US Pharm. 2024;49(4):HS1-HS5.
ABSTRACT: Over the past few years, the FDA has approved several new antibiotics to combat resistant bacteria. These new drugs are used primarily in the hospital setting, although some are also employed in outpatient clinics or administered by home healthcare agencies. Many of these antibiotics may be restricted to use by infectious-disease physicians or antimicrobial-stewardship teams, on which pharmacists can play an extremely important role. It is important for all healthcare practitioners to have a thorough understanding of these drugs before prescribing them. Used judiciously, these antibiotics may offer lifesaving therapy for many difficult-to-treat infections.
In the era of antimicrobial resistance, most hospitals and many outpatient clinics have instituted antimicrobial-stewardship programs to ensure appropriate use of antibiotics. Physicians, pharmacists, physician assistants, nurse practitioners, and infection-control specialists are instrumental in providing concurrent antibiotic-use assessments in both inpatient and outpatient settings. Most of the antibiotics discussed in this article are restricted to use by infectious-disease physicians or antimicrobial-stewardship teams, on which pharmacists can play an extremely important role. This is to ensure that these drugs are used only when absolutely necessary, in the appropriate patient, at the appropriate dosage, and for the appropriate length of time. This will help curb the incidence of antibiotic resistance, which is a major healthcare issue in the United States and worldwide.1,2
Bacteria constantly evolve to become resistant to currently used antibiotics. Antibiotic-resistance patterns vary greatly from country to country as well as from institution to institution. Understanding and monitoring resistance patterns is vital to informing how healthcare practitioners (HCPs) treat common infections.1,2
The mechanisms of antibiotic resistance are plentiful and extraordinary. Bacteria are adept at finding ways to survive and multiply in humans despite being attacked by antibiotics, which ultimately lessens an antibiotic’s effectiveness. Among these mechanisms are bacterial mutation that alters potential antibiotic binding sites; alteration of the bacterial cell membrane via barriers such as proteins or efflux pumps; and bacterial production of enzymes such as beta-lactamases (BLs).1-4
Fortunately, researchers have been successfully developing new antibiotics. This has been accomplished by discovering new antibiotic entities with varied mechanisms of action; altering the structure of older antibiotics to change resistance patterns; combining certain antibiotics with enzyme inhibitors to prevent resistance; and repurposing older, less frequently used antibiotics that may now be effective against specific bacteria.1,3 Researchers have also refined laboratory techniques to improve the culturing of the bacterium causing infection and the identification of specific enzymes (e.g., BLs) the bacterium is producing to potentially achieve resistance. All of these developments have enabled HCPs to continue to effectively treat bacterial infections.3,5
This article will describe some of the newer antibiotics approved by the FDA over the past several years. Many of them are restricted for use in most hospitals because of their ability to treat infections caused by multidrug-resistant organisms; however, some may also be administered in outpatient clinics or by home healthcare agencies. This review will discuss antibiotics that target gram-positive or gram-negative bacteria for treatment of infections in adults.
NEWER ANTIBIOTICS THAT TARGET GRAM-POSITIVE BACTERIA
The following sections review lipoglycopeptides, oxazolidinones, cephalosporins, and fluoroquinolones.6,7
Lipoglycopeptides
Vancomycin is the prototypical glycopeptide antibiotic. Like vancomycin, newer lipoglycopeptides bind to the d-alanyl-d-alanine terminus of the lipid II bacterial cell wall precursor, preventing cross-linking of the peptidoglycan layer of the bacterial cell wall.8 The newer lipoglycopeptides telavancin and oritavancin possess a secondary mechanism, namely, disruption of bacterial cell membrane potential, which results in increased permeability of the cell membrane. Because the newer glycopeptides differ structurally from vancomycin, they may offer a therapeutic alternative for treating infections caused by certain vancomycin-resistant organisms.8
