Drug–Drug Interactions in Recently Approved Antibacterials: A Mini Review

Abstract

Drug–drug interactions (DDIs) pose an important concern in elderly and multimorbid patients receiving complex pharmacotherapy. The addition of antimicrobial therapy can increase DDI risk, potentially reducing therapeutic efficacy or increasing toxicity. This review evaluates pharmacokinetic DDIs associated with antibacterial agents approved between 2012 and 2024 in the European Union (EU) and UK. To this end, all studies published on recently introduced antibiotics were consulted, with a focus on cytochrome P450 (CYP450) modulation, renal transporter interactions, and their clinical implications, excluding the papers concerning pharmacodynamics and spectrum of action. A systematic search of the PubMed database and summary of product characteristics (SmPCs) was conducted using key terms such as “drug–drug interaction,” “DDI,” “antibiotic,” and “CYP450,” combined with the name of the respective antibacterial agent. Human data were prioritized, although in vitro studies were included when clinical data were unavailable. Among the evaluated agents, cefiderocol, oritavancin, and meropenem/vaborbactam showed capacity for CYP450-mediated interactions. Although most examined antibiotics carry minimal risk of CYP-mediated DDIs, interactions with renal transporters may still pose clinical concerns, particularly when coadministered with nephrotoxic drugs. In conclusion, most recently approved antibiotics have a low potential for interaction, but certain agents may carry clinically significant risks, especially in vulnerable patient populations. Oritavancin poses notable clinical concern owing to its higher degree of CYP450‑mediated interactions. Further clinical studies are warranted to validate in vitro findings to better characterize the relevance of DDIs involving these novel agents.

Key Points

Several newly approved antibiotics show potential for pharmacokinetic interactions, including those mediated by CYP450 enzymes, hepatic transporters, and other mechanisms. While CYP-mediated drug–drug interactions appear limited, renal transporter involvement may still raise concerns, especially with nephrotoxic comedications.

Introduction

Drug–drug interactions (DDIs) are a major clinical concern, particularly in patients with multiple comorbidities requiring complex pharmacotherapy. In these subjects, the addition of antibiotics to an existing complex medication regimen can increase the risk of DDIs [1]. Some antibiotics are among the most potent modulators of cytochrome P450 isoenzymes and drug transporters, meaning they can actively alter the metabolism of coadministered drugs. For example, it is known that some macrolide antibiotics are involved in numerous pharmacokinetic (PK) DDIs, primarily due to their inhibition of hepatic CYP3A enzymes. This inhibitory effect can significantly increase the exposure of several coadministered medications. Clinically relevant interactions have been documented with statins, calcineurin and mechanistic target of rapamycin (mTOR) inhibitors, benzodiazepines, digoxin, and ketamine [2]. Among these drugs, one of the most clinically important interactions concerns statins that are CYP3A4 substrates. By inhibiting CYP3A4, macrolides can markedly increase serum concentrations of statins—particularly simvastatin and lovastatin—thereby elevating the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis [2]. Beside macrolides, another example are rifamycins (rifampin, rifabutin, and rifapentine), particularly rifampin, which are strong inducers of the P450 enzyme system, leading to substantial reductions in the exposure of many coadministered drugs. DDIs have been documented with anticoagulant and antiplatelet agents, immunosuppressants, azole antifungals, hormonal contraceptives, and midazolam [2, 3]. Notably, many anticoagulant and antiplatelet agents have narrow therapeutic indices and are metabolized by CYP enzymes. As a result, coadministration with rifamycins may reduce their plasma concentrations and increase the risk of thrombotic events, whereas discontinuation of rifamycin therapy can lead to elevated drug levels and a heightened risk of bleeding [2].

Recently, it was demonstrated that rifampin decreases tazemetostat exposure by 84%, indicating that coadministration of tazemetostat with strong CYP3A inducers should be avoided [4].

In addition to CYP enzymes, transporters such as P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATPs) also play a role in clinically significant interactions [5]. In this regard, when high doses of cephalosporins are administered together with nephrotoxic agents such as aminoglycosides or potent diuretics such as furosemide, their concomitant use may increase the risk of renal impairment [6].

