Pharmacology of Drugs Used in Hematopoietic Cell Transplant and Chimeric Antigen Receptor Therapies

Fluoroquinolones

Fluoroquinolones are some of the most frequently used antibiotics and have long been preferred prophylactic agents in the HCT setting. The most commonly used quinolones in HCT and IEC are ciprofloxacin and levofloxacin.

The hallmark of the quinolone structure is a bicyclic ring with a fluorine atom at position 6, which facilitates entry into the bacterial cell and enhances its bactericidal activity. Fluoroquinolones inhibit deoxyribonucleic acid (DNA)-gyrase (topoisomerase II) and topoisomerase IV, enzymes that are essential for bacterial DNA replication. Favorable qualities of this drug class include high oral bioavailability and a broad spectrum of activity.

The oral bioavailability of levofloxacin is comparable to that of intravenous administration of these agents, with a bioavailability of 99%. Ciprofloxacin has an oral bioavailability of around 70% in adults. Levofloxacin has a long half-life, which facilitates convenient once daily dosing. Initial dosing of levofloxacin ranges between 500 and 750 mg daily depending on indication for use. Ciprofloxacin is a substrate of OAT1/3 and P-glycoprotein/ABCB1, a weak inhibitor of CYP3A4 and moderate inhibitor of CYP1A2. Notably, concurrent administration of multivalent cations (i.e., sucralfate, magnesium, antacids, etc.) and oral quinolones should be avoided because these agents form complexes, which impairs absorption of the quinolone. It is recommended to separate administration of these agents by at least 2 hours.

The relatively short half-life of ciprofloxacin requires twice-daily dosing. Initial dosing of oral ciprofloxacin ranges between 500 and 750 mg every 12 hours depending on indication for use. Oral to intravenous conversion of ciprofloxacin is not interchangeable, intravenous ciprofloxacin is dosed 400 mg every 8 to 12 hours depending on the indication. Ciprofloxacin and levofloxacin must be dose adjusted in renal impairment.

Older-generation fluoroquinolones mainly cover gram-negative bacteria, including Pseudomonas species, which is an ideal characteristic in prophylactic agents in neutropenic patients. Ciprofloxacin, a second-generation quinolone, is primarily active against gram-negative bacteria with little activity against gram-positive organisms. Levofloxacin, a third-generation quinolone, has improved gram-positive coverage including Staphylococcus and Streptococcus species, with slightly less activity against Pseudomonas compared to ciprofloxacin. Quinolones often display a postantibiotic effect, inhibiting bacterial growth even after the drug concentration falls below the minimum inhibitory concentration (MIC). They are used to treat a wide variety of infections because of their excellent tissue penetration.

Fluoroquinolones are generally well tolerated. The most common adverse effects are headache, gastrointestinal (GI) upset, insomnia, rash, photosensitivity, and dizziness. Quinolones are known to prolong the QT interval and increased monitoring is recommended in patients with other risk factors for QT prolongation. A rare but serious side effect of fluoroquinolones is tendon rupture and tendinopathy, which is a boxed warning in the prescribing information for these agents. Fluoroquinolones should be used with caution in patients with risk factors for tendon rupture (older age, renal dysfunction, athletic activity while on corticosteroids, etc.) and should be discontinued and not rechallenged should this serious adverse effect occur.

Cephalosporins

Cephalosporins are often used for the treatment of infection and neutropenic fever. Third-generation oral cephalosporins, like cefpodoxime, are occasionally used for bacterial prophylaxis when use of a fluoroquinolone may not be appropriate (i.e., allergy or intolerance). The most commonly used cephalosporins in the transplant setting are cefepime and ceftazidime.

Cephalosporins are β-lactam antibiotics. Their structure differs from that of penicillins because the β-lactam ring is connected to a six-membered dihydrothiazine ring instead of a five-membered thiazolidine ring. This structure makes cephalosporins less reactive to nucleophilic addition or hydrolysis. The mechanism of action of cephalosporins, like other β-lactams, is inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), which inhibits peptidoglycan synthesis in bacterial cell walls, leading to cell death. β-lactam antibiotics are usually bactericidal toward bacteria they have activity against.

Cephalosporins are useful antibiotics because of their broad spectrum of activity. Third-generation cephalosporins have extended gram-negative coverage and limited gram-positive coverage compared to earlier generations. Ceftazidime covers Pseudomonas unlike some other third-generation cephalosporins. Importantly, ceftazidime has variable activity against viridans streptococci. Patients with severe mucositis on fluoroquinolone bacterial prophylaxis are at an increased risk of viridans streptococci bacteremia. In these cases, if ceftazidime is being used, prompt addition of a gram-positive agent like vancomycin may be necessary.