Dalbavancin (Dalvance): Dalbavancin is approved for treatment of skin and soft-tissue infections (SSTIs) caused by susceptible gram-positive bacteria. Clinical studies have demonstrated that it may be effective against Staphylococcus aureus, including some methicillin-resistant strains (e.g., methicillin-resistant S aureus [MRSA]), Streptococcus pyogenes, and other Streptococcus species (spp) as well as some strains of Enterococcus faecalis.9-11 Dalbavancin distributes throughout the body and undergoes partial elimination via the urine and feces. Uniquely, this drug’s terminal half-life of approximately 14 days enables one-time dosing for certain infections and once-weekly dosing for other types of infections (e.g., osteomyelitis). Common adverse effects (AEs) include nausea, vomiting, diarrhea, and headache. As with vancomycin, infusion reactions (flushing, itching, rash induced by histamine release) can occur with dalbavancin. Because of its extended half-life, dalbavancin is frequently used in the outpatient setting to treat infections caused by susceptible, resistant, gram-positive bacteria that normally would require inpatient antibiotic therapy.10,12 The approved dosage for most SSTIs is 1,500 mg IV administered either as a single dose or as a 1,000-mg dose followed 1 week later by a 500-mg dose.10,12 Dosage adjustment is recommended if creatinine clearance is less than 30 mL/minute.10
Oritavancin (Orbactiv): Oritavancin is approved for treatment of SSTIs caused by some gram-positive bacteria, including susceptible strains of S aureus (including MRSA), S pyogenes, and other Streptococcus spp. It may also be effective against various strains of vancomycin-resistant Enterococcus (VRE) spp.13-15 Oritavancin distributes throughout the body and appears to be eliminated via the urine and feces; it is not metabolized hepatically. The half-life is estimated to be approximately 10 days in patients with normal renal function, which enables one-time dosing for certain infections.13,14 Common AEs include nausea, vomiting, and diarrhea; infusion-related reactions (flushing, itching, rash induced by histamine release) also can occur. Oritavancin may affect activated thromboplastin time (aPTT) for up to 5 days after administration, as well as prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours. IV heparin is contraindicated for 5 days after oritavancin use, owing to artificial increases in coagulation tests.13 A single 1,200-mg IV dose of oritavancin infused over 3 hours is recommended for approved infections. Single-dose administration might make outpatient therapy possible for various infections; however, the drug is expensive. Oritavancin’s efficacy in treating more severe or resistant infections is unclear.13
Telavancin (Vibativ): Telavancin has demonstrated concentration-dependent bactericidal activity against susceptible strains of gram-positive organisms, including S aureus (methicillin-susceptible S aureus [MSSA] and MRSA), S pyogenes, and other Streptococcus spp as well as some Enterococcus spp.16,17 Telavancin is derived from vancomycin; therefore it is excreted primarily renally. Drug distribution appears to be similar to that of other lipoglycopeptides, and the terminal elimination half-life is 7 to 9 hours.17 Telavancin has a black box warning (BBW) for nephrotoxicity and embryo-fetal toxicity. AEs include taste disturbance, nausea, vomiting, foamy urine, and QTc prolongation (arrhythmia); infusion-related reactions (flushing, itching, rash induced by histamine release) can also occur. Telavancin may interfere with coagulation tests, including PT, INR, and aPTT. The recommended dosage is 10 mg/kg IV every 24 hours infused over 60 minutes to reduce the risk of infusion reaction. Dosage reduction is recommended in patients who have reduced renal function.17
Daptomycin (Cubicin): Daptomycin is approved for treating several types of infections, including uncomplicated and complicated SSTIs, bacteremia, and endocarditis. Daptomycin has activity against S aureus (including MRSA), S pyogenes, and other Streptococcus spp as well as susceptible Enterococcus spp; it may also act against some strains of vancomycin-resistant S aureus.18-20 Daptomycin is cleared primarily renally. Its half-life is approximately 9 hours, enabling once-daily dosing.19 The most common AEs include gastrointestinal disorders, injection-site reactions, fever, headache, insomnia, dizziness, and rash. Daptomycin can also elevate creatine phosphokinase (CPK), which is associated with muscle discomfort and weakness that is usually reversible upon discontinuation; CPK elevation may be more common in patients taking statins.19,20 Dosing ranges from 4 mg/kg/day IV to 12 mg/kg/day IV depending on the infection being treated. Dosage adjustment is necessary in reduced renal function. Daptomycin should not be used to treat bacterial pneumonia because its activity is inhibited by surfactant.19,20