DDIs may reduce therapeutic efficacy or lead to toxicity and are broadly categorized into pharmacokinetic (PK) and pharmacodynamic (PD) interactions [1]. PK interactions can occur when one drug alters the absorption, distribution, metabolism, and excretion (ADME) of another, leading to changes in plasma concentrations and overall exposure [2]. These processes are influenced by both drug-specific properties and patient-specific factors such as age, organ function, and genetic background. As a result, several pharmacokinetic parameters, such as bioavailability, elimination half-life, clearance, and volume of distribution, can be affected. This is especially relevant for antibiotics that can have a narrow therapeutic index and rely on well-established pharmacokinetic–pharmacodynamic (PK–PD) relationships for clinical efficacy.

In contrast, PD interactions affect the drug’s action at its target site without altering its concentration [2]. These interactions may result in additive, synergistic, or antagonistic effects, potentially altering a drug’s efficacy or increasing its toxicity. In clinical practice, this often necessitates dose adjustments or close monitoring [2]. Particularly with drugs that have a narrow therapeutic index, even small PK or PD changes can lead to clinically relevant outcomes.

Given the complexity of modern treatment regimens and the critical importance of maintaining effective antibiotic exposure, identifying and managing clinically relevant DDIs is essential for optimizing patient outcomes. This narrative review focuses on key pharmacokinetic DDIs associated with antibacterial agents approved between 2012 and 2024.

Methods

Recently approved systemically used antibiotics were identified through a comprehensive search of the European Medicines Agency (EMA) database, including consultation of their corresponding summaries of product characteristics (SmPCs). To complement this, a systematic literature search was performed in PubMed to identify antibacterial agents authorized in the European Union or the UK between 2012 and 2024. Both original research articles and review papers were considered.

Studies focusing primarily on pharmacodynamics or antibacterial spectrum were excluded. Accordingly, antibiotics intended exclusively for topical or inhalation use, as well as generic versions of previously authorized agents, were not included.

The PubMed strategy incorporated core terms such as “drug–drug interaction,” “DDI,” “DDIs,” and “CYP450,” each combined with the name of the respective antibacterial agent. Priority was given to human clinical studies, although relevant in vitro research was also considered when human data were unavailable.

Results

Table 1 lists the antibacterial agents included in this study, along with their therapeutic indications and authorization dates by the European Medicines Agency (EMA), except for ceftobiprole, which was authorized in the UK. Table 2 summarizes the interactions of antibiotics with cytochrome P450 isoenzymes, hepatic transporters, and other transporters. Table 3 summarizes the renal clearance and known interactions of recently approved antibiotics with renal transporters.

Table 1.

Overview of antibacterial agents approved in the European Union (EU) and UK between 2012 and 2024 (relevant references are in parentheses)

Trade name	Substance(s)	Indications	Authorization date
Emblaveo	Aztreonam/avibactam	Complicated intra-abdominal infection, hospital-acquired pneumonia, complicated urinary tract infections, aerobic Gram-negative infections	22 April 2024 [7]
Exblifep	Cefepime/enmetazobactam	Complicated urinary tract infections, hospital-acquired pneumonia	21 March 2024 [8]
Fetcroja	Cefiderocol	Gram-negative bacterial infections	23 April 2020 [10]
Quofenix	Delafloxacin	Bacterial skin diseases	16 December 2019 [18]
Recarbrio	Imipenem/cilastatin/relebactam	Gram-negative bacterial infections	13 February 2020 [21]
Tenkasi	Oritavancin	Soft tissue infections, bacterial skin diseases	18 March 2015 [28]
Vaborem	Meropenem/vaborbactam	Urinary tract infections, bacteremia, bacterial infections, respiratory tract infections, pneumonia, ventilator-associated pneumonia	20 November 2018 [25]
Xenleta	Lefamulin	Bacterial pneumonia, community-acquired infections	27 July 2020 [24]
Xerava	Eravacycline	Bacterial infections	20 September 2018 [20]
Xydalba	Dalbavancin	Soft tissue infections, bacterial skin diseases	19 February 2015 [16]
Zavicefta	Ceftazidime/avibactam	Bacterial pneumonia, soft tissue infections, urinary tract infections, Gram-negative bacterial infections	23 June 2016 [6]
Zerbaxa	Ceftolozane/tazobactam	Bacterial infections	18 September 2015 [14]
Zevtera	Ceftobiprole medocaril	Bacteremia, acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia	3 April 2024 [13]
Zinforo	Ceftaroline fosamil	Community-acquired infections, infectious skin diseases, pneumonia	22 August 2012 [12]

Table 2.