Of note, ceftazidime-avibactam is a novel antibiotic that consists of a cephalosporin and β-lactamase inhibitor. The result is broadened coverage against β-lactamase producing gram-negative bacilli. Ceftazidime-avibactam is a potential alternative in the setting of resistance and its use should be reserved only for such circumstances. Cefepime, a fourth-generation cephalosporin, offers the same gram-negative activity as ceftazidime, including Pseudomonas coverage, and increased gram-positive activity. Cefepime is commonly used as monotherapy for the treatment of neutropenic fever. Table 11.1 summarizes dosing, administration, and adverse effects for commonly used cephalosporins in the transplant setting.

Carbapenems

Carbapenems have the most robust activity of all β-lactam antibiotics and are typically reserved for use in critically ill patients or when the presence of resistant bacteria is suspected. The hallmark structure of a carbapenem is the 4:5 penicillin lactam ring with a double bond between C-2 and C-3 and the substitution of carbon for sulfur at the C-1 position. This structure confers resistance to hydrolysis by most β-lactamases.

The mechanism of action of carbapenems is the same as other β-lactam antibiotics previously described. The carbapenems currently available in the United States are imipenem-cilastatin, meropenem, and ertapenem. Carbapenems have a broad spectrum of activity against both gram-positive and gram-negative bacteria as well as anaerobic bacteria. Methicillin-resistant Staphylococcus aureus and Enterococcus faecium have intrinsic resistance to carbapenems. Importantly, ertapenem has no activity against Pseudomonas , unlike the other carbapenems and is an unsuitable choice for empiric treatment of neutropenic fever.

Imipenem undergoes rapid degradation in vivo by dehydropeptidase (DHP-1) found in the kidneys and therefore has to be combined with a DHP-1 inhibitor, cilastatin, which prevents imipenem from being inactivated as well as reduces the nephrotoxicity associated with toxic metabolites. The other carbapenems are resistant to renal DHP-1 metabolism. Carbapenems are generally well tolerated; however, they have been associated with the rare but serious side effect of seizures. Table 11.2 outlines the adverse effect profile of these agents as well as other pertinent clinical information.

Given the indispensable role carbapenems have in the treatment of serious infections, carbapenem resistance is a critical problem worldwide. Mechanisms of resistance against carbapenems include the development of mutations that change functions or expression of porins and PBPs, overexpression of efflux pumps, and β-lactamase or carbapenemase production. Continued vigilance and antimicrobial stewardship are necessary to preserve the clinical utility of carbapenems.

Piperacillin-Tazobactam

Piperacillin is a semisynthetic ureidopenicillin, which is the result of adding a ureido group plus a piperazine side chain to the ampicillin molecule. The mechanism of action of piperacillin, like all β-lactams, is inhibition of bacterial cell wall synthesis by binsding to penicillin-binding proteins, which inhibits peptidoglycan synthesis in bacterial cell walls, leading to cell death. Piperacillin is combined with the β-lactamase inhibitor, tazobactam, which confers a broader spectrum of activity.

Piperacillin-tazobactam is active against many gram-positive and gram-negative bacteria as well as anaerobes. It is unique among other available penicillins because it has activity against Pseudomonas , which makes it an option for empiric treatment of neutropenic fever. Dosing for neutropenic fever and severe infections is 4.5 grams intravenously (IV) every 6 hours.

Like most β-lactams, piperacillin-tazobactam achieves good tissue penetration and can be used to treat a variety of infections. It is well tolerated with the most common adverse effects being diarrhea, nausea, and headache. Piperacillin-tazobactam can be neurotoxic, especially in the setting of renal impairment, although to a lesser degree than penicillin. It is primarily excreted as unchanged drug in the urine. Its clearance is directly proportional to renal function and must therefore be dose adjusted in renal impairment. Acute kidney injury is well documented with concurrent use of piperacillin-tazobactam and vancomycin. Caution should be used when using these agents together.

Vancomycin

Vancomycin is a tricyclic glycopeptide that binds to D-alanyl-D-alanine and inhibits polymerization of peptidoglycans within the bacterial cell wall, which is a late-stage process of cell wall synthesis. It is bactericidal against most gram-positive organisms, bacteriostatic against enterococci, and has no activity against gram-negative organisms. Vancomycin is poorly absorbed via the GI tract, making oral vancomycin inappropriate for the treatment of systemic infections but useful for the treatment of Clostridium difficile colitis. Intravenous vancomycin is used to treat a variety of infections given its activity against gram-positive bacteria. There is increasing resistance to vancomycin among enterococci and resistance among other gram-positive bacteria is rare but concerning. Antimicrobial stewardship can safeguard the future of vancomycin and its critical role in the treatment of infection especially in the HCT population.