Oxazolidinones
Linezolid (Zyvox): Linezolid was the first FDA-approved oxazolidinone antibiotic.21 Its bacteriostatic mechanism is due to the drug’s ability to inhibit specific protein synthesis at the bacterial ribosome in susceptible bacteria. Linezolid has demonstrated activity against a number of VRE, Staphylococcus (MRSA), and Streptococcus spp. Recent data have demonstrated that linezolid may be effective against multidrug-resistant strains of Mycobacterium tuberculosis and Bacillus anthracis (anthrax).22-24 Linezolid is partially metabolized hepatically, and approximately 30% is excreted unchanged renally. Its half-life is approximately 4 to 6 hours.22,23 AEs include nausea/vomiting, diarrhea, thrombocytopenia, leukopenia, optic neuropathy, severe skin rash (Stevens-Johnson syndrome, toxic epidermal necrolysis), seizures, hyponatremia, anemia, and headache. Linezolid may act as a weak, nonselective, reversible inhibitor of monoamine oxidase; therefore, it can interact with tyramine, resulting in severe hypertension. Linezolid can also interact with selective serotonin reuptake inhibitors, resulting in the development of serotonin syndrome.22,23 For most infections, the adult dosage is 600 mg IV or orally every 12 hours. Therapy duration depends on the type of infection being treated.23
Tedizolid (Sivextro): Tedizolid is the active compound of the prodrug tedizolid phosphate. Like linezolid, tedizolid inhibits protein synthesis by preventing the formation of the ribosome complex that initiates protein synthesis within the bacterium.21 Tedizolid has activity against Staphylococcus spp (including MRSA), VRE, Streptococcus spp, and gram-positive anaerobes.10,25,26 Tedizolid distributes throughout the body (muscle, adipose, and pulmonary tissues) and is eliminated primarily in the feces, with some excreted unchanged in the urine. The terminal half-life is approximately 10 to 12 hours, enabling once-daily dosing.10,26 AEs include nausea, vomiting, headache, diarrhea, dizziness, and thrombocytopenia. Like linezolid, tedizolid has been associated with peripheral and optic neuropathy as well as serotonin syndrome.10 Tedizolid is approved for treating SSTIs. The recommended adult dosage is 200 mg IV or orally every 24 hours for 6 days. No dosage adjustment is necessary for renal or hepatic dysfunction.10,26
Cephalosporins
Ceftaroline fosamil (Teflaro): Ceftaroline is a fifth-generation cephalosporin.27-29 As with other cephalosporins (and other BL antibiotics), ceftaroline binds to penicillin-binding proteins (PBPs), inhibiting cell wall synthesis. Unlike other BL antibiotics, ceftaroline appears to have a high affinity for PBP-2a, which is genetically encoded in some forms of MRSA.28,30 Ceftaroline has broad-spectrum activity against several gram-positive bacteria, including MSSA, MRSA, and various Streptococcus spp (including resistant strains of Streptococcus pneumoniae and S pyogenes), and it may act against some forms of vancomycin-resistant S aureus. It also appears to have activity against some gram-negative bacteria, including Escherichia coli, various Klebsiella spp, Citrobacter freundii, and Enterobacter cloacae. Ceftaroline is not effective against Enterococcus spp, Acinetobacter spp, or Pseudomonas aeruginosa.28,30,31 Ceftaroline fosamil, a prodrug, is converted in plasma by phosphatases to the active drug ceftaroline. It is cleared primarily renally and has a half-life of approximately 2.6 hours. Ceftaroline is largely well tolerated; its most common AEs are diarrhea, nausea, and rash. Patients with a history of hypersensitivity reaction to other BL antibiotics may also be allergic to ceftaroline.30 Ceftaroline is approved to treat SSTIs and community-acquired pneumonia (CAP). The recommended dosage is 600 mg IV every 12 hours. Dosage reduction is necessary in reduced renal function.30
Fluoroquinolones