Interactions of antibiotics with cytochrome P450 isoenzymes and other transporters (relevant references are in parentheses)

Drug	CYP interactions	Interactions with hepatic transporters	Other interactions
Cefiderocol	3A4a [2]	–	–
Ceftobiprole medocaril	–	OATP1B1, OATP1B3 [13]a	–
Delafloxacin	–		BCRP [18]
Eravacycline	–	OATP1B1, OATP1B3 [20]a	P-gpa [20]
Imipenem/cilastatin/relebactam	–	–	MATE1, MATE2K [21]
Lefamulin	–	OATP1B1, OATP1B3 [24]	BCRP, OCT2, MATE1 [24]
Meropenem/vaborbactam	1A2, 3A4 [25]a	–	–
Oritavancin	2C9, 2C19,3A4, 2D6 [28]	–	–

^aBased on in vitro data

OATP1B1, OATP1B3, OCT2: uptake transporters; BCRP, P-gp, MATE1/2K: efflux transporters [35]

DDIs listed are clinically confirmed

BCRP, breast cancer resistance protein; CYP, cytochrome P450; MATE, multidrug and toxin extrusion protein; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein

Table 3.

Transporter-mediated interactions and clearance profiles of antibiotics (relevant references are in parentheses)

Drug	Renal clearance	Renal transporters	Type of interaction
Aztreonam/avibactam	75–80%/83.8–100%	OAT1, OAT3a	Substrate [7]
Cefepime/enmetazobactam	85%/90%	–	No evidence of transporter-mediated renal clearance identified [8]
Cefiderocol	90.6%	–	No evidence of transporter-mediated renal clearance identified [10]
Ceftaroline fosamil	88%	–	No evidence of transporter-mediated renal clearance identified [12]
Ceftazidime/avibactam	80–90%/97%	aOAT1, OAT3	Substrate [6]
Ceftobiprole medocaril	89%	–	No evidence of transporter-mediated renal clearance identified [13]
Ceftolozane/tazobactam	95%	OAT1, OAT3a	Substrate [14]
Dalbavancin	19–33%	–	No evidence of transporter-mediated renal clearance identified [16]
Delafloxacin	50%	BCRP	Probable substrate [18]
Eravacycline	35%	–	No evidence of transporter-mediated renal clearance identified [20]
Imipenem/cilastatin/relebactam	63%/77%/90%	OAT3, OAT4	Substrate [21]
Lefamulin	9.6–14.1%	BCRP, OCT2, MATE1	Inhibitor [24]
Meropenem/vaborbactam	75–95%	OAT3	Substrate [25]
Oritavancin	5%	–	No evidence of transporter-mediated renal clearance identified [28]

^aBased on in vitro data

All listed antibiotics are administered via intravenous infusion

BCRP, breast cancer resistance protein; MATE, multidrug and toxin extrusion protein; OAT, organic anion transporter; OCT, organic cation transporter

While most interactions identified were already documented in the respective SmPCs, this likely reflects the overall low interaction potential of the agents reviewed. It is important to note that the SmPC may not capture the full spectrum of potential DDIs, particularly those identified in recent literature or mechanistic studies, highlighting the need for ongoing review and clinical vigilance.

Aztreonam/Avibactam

Aztreonam/avibactam is a novel combination to target multidrug-resistant Gram-negative pathogens, especially strains producing metallo-β-lactamases (MBL). Aztreonam is naturally stable to class B β-lactamases, while avibactam inhibits class A, C, and some D enzymes, including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase (KPC), and OXA-48 (D β-lactamases). Resistance may still occur through non-inhibited β-lactamases, altered penicillin-binding proteins (PBPs), reduced permeability, or efflux mechanisms [7].

