There are some characteristics that all antibiotics share. All antibiotics can elicit allergic responses, although some are more allergenic than others. Allergic reactions can range from mild, annoying rashes to life-threatening reactions such as anaphylaxis and the Stevens-Johnson syndrome. In some cases, there is a cross-sensitivity between agents in different classes. In addition, all antibiotics exert some impact on normal body flora as well as pathogens, in some cases leading to the emergence of Candida species and pathogenic bacteria such as Clostridioides difficile. Overgrowth of C. difficile within intestinal flora is often a serious complication of antimicrobial therapy that can produce symptoms ranging from mild diarrhea to severe, life-threatening pseudomembranous colitis [1]. Most cases resolve with supportive care and discontinuation of the offending antibiotic, but many require treatment. Furthermore, C. difficile colitis can develop days or weeks after the primary antimicrobial has been discontinued. A high degree of suspicion and judicious use of laboratory testing are the keys to recognizing and managing these complications.

Repeated exposure to an antibiotic may lead to the emergence of selective subpopulations of the same or related bacteria now resistant to the therapeutic agent. The Centers for Disease Control and Prevention (CDC) note that approximately 2.8 million people become infected with bacteria that are resistant to antibiotics, and approximately 35,000 people die annually because of these infections [2]. When C. difficile colitis, not typically resistant but associated with antimicrobial use, is added to these, the U.S. toll of all threats exceeds 3 million infections and 48,000 deaths [2]. Mechanisms of microbial resistance include altered cellular permeability (leading to greatly diminished intracellular concentration of the drug), increased efflux of the antibiotic from the cell, and elaboration of deactivating enzymes that alter the antibiotic's interaction at binding sites within the cell wall or cytoplasm [3].

These resistance mechanisms may be acquired through mutations in the genes that encode for the target or affected transport proteins. As the bacterial cells without the adaptive mutations succumb to the action of the antibiotic, the subpopulation that has the adaptive mutation continues to replicate, replacing the original population with a resistant one.

In addition, new categories of antibiotics are being created to stay ahead of the rapid evolution of bacterial resistance. Linezolid and tedizolid, the only two FDA-approved drugs in the oxazolidinone category, are examples of this, with linezolid being the first of the two to be developed. Oxazolidinones are a unique category of drugs that prevent formation of the 70S protein synthesis complex in bacteria and may be useful in the treatment of vancomycin-resistant enterococci and MRSA [6,7]. Nonetheless, development of resistance in bacteria is relentless.

Considering the efficient means by which bacteria develop resistance, clinicians should avoid, where possible, practice patterns that contribute to the process. In 2002, the CDC issued a position paper outlining recommendations for minimizing nosocomial infection and the emergence of resistant organisms [8]. In this paper, the CDC recommended a multistep approach that included: preventing infection (by paying careful attention to the proper use of invasive medical devices); tailoring medical treatment to fit the infection (by avoiding broad-spectrum antibiotics and prolonged treatment when possible); and preventing the transmission of resistant bacteria between patients (by emphasizing hand washing and implementing hospital infection control programs) [8]. Since issuance of the CDC's position paper, the agency has taken many additional steps and implemented coordinated, strategic action plans to change the course of antibiotic resistance. This includes publication of The National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), 2020–2025 [9]. The CARB builds on the first National Action Plan, released in 2015, and prioritizes infection prevention and control to slow the spread of resistant infections and reduce the need for antibiotic use. The CARB also integrates a "one health" approach, which recognizes the relationships between the health of humans, animals, plants, and the environment [9]. It has also been hypothesized that the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated COVID-19 illness might increase use of antibiotics and other antimicrobial medicines (both appropriate and inappropriate) to address primary or secondary infections, with the potential to further accelerate the emergence of antibiotic resistance despite the rate of the development of new antibiotics [9].

Penicillin is bactericidal, killing susceptible bacteria by interrupting cell wall synthesis. The drug exerts its effect by preventing cross-binding of the peptidoglycan polymers necessary for cell wall formation and by binding with carboxypeptidases, endopeptidases, and transpeptidase ("penicillin-binding proteins" [PBPs]) that participate in cell wall synthesis [12]. Although the exact mechanisms involved are not known, the result is that the cell wall is structurally weakened and lyses, leading to cell death.

The natural penicillins are active against gram-positive organisms such as streptococci, Enterococcus faecalis, and Listeria monocytogenes. However, most S. aureus isolates are now resistant. The natural penicillins are also active against anaerobic species, such as Bacteroides species and Fusobacterium species. At serum levels achieved by parenteral administration, the natural penicillins are effective against some gram-negative bacteria, such as Escherichia coli, H. influenzae, Neisseria gonorrhoeae, and Treponema pallidum. For the treatment of moderate-to-severe infections in which resistant organisms are considered a possibility, reliance upon penicillin alone should be avoided unless the identity and sensitivity of the infecting organism have been confirmed. Labeled uses include treatments for infections of the upper and lower respiratory tract, throat, skin, and genitourinary tract and prophylaxis of recurrent rheumatic fever and pneumococcal infections [6].