Delafloxacin (Baxdela): This novel fluoroquinolone is approved to treat acute bacterial SSTIs. As with other fluoroquinolones, delafloxacin’s bactericidal activity involves inhibiting DNA gyrase (topoisomerase II), thus preventing replication, transcription, repair, and recombination of bacterial DNA.32-35 Delafloxacin has activity against a broad range of bacteria, including S aureus (including MRSA) and other gram-positive Staphylococcus spp; various Streptococcus spp, including S pneumoniae (including multidrug-resistant strains); and E faecalis. It may also have activity against E coli, E cloacae, Klebsiella pneumoniae, and P aeruginosa.33,35 Delafloxacin is highly protein bound and is eliminated primarily renally. It has an estimated half-life of approximately 4.2 to 8.5 hours.33,35 As with other fluoroquinolones, delafloxacin can potentially cause numerous AEs, including nausea, vomiting, headache, arthralgia, myalgia, and confusion. Like other fluoroquinolones, delafloxacin has a BBW regarding the potential risk of developing tendinitis and tendon rupture, peripheral neuropathy, and central nervous system (CNS) effects (e.g., aggravation of myasthenia gravis, dizziness, restlessness, lightheadedness). It does not appear to cause QTc-interval prolongation or phototoxicity reactions.33 In adults, the approved dosage for SSTIs is 300 mg IV every 12 hours or 450 mg orally every 12 hours for 5 to 14 days; the dosage for CAP is 300 mg IV every 12 hours or 450 mg orally every 12 hours for 5 to 10 days. Dosage adjustment is necessary for renal dysfunction.33
NEWER ANTIBIOTICS THAT PRIMARILY TARGET GRAM-NEGATIVE BACTERIA
The following sections will review cephalosporins and carbapenems.36-38
Cephalosporins
Ceftazidime/Avibactam (Avycaz): This drug combines the third-generation cephalosporin ceftazidime and the novel BL inhibitor avibactam. Ceftazidime, which is effective chiefly against gram-negative organisms (including Pseudomonas spp), binds to penicillin-binding proteins, inhibiting bacterial cell wall synthesis. Avibactam prevents the degradation of ceftazidime by inhibiting a broader range of BLs than currently available BL inhibitors.38-40 Ceftazidime/avibactam is active against many gram-negative bacteria, including those producing enzymes that can be inactivated by avibactam. These enzymes include K pneumoniae carbapenemase (KPC), AmpC BLs, and oxacillinase BLs. Ceftazidime/avibactam acts against various strains of multidrug-resistant gram-negative bacteria, such as Enterobacteriaceae, and many strains of P aeruginosa; it has little to no activity against anaerobic or gram-positive pathogens.39,40 Both ceftazidime and avibactam are excreted primarily renally, and the half-life of both is 2 to 3 hours. AEs include diarrhea, nausea, vomiting, headache, agranulocytosis, thrombocytopenia, and infusion-related reactions. The combination may increase the risk of developing Clostridioides difficile infection.39,40 Ceftazidime/avibactam is approved for treatment of infections that are caused by susceptible gram-negative bacteria, including hospital-acquired infections. The recommended adult dosage is 2.5 g IV every 8 hours. Dosage adjustment is necessary in reduced renal function. Dosing is expressed as a total dosage amount of ceftazidime plus avibactam (i.e., 2.5 g ceftazidime/avibactam contains 2 g ceftazidime + 0.5 g avibactam).39
Ceftolozane/Tazobactam (Zerbaxa): This drug combines ceftolozane, a new fifth-generation cephalosporin, with the BL inhibitor tazobactam. Ceftolozane’s bacteriocidal activity involves inhibition of bacterial cell wall synthesis. Its structure is similar to that of ceftazidime, making it effective against infections caused by various gram-negative organisms. A modified side-chain in ceftolozane’s structure may increase its activity against P aeruginosa.41,42 The addition of tazobactam appears to extend ceftolozane’s activity to include extended-spectrum BL (ESBL)-producing gram-negative organisms and adds some anaerobic activity. This makes ceftolozane/tazobactam a reasonable therapeutic alternative for multidrug‑resistant, gram‑negative bacterial infections.41-43 Ceftolozane/tazobactam’s spectrum of activity is similar to that of other third-generation cephalosporins, with increased activity against various antibiotic-resistant gram-negative organisms, including ESBL-producing Enterobacteriaceae, P aeruginosa, and Bacteroides fragilis; it has little to no activity against gram-positive organisms.41,42 Both ceftolozane and tazobactam are excreted unchanged almost entirely renally. The half-life of ceftolozane is approximately 3 to 4 hours; that of tazobactam is 2 to 3 hours. AEs include diarrhea, nausea, pyrexia (in complicated intraabdominal infections), increased liver-function tests, interstitial nephritis, thrombocytopenia, infusion-related reactions, and increased potential for C difficile infection.41 Ceftolozane/tazobactam is approved for complicated intraabdominal infections, complicated urinary tract infections (UTIs), and hospital-acquired or ventilator-associated pneumonia caused by susceptible gram-negative bacteria. The adult dosage is 1.5 g to 3 g IV every 8 hours. Dosage modification is necessary in reduced renal function.41
