Continuing Education Activity

Beta-lactam antibiotics are used in the management and treatment of bacterial infections. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of an interprofessional healthcare team in the treatment of patients.

Objectives:

• Identify the mechanism of action of beta-lactam antibiotics.
• Describe the possible adverse effects of beta-lactam antibiotics.
• Outline the appropriate monitoring of patients taking beta-lactam antibiotics.
• Summarize interprofessional team strategies for improving care coordination and communication to advance beta-lactam antibiotics and improve outcomes.

Indications

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 fight against bacterial infectious diseases. Nowadays, it has been calculated that the annual expenditure for these antibiotics amounts to approximately $15 billion 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:

• Penicillins. These antibiotics (most of which end in the suffix -cillin) contain a nucleus of 6-animopenicillanic acid (lactam plus thiazolidine) ring and other ringside chains. The group includes natural penicillins, beta-lactamase-resistant agents, aminopenicillins, carboxypenicillins, and ureidopenicillins.
• Cephalosporins. They contain a 7-aminocephalosporanic acid nucleus and side-chain containing 3,6-dihydro-2 H-1,3- thiazane rings. Cephalosporins are traditionally divided into five classes or generations, although acceptance of this terminology is not universal. 
• Carbapenems. Their defining structure is a carbapenem coupled to a beta-lactam ring that confers protection against most beta-lactamases, although resistance to these compounds is a significant issue and occurs mainly among gram-negative pathogens (e.g., Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii), which produce different classes of beta-lactamases termed as carbapenemase. 
• Monobactams. The beta-lactam ring stands alone and not fused to another ring.
• Beta-lactamase inhibitors. They work primarily by inactivating serine beta-lactamases, which are enzymes that hydrolyze and inactivate the beta-lactam ring (especially in gram-negative bacteria). These agents include the first-generation beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and the newer avibactam and vaborbactam that are active against carbapenemase such as Klebsiella pneumoniae carbapenemase (KPC).

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 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[2]:

• Inactivation by the production of beta-lactamases 
• Decreased penetration to the target site (e.g., the resistance of Pseudomonas aeruginosa 
• Alteration of target site PBPs (e.g., penicillin resistance in pneumococci)
• Efflux from the periplasmic space through specific pumping mechanisms

Indications For Beta-Lactam Antibiotics

The indications for using the beta-lactam antibiotics are many and vary according to the subclass considered[3]

Penicillins

Natural penicillins [penicillin G (IV), penicillin V (PO)] are used to treat selected gram-positive and gram-negative infections:

• Penicillin susceptible Streptococcus pneumonia and meningitis
• Streptococcal pharyngitis
• Endocarditis
• Skin and soft tissue infections
• Neisseria meningitides infections
• Syphilis

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):

• Skin and soft tissue infections (MSSA)
• Serious infections due to 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):

• Upper respiratory tract infections (sinusitis, pharyngitis, otitis media)
• Enterococcus faecalis infections
• Listeria infections
• Aminopenicillins/beta-lactamase inhibitors: amoxicillin/clavulanate (PO), ampicillin-sulbactam (IV)
• Upper respiratory tract infections (sinusitis, otitis media)
• Intra-abdominal infections

Ureidopenicillins

Piperacillin (ureidopenicillin) has activity against aminopenicillin-resistant gram-negative bacilli (Pseudomonas aeruginosa). They are commonly combined with beta-lactamase inhibitors.

Cephalosporins

First-generation cephalosporins

Cefazolin(IV), cephalexin (PO), cefadroxil (PO)

• Skin and soft tissue infections serious infections due to MSSA 
• Perioperative surgical prophylaxis

Second-generation cephalosporins

Cefuroxime (IV/PO), cefoxitin (IV), cefotetan (IV), cefaclor (PO) cefprozil (PO)

• Upper respiratory tract infections (sinusitis, otitis media)
• Cefoxitin, cefotetan-gynecologic infections,
• perioperative surgical prophylaxis

Third-generation cephalosporins

Cefotaxime (IV), ceftriaxone (IV), cefpodoxime (PO), cefixime (PO), cefdinir (PO), cefditoren (PO), ceftibuten (PO)

• Community-acquired pneumonia, meningitis
• Urinary tract infections
• Streptococcal endocarditis
• Gonorrhea
• Severe Lyme disease.

Anti-pseudomonal Cephalosporins

Ceftazidime (IV), ceftazidime/avibactam (IV), cefepime (IV) [Fourth-generation], ceftolozone/tazobactam (IV) [also been described as "fifth-generation"]

• Nosocomial infections-pneumonia
• Meningitis
• Complicated Intra-abdominal Infections (cIAI) [ceftazolone plus beta-lactamase inhibitor]
• Complicated Urinary Tract Infections (cUTI) [ceftazolone plus beta-lactamase inhibitor]

Anti-Methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins

Ceftaroline (IV), ceftobiprole (IV) [Also been described as "fifth-generation"] 

• Community-acquired pneumonia
• Hospital-acquired pneumonia (excluding ventilator-acquired pneumonia)
• Skin and soft tissue infection

Carbapenems

Imipenem/cilastatin (IV), meropenem (IV), doripenem (IV)

• Nosocomial infections-pneumonia, intra-abdominal infections, urinary tract infections
• Meningitis (especially meropenem)      

Ertapenem (IV)

• Community-acquired infections
• Nosocomial infections.

Monobactams

Aztreonam (IV). It is effective only against aerobic gram-negative organisms but shows no activity against gram-positive bacteria or anaerobes.

• Nosocomial infections, e.g., pneumonia
• Urinary tract infections    

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 the intensive care unit.[4][5]

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.[6] 

Administration

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.

• Penicillin V is preferable for oral administration, given 30 min before the meal or 2 hours after.
• Penicillin G is available in 2 parenteral preparations: benzathine and procaine.
• Penicillin G benzathine dosing is once monthly as it has a longer half-life.
• Penicillin G procaine is given once daily due to a shorter half-life.
• Neither should be administered intravenously to avoid serious toxicity.
• Penicillinase-resistant penicillins (oxacillin, cloxacillin, and dicloxacillin) are available in oral and parenteral preparations.
• Aminopenicillins: ampicillin and amoxicillin are available in both oral and parenteral preparations, though amoxicillin is preferred orally.
• Antipseudomonal penicillins: piperacillin is only available for parenteral administration.
• Most cephalosporins are absorbed readily after oral administration; the administration of others can be intramuscularly or intravenously. 

Because 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 free drug concentrations remain above the MIC (fT>MIC) becomes a better predictor of killing.

Adverse Effects

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, these are:

• Penicillin G and piperacillin are also associated with impaired hemostasis due to defective platelet aggregation.
• An IV injection of benzathine penicillin G has correlations with cardiorespiratory arrest and death.
• Cephalosporins carry associations with rare instances of bone marrow depression, including granulocytopenia.
• Some cephalosporins are potentially nephrotoxic and correlate with renal tubular necrosis. Ceftriaxone can cause jaundice in neonates by displacing bilirubin from albumin.
• It can also lead to biliary pseudolithiasis due to its high affinity for biliary calcium.
• Cefepime correlates with encephalopathy and nonconvulsive status epilepticus at high doses or in patients with renal dysfunction.
• Imipenem is associated with seizures when given in high doses to patients with CNS lesions or renal insufficiency.[10]

Contraindications

Penicillins are contraindicated in patients with previous anaphylactic reactions or serious skin reactions, for example, Stevens-Johnson syndrome and toxic epidermal necrosis.[8]

Monitoring

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). 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]

Enhancing Healthcare Team Outcomes

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, and 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 5]