Beta-lactam antibiotics are one of the most commonly prescribed drug classes with numerous clinical indications. Their advent starting from the 30s of the twentieth century drastically changed the scenario of the fight against bacterial infectious diseases. Nowadays, it has been calculated that the annual expenditure for these antibiotics amounts to approx $15 billion of USD and it makes up 65% of the total antibiotics market.[1] Their use, however, clashes with the worrying phenomenon of antimicrobial resistance remains, which represents a global health issue.
From a biochemical point of view, these drugs have a common feature, which is the 3-carbon and 1-nitrogen ring (beta-lactam ring) that is highly reactive. This class includes:
Mechanism of Action
Peptidoglycan or murein is a vital constituent of the bacterial cell wall that provides mechanical stability to it. It is an extremely conserved constituent of both the gram-positive and gram-negative envelopes. Nevertheless, peptidoglycan is a thick structure in gram-positive bacteria (≥10 layers), while it is thin (one or two layers) in gram-negative ones. Concerning its structure, peptidoglycan is composed of glycan chains made of N-acetylglucosamine and N-acetylmuramic acid disaccharide subunits; the N-acetylmuramic part is linked to highly conserved pentapeptide or tetrapeptide stems (l-alanine–d-isoglutamine–l-lysine–d-alanine–[d-alanine].
The beta-lactam antibiotics inhibit the last step in peptidoglycan synthesis by acylating the transpeptidase involved in cross-linking peptides to form peptidoglycan. The targets for the actions of beta-lactam antibiotics are known as penicillin-binding proteins (PBPs). This binding, in turn, interrupts the terminal transpeptidation process and induces loss of viability and lysis, also through autolytic processes within the bacterial cell.[2]
Mechanism of Resistance
Resistance to beta-lactams is an alarming and growing phenomenon and, in turn, a public health challenge. It concerns above all Streptococcus pneumoniae and individual gram-negative bacilli such as Pseudomonas aeruginosa. With emerging resistance for antibiotics, it makes sense to look into mechanisms of resistance as it can help to decide which drugs to prescribe in different scenarios and ways to overcome the same. Although bacterial resistance to beta-lactams mostly expresses through the production of beta-lactamases, other mechanisms are involved. Following are the mechanisms of resistance[3]:
Indications For Beta-Lactam Antibiotics
The indications for using the beta-lactam antibiotics are many and vary according to the subclass considered[4]
Penicillins
Natural penicillins [penicillin G (IV), penicillin V (PO)] are used to treat selected gram-positive and gram-negative infections:
Beta-lactamase-resistant agents
These agents [oxacillin (IV), nafcillin (IV), dicloxacillin (PO)] are active against gram-positive organisms. Despite the occurrence of widespread resistance among staphylococci, they remain antibiotics of choice in managing methicillin-susceptible staphylococci (MSSA):
Aminopenicillins
These antibiotics have activity against gram-positive and gram-negative bacteria (e.g., many Enterobacteriaceae) anaerobic organisms. They are commonly used together with beta-lactamase inhibitors.
Amoxicillin (PO), ampicillin (PO/IV):
Carboxypenicillins and ureidopenicillins
Ticarcillin (carboxypenicillin) and piperacillin (ureidopenicillin) have activity against aminopenicillin-resistant gram-negative bacilli (Pseudomonas aeruginosa). Are commonly combined with beta-lactamase inhibitors
Cephalosporins
First-generation cephalosporins
Cefazolin(IV), cephalexin (PO), cefadroxil (PO)
Second-generation cephalosporins
Cefuroxime (IV/PO), cefoxitin (IV), cefotetan (IV), cefaclor (PO) cefprozil (PO)
Third-generation cephalosporins
Cefotaxime (IV), ceftriaxone (IV), cefpodoxime (PO), cefixime (PO), cefdinir (PO), cefditoren (PO), ceftibuten (PO)
Anti-pseudomonal Cephalosporins
Ceftazidime (IV), ceftazidime/avibactam (IV), cefepime (IV) [Fourth-generation], ceftolozone/tazobactam (IV) [also been described as "fifth-generation"]
Anti-Methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins
Ceftaroline (IV), ceftobiprole (IV) [Also been described as "fifth-generation"]
Carbapenems
Imipenem/cilastatin (IV), meropenem (IV), doripenem (IV)
Ertapenem (IV)
Monobactams
Aztreonam (IV). It is effective only against aerobic gram-negative organisms but shows no activity against gram-positive bacteria or anaerobes.
Because the emergence of antimicrobial resistance has become a progressively great concern, new beta-lactam, and beta-lactamase inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, aztreonam/avibactam), siderophore-conjugated cephalosporins (cefiderocol), and siderophore-conjugated monobactams have been developed and represent options for the management of complicated infections, especially in intensive care unit.[5][6]
When administered orally, one must consider that food can affect oral absorption. Moreover, the absorption of some molecules such as cefuroxime and cefpodoxime becomes decreased by H2 blockers or nonabsorbable antacids. The administration of these agents can be through different routes.
Becouse beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication (the duration that the pathogen is exposed to the antibiotic is crucial for bacterial eradication), their continuous infusions may have advantages over standard intermittent bolus dosing. This therapeutic approach is particularly effective especially when pathogens present higher minimum inhibitory concentrations (MIC).[7] Thus, the time that free drug concentrations remain above the MIC (fT>MIC) becomes a better predictor of killing
Compared to other classes, beta-lactam agents are usually safe and well-tolerated.[8] The most frequent side effects are allergic reactions that vary from 0.7% to 10%. These reactions may occur with any dosage form of penicillin and are mostly maculopapular rashes, whereas reports of anaphylaxis appear in 0.004 to 0.015% of patients.[9]. Apart from allergic reactions, beta-lactams can induce other side-effects. In particular:
Penicillins are contraindicated in patients with previous anaphylactic reactions or serious skin reactions, for example, Stevens-Johnson syndrome and toxic epidermal necrosis.[8]
Most of the available penicillins have a short half-life, less than an hour mostly. Administration of the parenteral agents is every four hours, usually when treating serious systemic infections with normal renal function. Piperacillin and ampicillin require dose adjustment when given in patients with renal insufficiency (GFR less than 10 ml/min). For ticarcillin, this dose adjustment is at 50 ml/min. Other agents like nafcillin, oxacillin, cloxacillin, and dicloxacillin have the hepato-biliary mode of excretion and therefore require no modification in renal impairment.
All penicillins achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids, and urine. Of note, cerebrospinal fluid (CSF) penetration is poor in the absence of inflammation but achieves therapeutic levels in meningitis.[11]
Penicillins are the most commonly used broad-spectrum antibiotics by many clinicians, including primary care providers, internists, infectious disease experts, and nurse practitioners. Within the subgroups of penicillins, there are differences between the antibiotics in pharmacokinetics, coverage, safety, and cost, which gives a fair amount of choice to make in selecting which drug to use.[12]
Their use still requires the coordination of an interprofessional team. The clinicians above will be ordering/prescribing, but nursing will often administer (inpatient) or counsel on administration (outpatient). Pharmacists need to involve themselves via medication reconciliation, looking for interactions, as well as reinforcing administration instructions. Nurses will often be the first line of contact in the event of adverse events and are also well-positioned to evaluate therapeutic effectiveness. Pharmacists shall verify dosing and duration of therapy, and contact the prescriber on encountering any discrepancy. All healthcare team members need to be mindful of anaphylactic reactions to beta-lactam agents and the potential for crossover allergies and communicate these to the team when present.
Although beta-lactams use is very common, their effective prescription requires an interprofessional team approach for optimal patient outcomes. [Level V]
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