Adverse drug reactions

Common adverse drug reactions for the β-lactam antibiotics include diarrhea, nausea, rash, urticaria, superinfection (including candidiasis).^[8]

Infrequent adverse effects include fever, vomiting, erythema, dermatitis, angioedema, pseudomembranous colitis.^[8]

Pain and inflammation at the injection site is also common for parenterally administered β-lactam antibiotics.^{[citation needed]}

Allergy/hypersensitivity

Immunologically mediated adverse reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent (a small fraction of which are truly IgE-mediated allergic reactions, see amoxicillin rash). Anaphylaxis will occur in approximately 0.01% of patients.^[8][9] There is perhaps a 5–10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems;^{[citation needed]} but this figure has been challenged by various investigators.^{[who?][citation needed]}

Nevertheless, the risk of cross-reactivity is sufficient to warrant the contraindication of all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic. Rarely, allergic reactions have been triggered by exposure from kissing and sexual contact with a partner who is taking these antibiotics.^[10]

A Jarisch–Herxheimer reaction may occur after initial treatment of a spirochetal infection such as syphilis with a β-lactam antibiotic.^{[citation needed]}

Inhibition of cell wall synthesis

In the absence of β-lactam antibiotics (left), the cell wall plays an important role in bacterial reproduction. Bacteria attempting to grow and divide in the presence of β-lactam antibiotics (right) fail to do so, and instead shed their cell walls, forming osmotically fragile spheroplasts.^[12]

β-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity,^[6] especially in gram-positive organisms, being the outermost and primary component of the wall. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by DD-transpeptidases, also known as penicillin binding proteins (PBPs). PBPs vary in their affinity for penicillin and other β-lactam antibiotics. The number of PBPs varies between bacterial species.^[11]

β-Lactam antibiotics are analogues of d-alanyl-d-alanine—the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and d-alanyl-d-alanine facilitates their binding to the active site of PBPs. The β-lactam nucleus of the molecule irreversibly binds to (acylates) the Ser₄₀₃ residue of the PBP active site. This irreversible inhibition of the PBPs prevents the final crosslinking (transpeptidation) of the nascent peptidoglycan layer, disrupting cell wall synthesis.^[13] β-Lactam antibiotics block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This is supporting the endosymbiotic theory and indicates an evolution of plastid division in land plants.^[14]

Under normal circumstances, peptidoglycan precursors signal a reorganisation of the bacterial cell wall and, as a consequence, trigger the activation of autolytic cell wall hydrolases. Inhibition of cross-linkage by β-lactams causes a build-up of peptidoglycan precursors, which triggers the digestion of existing peptidoglycan by autolytic hydrolases without the production of new peptidoglycan. As a result, the bactericidal action of β-lactam antibiotics is further enhanced.^{[citation needed]}

Guanine oxidation

Another possibility that has been proposed to account for much of the cytotoxicity of β-lactams focuses on the oxidation of the guanine nucleotide in the bacterial nucleotide pool.^[15] The incorporation of oxidized guanine nucleotide into DNA could cause cytotoxicity. Bacterial cytotoxicity could arise from incomplete repair of closely spaced 8-oxo-2'-deoxyguanosine lesions in the DNA resulting in double-strand breaks.^[15]

Enzymatic hydrolysis of the β-lactam ring

If the bacterium produces the enzyme β-lactamase or the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.^[19] (An example of such an enzyme is New Delhi metallo-beta-lactamase 1, discovered in 2009.) The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer (plasmid-mediated resistance), and β-lactamase gene expression may be induced by exposure to β-lactams.^{[citation needed]}

The production of a β-lactamase by a bacterium does not necessarily rule out all treatment options with β-lactam antibiotics. In some instances, β-lactam antibiotics may be co-administered with a β-lactamase inhibitor. For example, Augmentin (FGP) is made of amoxicillin (a β-lactam antibiotic) and clavulanic acid (a β-lactamase inhibitor). The clavulanic acid is designed to overwhelm all β-lactamase enzymes, and effectively serve as an antagonist so that the amoxicillin is not affected by the β-lactamase enzymes. Another β-lactam/β-lactamase inhibitor combination is piperacillin/tazobactam with a broad spectrum of antibacterial activity that includes gram-positive and -negative aerobic and anaerobic bacteria. The addition of tazobactam to piperacillin has enhanced its stability against a wide range of β-lactamase enzymes including some Extended-Spectrum β-lactamases.^[20]

Other β-lactamase inhibitors such as boronic acids are being studied in which they irreversibly bind to the active site of β-lactamases. This is a benefit over clavulanic acid and similar β-lactam competitors, because they cannot be hydrolysed, and therefore rendered useless. Extensive research is currently being done to develop tailored boronic acids to target different isozymes of beta-lactamases.^[21]

However, in all cases where infection with β-lactamase-producing bacteria is suspected, the choice of a suitable β-lactam antibiotic should be carefully considered prior to treatment. In particular, choosing appropriate β-lactam antibiotic therapy is of utmost importance against organisms which harbor some level of β-lactamase expression. In this case, failure to use the most appropriate β-lactam antibiotic therapy at the onset of treatment could result in selection for bacteria with higher levels of β-lactamase expression, thereby making further efforts with other β-lactam antibiotics more difficult.^[22]

In the context of medical pharmacology, penicillins, cephalosporins, and carbapenems, while all have the β-lactam ring that serves as the fundamental structure, also have an auxiliary ring that carries a carboxylate group that is positioned on the same side as the carbonyl group within the β-lactam ring, and, as such, this structural configuration is critical to their antimicrobial activity.^[23] Bacterial resistance to these antibiotics primarily occurs through the production of β-lactamases, enzymes that hydrolyze the amide bond of the β-lactam ring, thereby eliminating the antimicrobial activity of these antibiotics. This resistance mechanism underscores the importance of the structural integrity of the β-lactam ring for the antibiotic's function.^[24] The color change from colorless or light yellow to amber or even red in an aqueous solution of a β-lactam antibiotic can denote β-lactamase hydrolysis of amide bonds in the β-lactam ring.^[25][26] This is often observed with a chromogenic β-lactamase substrate like ceftriaxone, merapenem, or nitrocefin,^[27] that undergoes a distinctive color change from yellow to red as the amide bond in the β-lactam ring is hydrolyzed by β-lactamase.^[27][28] This color change is a visual indicator of the presence and activity of β-lactamase enzymes, which are responsible for conferring resistance to β-lactam antibiotics in many bacterial species. The hydrolysis of the β-lactam ring by β-lactamase enzymes renders the antibiotic ineffective, thereby allowing the bacteria to survive in the presence of the antibiotic.^[28] Some β-lactam antibiotics like ceftriaxone and meropenem are known to be relatively unstable in solution, especially when stored for extended periods, and degrade in an aqueous solution even without the presence of β-lactamase.^[29] For ceftriaxone, the color of solutions can range from light yellow to amber, depending on the length of storage, concentration, and diluent used.^[30][31] A study found that meropenem concentrations dropped to 90% of the initial concentration at 7.4 hours at 22°C and 5.7 hours at 33°C, indicating degradation over time.^[29]

Possession of altered penicillin-binding proteins

As a response to the use of β-lactams to control bacterial infections, some bacteria have evolved penicillin binding proteins with novel structures. β-Lactam antibiotics cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA)^[32] and penicillin-resistant Streptococcus pneumoniae. Altered PBPs do not necessarily rule out all treatment options with β-lactam antibiotics.^{[medical citation needed]}