Drug–drug interactions represent a potential consideration for aztreonam/avibactam therapy. Aztreonam/avibactam is a substrate of renal OAT1/OAT3 transporters (Table 3) and thus, its renal transport could be altered by medications that modulate (i.e., inhibit or induce) these proteins. In vitro evidence indicates that probenecid, a potent organic anion transporter (OAT) inhibitor, may significantly alter avibactam elimination, and in the absence of clinical data, coadministration should be avoided. Furthermore, the potential impact on coagulation parameters necessitates careful monitoring in patients receiving anticoagulants, underscoring the need for vigilance when aztreonam/avibactam is used in polypharmacy settings [7].

Cefepime/Enmetazobactam

Cefepime has limited activity against most Gram-positive bacteria and anaerobes. However, when combined with enmetazobactam, it gains stability against hydrolysis by class C and some class D β-lactamases, such as OXA-48. Enmetazobactam, a penicillanic acid sulfone inhibitor, protects cefepime from class A ESBLs but is ineffective against KPC, class B, and most class D enzymes [8].

Although no clinical interaction studies are available for enmetazobactam, in vitro data and its elimination profile, including the fact that it does not appear to be a substrate for common renal transport proteins, suggest a low likelihood of pharmacokinetic interactions (Table 3). As reported for some beta-lactam antibiotics, cefepime may enhance the effect of coumarin anticoagulants, increasing the risk of bleeding. This possibility makes careful monitoring of coagulation parameters essential and highlights the need for particular attention when cefepime/enmetazobactam is used in patients receiving anticoagulant therapy [8].

Cefiderocol

Cefiderocol is a novel parenteral siderophore cephalosporin and represents a unique subclass within the β-lactam antibiotics. Cefiderocol has broad-spectrum activity against aerobic Gram-negative bacteria, including multidrug-resistant (MDR) strains [9].

In vitro studies and data from two phase 1 clinical trials indicate that cefiderocol does not exhibit clinically relevant interactions with CYP450 isoenzyme substrates, inhibitors, or inducers, and it does not appear to be a substrate for common renal transport proteins, suggesting minimal involvement with renal transporters (Table 3) [10]. However, laboratory studies demonstrated that cefiderocol may induce CYP3A4 via pregnane X receptor (PXR) activation, potentially reducing the efficacy of hormonal contraceptives and affecting other PXR-regulated proteins, even though the clinical relevance of these interactions remains unclear (Table 2). However, it is advisable to use an additional contraceptive method throughout the duration of cefiderocol therapy and continue this precaution for 28 days following treatment completion [2]. If it is demonstrated that cefiderocol activates PXR in humans, there could likely be numerous potential drug interactions with this agent. Therefore, further investigations are needed to confirm this finding.

Coadministration with cefiderocol did not alter the exposures of furosemide or metformin, and although a small increase in rosuvastatin exposure was observed, it was not deemed clinically relevant. All treatments were well tolerated, supporting a low concern for meaningful PK interactions [11].

Ceftaroline Fosamil

Ceftaroline fosamil is a cephalosporin active against key resistant gram‑positive pathogens owing to its high affinity for PBP2a in methicillin-resistant Staphylococcus aureus (MRSA) and PBP2x in penicillin‑nonsusceptible S. pneumoniae. Its gram‑negative activity is limited, and it is ineffective against Enterobacterales producing ESBLs, KPC, class B metallo‑β‑lactamases, or AmpC enzymes [12].

No clinical studies investigating drug–drug interactions have been performed for ceftaroline fosamil. On the basis of in vitro data, the likelihood of ceftaroline or its prodrug interacting with medicinal products metabolized by CYP450 enzymes is considered low, as neither compound acts as an inhibitor or inducer of these pathways. Furthermore, since ceftaroline and ceftaroline fosamil are not metabolized by CYP450 enzymes, coadministration with CYP450 inducers or inhibitors is unlikely to alter ceftaroline pharmacokinetics. In vitro findings also indicate that ceftaroline is neither a substrate nor an inhibitor of the renal uptake transporters OCT2, OAT1, and OAT3 (Table 3); therefore, interactions with drugs that utilize or inhibit these transporters, such as probenecid, are not expected [12].

Ceftazidime/Avibactam

Ceftazidime/avibactam, marketed as Zavicefta, is a fixed-dose combination of a third-generation cephalosporin and a non-β-lactam β-lactamase inhibitor. Ceftazidime inhibits bacterial cell wall synthesis by binding to PBPs, while avibactam protects ceftazidime from degradation by forming a stable covalent complex with serine β-lactamases. Ceftazidime/avibactam exhibits potent activity against a broad range of Gram-negative pathogens [6].