Vancomycin has a concentration-independent killing effect where the primary predictor of efficacy is the area under the curve (AUC) divided by the MIC, meaning that peak levels are not as important as the time over the MIC. The goal of therapeutic drug monitoring is to account for interpatient variability and to reduce toxicity. Historically, trough levels of vancomycin have been used as a surrogate marker for AUC, with goal troughs ranging between 10 and 15 mcg/mL for most infections and 15 and 20 mcg/mL for infections in areas with poor tissue penetration. Trough levels greater than 15 mcg/mL have been associated with greater risk of nephrotoxicity. Therapeutic drug monitoring utilizing AUC/MIC has been studied for the treatment of methicillin-resistant S. aureus . Achieving an AUC/MIC greater than or equal to 400 mg*h/L has been associated with improved outcomes and reduced resistance; however, further research is necessary to be able to apply this goal to other organisms. AUC-driven dosing of vancomycin has been associated with less nephrotoxicity compared to trough-based dosing, primarily because of reduced vancomycin exposure.

Vancomycin is renally eliminated and increased monitoring and dose adjustments are necessary in renal impairment. The risk for nephrotoxicity with vancomycin is associated with patient age, duration of therapy, high troughs/AUCs, and concomitant use with other nephrotoxic agents like piperacillin-tazobactam and aminoglycosides. Other adverse effects include ototoxicity, which may present as tinnitus (historically caused by impurities in early forms of vancomycin), as well as neutropenia, and thrombocytopenia. Vancomycin infusion reactions may occur, including its hallmark reaction characterized by an erythematous rash, flushing, and pruritus. This reaction, caused by rapid infusion of large vancomycin doses, usually resolves with stopping the infusion and slowing down the infusion rate. Premedications, like diphenhydramine, may also be used for this reaction.

Trimethoprim-Sulfamethoxazole

Sulfamethoxazole (SMX) is a sulfonamide that works sequentially and synergistically with trimethoprim (TMP) to inhibit bacterial folate synthesis. SMX inhibits dihydrofolic acid and stops the formation of tetrahydrofolic acid (THF) whereas TMP prevents the formation of THF by binding to dihydrofolate reductase. THF is necessary for bacterial DNA synthesis. The synergistic effects of using SMX with TMP (SMX-TMP) enhances the bactericidal effect of both agents.

SMX-TMP has a broad spectrum of activity against both gram-positive and gram-negative bacteria. While predominantly used in the HCT setting for Pneumocystis jirovecii pneumonia (PJP) prophylaxis, SMX-TMP also covers a variety of organisms that can affect HCT recipients and other immunocompromised patients like Toxoplasma gondii , Stenotrophomonas maltophilia , Norcardia species, and Burkholderia cepacia .

SMX-TMP may be given orally or IV. It undergoes rapid absorption with greater than 90% bioavailability and is excreted via the urine. Dose adjustment is required in renal impairment. Importantly, dosing of SMX-TMP is based on the TMP component. PJP prophylaxis dosing of SMX-TMP may either be a single-strength tablet (400 mg/80 mg SMX/TMP) daily or a double-strength tablet (800 mg/160 mg SMX/TMP) three times weekly.

SMX-TMP is a selective CYP2C9 inhibitor and may increase the serum concentration of phenytoin and the anticoagulant effect of vitamin K antagonists. It also may contribute to methotrexate bone marrow suppression through its folic acid antagonist activity and by inhibiting renal excretion of methotrexate. Common adverse effects include GI upset, rash, and hyperkalemia. Rare but serious adverse effects include toxic epidermal necrolysis, Stevens-Johnson syndrome, agranulocytosis, hemolytic anemia, and thrombocytopenia. The hematologic adverse effects of SMX-TMP are of particular concern in the HCT setting, which may limit the use of this agent early posttransplant.

Other notable antimicrobial agents used in the HCT setting are summarized in Table 11.3 .

Triazoles

Triazole antifungal agents are widely used in the HCT setting for both prophylaxis and treatment of fungal infections. They inhibit lanosterol 14α-demethylase, which then impairs synthesis of a critical component of the fungal cell membrane, ergosterol, leading to fungal growth arrest. Table 11.4 provides a summary of commonly used triazole antifungals in HCT: fluconazole, posaconazole, voriconazole, and isavuconazonium sulfate (water soluble prodrug of isavuconazole). Triazoles are generally well tolerated; however, toxicities and spectrum of activity differ depending on the agent. Most triazoles are hepatically metabolized and are associated with many major drug interactions. Common triazole drug interactions with HCT medications are listed in Table 11.5 .