Allergy to any of the penicillins is the only absolute contraindication to use of a penicillin agent. However, studies have found that penicillin allergy is less common than previously thought [22,23,24,25]. Traditionally, allergic reactions were believed to occur in up to 10% of patients; however, more recent studies have found the rate to be much lower. While penicillin-induced anaphylaxis death rate estimates are similar to previous statistics (i.e., approximately 0.002% among the general population), the percentage of individuals with a true penicillin allergy as defined by immunoglobulin E (IgE)-mediated reaction is generally less than 10%, with some studies showing a true penicillin allergy rate of only 0.7% [22,23,24,26]. It is also important to note that approximately 90% of patients previously diagnosed with a penicillin allergy will show no reactivity if not exposed to the antibiotic for 10 years or more, due to the absence of a true allergy or loss of allergy over time [22,24,25]. Allergy skin testing is the most reliable way to determine true penicillin allergy and may allow for previously avoided antibiotics to be used as indicated.

Most cephalosporins are eliminated by the kidney. The exception in the oral cephalosporins is cefixime, half of which is excreted in the urine [6]. The remaining half is metabolized in the liver to inactive metabolites and partly excreted in the bile. Cefotaxime is deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are excreted by the kidney. Cefditoren is excreted predominantly in the bile.

The serum levels of all the cephalosporins are increased with co-administration of probenecid. The effects of warfarin may be enhanced by co-administration of cefotetan, cefazolin, cefoxitin, and ceftriaxone [6].

Imipenem and ertapenem have a wide antimicrobial spectrum with excellent activity against enteric gram-negative bacilli and pseudomonas as well as anaerobic bacteria, including Bacteroides species. They also cover many gram-positive cocci, such as Enterococcus and Streptococcus [60]. Meropenem has somewhat greater activity against gram-negative bacteria, which are not affected by most beta-lactamases. Doripenem has good activity against Pseudomonas aeruginosa. Imipenem and ertapenem are approved by the FDA for use in urinary tract infections, pneumonia, intra-abdominal infections, and skin and soft-tissue infections [6]. Meropenem is approved by the FDA for treatment of intra-abdominal infections, skin and skin structure infections, and meningitis in patients older than 3 months of age [6]. Combination meropenem/vaborbactam is approved for the treatment of complicated urinary tract infections caused by susceptible micro-organisms [6,61]. The combination imipenem/cilastatin/relebactam was approved by the FDA in 2019 for the treatment of complicated urinary tract infections and complicated intra-abdominal infections [6,62].

The carbapenems are generally well tolerated. Occasional reactions include nausea and vomiting, phlebitis at the infusion site, elevation of liver enzymes, and leukopenia. Seizures may occur. The risk is higher in patients with underlying central nervous system (CNS) disease and in patients with renal disease, which results in high serum levels of the drug [66]. Hypersensitivity reactions may occur, and while there is a degree of cross-sensitivity with penicillins, this risk is lower than previously believed [22,23,24]. Carbapenems should be used with caution in patients allergic to the carbapenems or penicillins [6].

Aztreonam is pregnancy category B, based on animal studies that have shown no ill effects of the drug. There are no human data available [6].

The aminoglycosides are effective for the treatment of aerobic gram-negative bacilli, such as Klebsiella species, Enterobacter, and P. aeruginosa. There is very little activity against anaerobes and gram-positive organisms, so combination therapy with a beta-lactam, vancomycin, or other agents active against gram-positive organisms and anaerobes is commonly used. The aminoglycosides are indicated for infections caused by susceptible organisms of the urinary tract, respiratory tract, skin and soft tissues, and sepsis due to gram-negative aerobic bacilli.

The aminoglycosides commonly used at present for treatment of systemic bacterial infection include gentamicin, tobramycin, and amikacin. Kanamycin is discontinued [17]. Aminoglycosides have negligible oral absorption and thus require parenteral administration. They also can be administered directly into body cavities and have a role in the management of pleural and peritoneal infection. Tobramycin is particularly useful for treatment of recurrent Pseudomonas infection in patients with cystic fibrosis and can be administered by aerosolized inhalation to facilitate optimal local antimicrobial effect [79]. In a large randomized, placebo-controlled clinical trial involving critically ill adults who had undergone invasive mechanical ventilation, a three-day prophylactic regimen of inhaled amikacin reduced the subsequent incidence of ventilator-associated pneumonia [174]. Neomycin is often used orally as part of a pre-operative bowel decontamination protocol.

The most common adverse effect associated with aminoglycoside usage is nephrotoxicity, occurring in 10% to 25% of therapeutic courses [84]. Aminoglycosides are freely filtered by the glomeruli and quickly taken up by the proximal tubular epithelial cells, where they exert their main toxic effect by altering phospholipid metabolism. Aminoglycosides also cause renal vasoconstriction [85]. Critical factors in the development of acute kidney injury secondary to aminoglycoside nephrotoxicity are dosing and duration of therapy. A single daily large dose is preferable to more frequent dosing, as it appears to cause less accumulation in the tubular cells once the saturation point is reached [84]. Additionally, extending the dose interval to more than 24 hours in patients with renal impairment has been found to be effective, with irreversible nephrotoxicity reported in only 1% of patients studied [86].

Most of the tetracycline dose is excreted unchanged into the urine by glomerular filtration, although there is some biliary excretion as well. Nonrenal, possibly hepatic, mechanisms account in large part for excretion of doxycycline and minocycline. Approximately 23% to 40% of doxycycline and 5% to 12% of minocycline is excreted in the urine [6].

Allergic reactions to tetracyclines are not common but may range from mild rashes to anaphylaxis. Tetracyclines are contraindicated in patients who have shown hypersensitivity to any tetracyclines.