While ceftazidime/avibactam does not interact with the cytochrome P450 enzyme system in vitro, it is an in vitro substrate for renal transporters such as OAT1 and OAT3, suggesting the potential for renal transporter-mediated drug interactions (Table 3). Caution is warranted when high doses of cephalosporins are used concurrently with nephrotoxic agents such as aminoglycosides or potent diuretics (e.g., furosemide), as this combination may increase the risk of renal impairment [6].

Ceftobiprole Medocaril

Ceftobiprole is a cephalosporin that exerts a bactericidal effect by binding to key PBPs in susceptible bacteria, including PBP2a in MRSA and altered PBPs in resistant Streptococcus pneumoniae and Enterococcus faecalis. However, it is inactive against Enterobacteriaceae-producing class A ESBLs (e.g., TEM, SHV, CTX-M), class B and D β-lactamases (including KPC and OXA-48), and strains with high expression of class C β-lactamases. It is used for the treatment of infections caused by Gram-positive and Gram-negative pathogens [13].

Although in vitro studies on ceftobiprole’s interaction with cytochrome P450 enzymes were limited owing to its low solubility, CYP-mediated drug–drug interactions cannot be fully ruled out, according to the SmPC. Furthermore, ceftobiprole has been shown to inhibit the hepatic transporters organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3) in vitro (Table 2), suggesting a potential to increase plasma concentrations of transporter substrates such as certain statins (pitavastatin, pravastatin, rosuvastatin), glyburide, and bosentan. Conversely, ceftobiprole does not appear to be a substrate for common renal transport proteins, indicating a low likelihood of renal transporter-mediated interactions (Table 3). In the absence of dedicated clinical pharmacokinetic interaction studies, caution is advised when coadministering ceftobiprole with drugs that have a narrow therapeutic index [13].

Ceftolozane/Tazobactam

Ceftolozane is a cephalosporin antibiotic, while tazobactam, a β-lactam compound structurally related to penicillins, functions as an inhibitor of several class A β-lactamases, enhancing the antimicrobial efficacy of ceftolozane against β-lactamase-producing pathogens. These two active components are coformulated in the fixed-dose combination known as Zerbaxa. The combination exhibits a broad spectrum of activity against both Gram-negative and certain Gram-positive bacteria [14].

On the basis of both in vitro and in vivo studies, ceftolozane does not exhibit significant effects on CYP450 enzyme activity. Consequently, the potential for clinically relevant drug–drug interactions mediated through the CYP450 pathway is considered negligible. Tazobactam is an in vitro substrate of the renal transporters OAT1 and OAT3 (Table 3); therefore, coadministration with inhibitors of these transporters, such as probenecid, may lead to elevated plasma concentrations of tazobactam, and caution is warranted owing to the potential for altered pharmacokinetics [14]. Data from phase I studies suggest a decrease in dose and frequency of administration of ceftolozane/tazobactam for patients with moderate or severe renal impairment [15].

Dalbavancin

Dalbavancin is a bactericidal lipoglycopeptide that exerts its activity against susceptible Gram-positive organisms by inhibiting peptidoglycan cross-linking during cell wall synthesis. Gram-negative bacteria are intrinsically resistant to dalbavancin [16].

It remains uncertain whether dalbavancin is a substrate of hepatic uptake and efflux transporters. If this is the case, then coadministration with known inhibitors of these transporters such as human immunodeficiency virus (HIV) protease inhibitors, verapamil, quinidine, itraconazole, clarithromycin, and cyclosporine could lead to increased systemic exposure to dalbavancin. Furthermore, the possibility that dalbavancin administration may enhance the systemic exposure of transporter substrates, including statins and digoxin, cannot be ruled out [17]. No clinical trials have been performed to determine the potential for drug–drug interactions with dalbavancin; however, in vitro data indicate that dalbavancin is not metabolized by cytochrome P450 enzymes and is not recognized as a substrate of major renal transporters, suggesting a minimal risk of drug interactions mediated by these pathways (Table 3) [16].

