component of the cell wall of acid-fast organisms. It is used to treat infections with Mycobacterium tuberculosis but is effective only against growing cells. It is often prescribed along with rifampin and other drugs to treat tuberculosis. In late 2019, a new drug, Pretomanid, was approved for the treatment of some strains of drug-resistant. Ethambutol, a closely related compound, is another antituberculosis drug added to treatment regimens.