Cefiderocol (Fetroja): This drug’s structure is similar to that of the 3rd- and 4th-generation cephalosporins ceftazidime and cefepime. Like other cephalosporins, cefiderocol binds to penicillin-binding proteins to disrupt bacterial cell wall synthesis; however, its structure also contains a catechol group that enables it to function as a siderophore (iron-chelating molecule). As a siderophore antibiotic, cefiderocol binds extracellular free ferric iron and uses the bacterial iron-transport system to penetrate the outer lipopolysaccharide membrane in gram-negative bacteria.44 This unique dual mechanism makes cefiderocol effective against various multidrug-resistant, gram-negative organisms.44,45 Cefiderocol has a broad spectrum of activity against several gram-negative spp, including Acinetobacter, P aeruginosa, and resistant Enterobacter spp; it also may be effective against gram-negative organisms that induce resistance caused by ESBLs and carbapenemase. Cefiderocol is not effective against gram-positive bacteria.44,45 It is excreted primarily unchanged renally and has a half-life of approximately 2 to 3 hours. AEs include nausea, vomiting, diarrhea, infusion-site reactions, cough, increased liver-function tests, headache, interstitial nephritis, and increased potential for C difficile infection.44 Cefiderocol is approved for treatment of complicated UTIs and hospital-acquired or ventilator-associated pneumonia that is caused by susceptible gram-negative bacteria. The recommended dosage is 2 g IV every 8 hours. Dosage adjustment is necessary in reduced renal function.44
Carbapenems
Meropenem/Vaborbactam (Vabomere): This drug is a fixed-dose combination of the carbapenem meropenem and the new BL inhibitor vaborbactam. Carbapenems, which are bacteriocidal, bind to specific PBPs on the bacterial cell wall, resulting in cell-wall leakage and cell death. Meropenem is approved for treatment of adults with complicated and severe bacterial infections, including complicated SSTIs, intra-abdominal infections, and bacterial meningitis.46-48 Like other carbapenems, meropenem is broad-spectrum and has activity against gram-negative bacteria (including E coli, K pneumoniae, Proteus spp, and Pseudomonas spp) and some gram-positive organisms; it also acts against many anaerobic organisms.46,47 Vaborbactam inhibits several BL classes, leading to its combination with other antibiotics. Vaborbactam may reduce the minimum inhibitory concentration of several types of bacteria that can produce different BLs, including KPC-producing E coli, K pneumoniae, and Enterobacter spp, and it extends its activity against most ESBL-producing gram-negative organisms. Meropenem is excreted primarily unchanged in the urine. Meropenem’s half-life is approximately 1.5 hours, and the half-life of vaborbactam is 1 to 2 hours.46 AEs of the combination include headache, infusion-site reactions, and diarrhea; seizures and other CNS effects also can occur. Meropenem may increase the risk of developing C difficile infection.46,47 Meropenem/vaborbactam is approved for treatment of complicated UTIs, but it has also been employed for other types of infections. The recommended dosage for complicated UTIs is 4 g IV every 8 hours. Dosage adjustment is necessary in renal dysfunction. Dosing is expressed as a total dosage amount of meropenem plus vaborbactam (i.e., 4 g meropenem/vaborbactam contains 2 g meropenem + 2 g vaborbactam).46
Imipenem/Cilastatin/Relebactam (Recarbrio): This drug is another new carbapenem/BL inhibitor combination. It is similar to meropenem/vaborbactam.49
CONCLUSION
The drugs reviewed here represent some common antibiotics used in hospitals or outpatient clinics to treat infections caused by multidrug-resistant bacteria. Many of these drugs are relatively new, but some have been on the market for a longer period of time. As with all medications, HCPs should further review additional information before prescribing any of these antibiotics. Used judiciously, these antibiotics may offer lifesaving therapy for many difficult-to-treat infections.
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