Delafloxacin

Delafloxacin, a fluoroquinolone-class antibiotic, inhibits bacterial DNA gyrase and topoisomerase IV, exhibiting broad-spectrum activity against both Gram-positive and Gram-negative organisms. While cross-resistance with other fluoroquinolones may occur, some resistant isolates may retain susceptibility to delafloxacin [18].

Caution is warranted when administering oral delafloxacin concomitantly with products containing divalent or trivalent cations such as antacids with aluminum or magnesium, sucralfate, iron supplements, or multivitamins with iron or zinc. These agents can significantly reduce the absorption of delafloxacin, leading to subtherapeutic systemic concentrations. To minimize this interaction, delafloxacin should be administered at least 2 h before or 6 h after such products [18]. According to the SmPC, delafloxacin is a probable substrate of breast cancer resistance protein (BCRP) (Tables 2, 3) [18]. BCRP efflux transporters are found in several key organs involved in drug disposition, including the intestine, brain, liver, and kidneys. BCRP inhibition is listed as a potential mechanism of a DDI. Evaluating DDIs related to BCRP inhibition at the liver and kidney is particularly important, especially for intravenously administered substrates or inhibitors. It has been reported that BCRP may also contribute to the biliary clearance of certain drugs, such as rosuvastatin. Although clinical evidence supporting BCRP’s role in the renal clearance of substrate drugs is limited, consistent with its low expression in the human kidney cortex, the absence of such evidence does not rule out potential drug–drug interactions. This is because changes in drug concentrations within liver or kidney cells may not always be reflected in systemic blood level [19].

Eravacycline

Eravacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit, thereby blocking peptide chain elongation. Its unique chemical modifications, not found in other tetracyclines, contribute to its sustained in vitro efficacy against both Gram-positive and Gram-negative bacteria, including strains harboring common tetracycline resistance mechanisms [20].

Eravacycline has been identified in vitro as a substrate for the transport proteins P-glycoprotein (P-gp), OATP1B1, and OATP1B3 (Table 2). This suggests a potential for pharmacokinetic interactions in vivo, particularly when eravacycline is administered alongside agents that inhibit these transporters. Drugs such as atazanavir, cyclosporine, lopinavir, and saquinavir—known inhibitors of OATP1B1 and OATP1B3—may enhance systemic exposure to eravacycline by increasing its plasma concentration. Furthermore, eravacycline is not a known renal transporter substrate, and its metabolites do not inhibit or induce CYP enzymes or transporters, making drug interactions via these pathways unlikely (Table 3) [20].

Imipenem/Cilastatin/Relebactam

Recarbrio is a fixed-dose combination consisting of imipenem, cilastatin, and relebactam. Imipenem, a β-lactam antibiotic of the carbapenem subclass, shares the core mechanism of action characteristic of β-lactams. Cilastatin inhibits renal dehydropeptidase-I, thereby preventing the degradation of imipenem in the kidneys and prolonging its systemic activity, despite having no intrinsic antibacterial properties. Relebactam is a non-β-lactam β-lactamase inhibitor active against class A and class C enzymes, including ESBLs, KPC, and AmpC-type enzymes. Although it lacks intrinsic antibacterial activity, it enhances the efficacy of imipenem by protecting it from enzymatic degradation. Recarbrio exhibits a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, including multidrug-resistant Enterobacterales-producing class A carbapenemases (such as KPC and ESBLs), as well as Pseudomonas aeruginosa and common Gram-positive pathogens such as methicillin-sensitive Staphylococcus aureus and Enterococcus faecalis [21].

Imipenem/cilastatin/relebactam is not associated with clinically meaningful interactions involving the CYP450 enzyme system. Nonetheless, relebactam serves as a substrate for transporters such as OAT3, OAT4 (Table 3), MATE1, and MATE2K (Table 2). Despite this, inhibition of these tubular transporters is considered to have minimal clinical impact, a conclusion supported by data from a drug interaction study conducted with probenecid and imipenem/cilastatin/relebactam. Conversely, the combined use of valproic acid or divalproex sodium with imipenem/cilastatin/relebactam is discouraged owing to the risk of decreased anticonvulsant effectiveness in patients taking these medications. Notably, the carbapenem antibiotic could block the enterohepatic recycling of valproic acid. Hence, the glucuronide conjugate of valproic acid does not get converted back to valproic acid in the gut, and valproic acid concentrations in the plasma are significantly reduced (and the risk of seizures increases precipitously). For patients whose seizures are well-managed with these therapies, alternative antibacterial options should be explored. If imipenem/cilastatin/relebactam is considered essential, additional anticonvulsant measures may be necessary [21].

Special Considerations

A recent study demonstrated that Jinhongtang (traditional Chinese medicine) enhances the antibacterial efficacy of imipenem/cilastatin in a Staphylococcus aureus-induced mouse sepsis model by inhibiting renal organic anion transporters (OATs), thereby reducing imipenem clearance [22]. However, further clinical studies are warranted to validate its potential as an adjuvant therapy. Li et al. [23] combined computational and experimental approaches to develop a compound‑pair method supporting clinical decisions on using XueBiJing with antibiotics in sepsis. Their findings indicate that combining imipenem with XueBiJing induces ALDH inhibition. Monitoring plasma levels of the active compounds of XueBiJing is critical to optimizing combination therapy, thereby minimizing adverse effects and maximizing clinical efficacy [23].

Lefamulin

Lefamulin is a novel pleuromutilin antibiotic approved for systemic use in humans. It inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit, interfering with transfer RNA (tRNA) positioning. Lefamulin shows potent activity against Gram-positive pathogens, including MRSA, atypical bacteria, and some Gram-negative organisms. Resistance to lefamulin mainly involves ribosomal modifications and cross-resistance with other pleuromutilins, while it remains active against bacteria resistant to many other antibiotic classes; intrinsic resistance occurs in Enterobacterales and some nonfermenting Gram-negative species [24].

Lefamulin should not be used together with drugs that are highly dependent on CYP2C8 for metabolism—such as repaglinide—because it can raise their blood levels and increase the risk of side effects [24]. Since clinical studies investigating drug interactions between lefamulin and substrates of renal transporters have not yet been conducted, in vitro data show that lefamulin inhibits several transporters, including OATP1B1, OATP1B3 (Table 2), BCRP, OCT2, and MATE1 (Tables 2, 3). As a result, caution is advised when lefamulin is coadministered with sensitive substrates of these transporters, particularly those with a narrow therapeutic index [24].

Meropenem/Vaborbactam

The combination of meropenem, a broad-spectrum carbapenem antibiotic, with vaborbactam, a non-β-lactam inhibitor of class A and class C serine β-lactamases, constitutes the formulation known as Vaborem, designed to enhance meropenem activity against resistant Gram-negative pathogens, particularly KPC-producing Enterobacterales while retaining its intrinsic efficacy against selected Gram-positive organisms [25].

Meropenem/vaborbactam in vitro induces CYP3A4, the enzyme responsible for the metabolism of a wide range of drugs (Table 2). Although no clinically relevant induction has been reported, caution is warranted when the antibiotic is administered concomitantly with medicinal products primarily metabolized by CYP3A4 owing to the potential for pharmacokinetic interactions. This includes a possible reduction in the effectiveness of hormonal contraceptives containing estrogen and/or progestin [25].

Statins such as simvastatin, lovastatin, and atorvastatin are substrates of the CYP3A4 enzyme. Coadministration with agents that induce (e.g., meropenem/vaborbactam) these pathways may lead to altered plasma concentrations, potentially impacting the efficacy and/or increasing the risk of toxicity [26]. Since meropenem/vaborbactam in vitro also induces CYP1A2 (Table 2), caution is warranted when coadministering the antibiotic with drugs that are substrates of this enzyme, such as phenacetin, caffeine, clozapine, tacrine, propranolol, and mexiletine [27], as well as drugs with a narrow therapeutic range, for example, theophylline and R-warfarin. However, meropenem/vaborbactam has not been established as a clinically meaningful inducer in humans. Both meropenem and vaborbactam are OAT3 substrates (Table 3), and coadministration with probenecid may inhibit their renal excretion, leading to increased plasma concentrations. Therefore, the use of probenecid with Vaborem is not recommended. Finally, concomitant administration of meropenem and valproic acid has been associated with marked reductions in valproic acid concentrations, potentially leading to loss of seizure control [25].

Oritavancin

Oritavancin is a lipoglycopeptide antibiotic that has broad-spectrum Gram-positive coverage. This antibiotic exerts its antibacterial activity through a multifaceted mechanism of action, involving the inhibition of transglycosylation and transpeptidation steps in cell wall biosynthesis, as well as the disruption of bacterial membrane integrity, ultimately leading to membrane depolarization, increased permeability, and rapid bacterial cell death. Oritavancin has been identified as a weak and nonspecific inhibitor of CYP2C9 and CYP2C19 or as a weak inducer of CYP3A4 and CYP2D6 (Table 2) [28]. Therefore, oritavancin may inhibit CYP2C9, potentially interfering with the metabolism of certain oral antidiabetic agents, particularly sulfonylureas such as glipizide and glyburide. This interaction is clinically relevant since it can lead to increased plasma concentrations of these drugs, thereby elevating the risk of hypoglycemia [29]. Hypoglycemia is a common but serious adverse effect that can result in mortality. Therefore, close monitoring of blood glucose levels is recommended during coadministration, and dose adjustments of the antidiabetic therapy may be required. Warfarin is a racemic mixture of R- and S-warfarin, and S-warfarin is the most potent anticoagulant. S-warfarin is metabolized by CYP2C9 (which is weakly inhibited by oritavancin). R-warfarin is the weaker anticoagulant (compared to S-warfarin), and it is metabolized by CYP1A2 and CYP3A4 (which may be induced by oritavancin). Hence, an interaction between warfarin and oritavancin could go in either direction (net induction or net inhibition). Since it would be nearly impossible to predict the net effect of this interaction, patient international normalized ratios (INRs) should be monitored closely when they receive this drug combination. Clinicians are required to increase the frequency of coagulation monitoring to reduce the risk of adverse outcomes [30]. Additionally, preliminary evidence indicates that combining CYP2D6 inhibitors with enzyme inducers is clinically important owing to the catastrophic inhibition of tamoxifen efficacy, potentially increasing the risk of cancer recurrence. Therefore, caution is advised when prescribing such combinations, particularly when using CYP2D6 inducers such as oritavancin [31].

A not so relevant interaction is between oritavancin (an inhibitor of CYP2C19) and abrocitinib (a Janus kinase 1-selective inhibitor) used for moderate-to-severe atopic dermatitis. Coadministration of both drugs may increase systemic exposure to abrocitinib. Since abrocitinib exposure is significantly affected by strong CYP2C19 inhibitors, a 50% dose reduction is recommended when used concomitantly. Therefore, caution is warranted to avoid potential toxicity [32].

Noteworthy, drugs that inhibit CYP2C19, such as oritavancin, are likely to prevent the formation of the active moiety of clopidogrel (a pro-drug), making it unlikely for the drug to exert effective antiplatelet activity.

Finally, from a renal interaction perspective, oritavancin does not appear to be a substrate of known renal transporters (Table 3).

Discussion and Conclusions

The antibiotics reviewed in this study generally exhibit a limited profile of pharmacological interactions, especially with regard to hepatic metabolism. While some in vitro studies suggest potential DDIs, clinical confirmation remains limited for the time being. Oritavancin and meropenem/vaborbactam represent notable exceptions, as they show a higher propensity for CYP450-mediated interactions. In contrast to oritavancin, clinical studies have demonstrated that telavancin, a member of an older generation of lipoglycopeptide antibiotics, does not exhibit clinically relevant interactions [33]. Likewise, unlike delafloxacin, which belongs to the fluoroquinolone class, several older fluoroquinolones—such as levofloxacin, ciprofloxacin, and moxifloxacin—display clinically significant interactions with simvastatin, atorvastatin, and tizanidine, leading to hypokalemia and subsequent arrhythmias through inhibition of CYP450 isoenzymes [34].

Future research should focus on in-depth clinical studies, advanced physiologically based pharmacokinetic (PBPK) modelling, and improved electronic prescribing alerts to better define the real‑world relevance of pharmacokinetic drug–drug interactions involving newly approved antibiotics, particularly in vulnerable patient populations.

Funding

Open access funding provided by Medical University of Vienna. None.

Declarations

Conflict of interest

The authors have no conflicts of interest.

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Code availability

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Author contributions

MZ developed the concept and outline for the review; IB searched the articles and extracted data; FB edited the manuscript; all authors wrote the manuscript and read and approved the final version.