Tigecycline as Therapeutic Choice in the Treatment of Infections Caused by Multidrug-Resistant Organisms - A Mini Review

Introduction

Tigecycline is an antibacterial agent of the tetracycline series, primarily used for treating polymicrobial multidrug-resistant infections resistant to both Gram-negative and Gram-positive bacteria. Tigecycline, also known as GAR-936 or Tygacil, is the first and distinct semisynthetic agent of the glycylcycline class which was approved for parenteral use by the Food and Drugs Administration (FDA) in the year 2005. In 2010, however, the FDA had to issue a warning regarding tigecycline use due to findings that its administration for the treatment of severe infection and sepsis was related to increased all-cause mortality. Currently, tigecycline is approved as a monotherapy for treating adult patients with three conditions, which include community-acquired pneumonia (CAP), complicated skin and soft tissue infections (cSSTI) and complicated intra-abdominal infections (cIAI). Current evidence suggests that it could also aid in the treatment of acute Clostridium difficile infection (European Medicines Agency, 2014).¹  Despite its official indications, however, the clinical use of tigecycline was rather unsystematic encompassing treatment for pulmonary infections, bloodstream infections, and infections caused by multidrug-resistant (MDR) bacteria, as patients do not adhere to clinical protocols. Confusion has arisen from its use not only within the approved indications but also in severe cases of respiratory or blood infections, whether administered alone or in combination with other agents, at either the conventional 50 mg twice daily dose or the high dose (HD) 100 mg twice a day regimen, in community-acquired (CA), healthcare-associated (HCA), and hospital-acquired (HA) infections. As a result, the two most recent sources highlight concerns about increased mortality and associated warnings, based on several meta-analyses conducted across various patient groups, including those with hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), diabetic foot infections, infections with multi-drug resistant (MDR) bacteria and shock (FDA, 2010; European Medicine Agency, 2011; European Medicines Agency, 2014).² The rising prevalence of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria poses an important public health problem, placing significant financial strain on the healthcare system, due to extended hospital stays and increased morbidity and mortality.¹ Antimicrobial resistance is particularly concerning in K. pneumoniae, where resistance to both carbapenems and colistin has emerged, resulting in an alarming trend due to the limited treatment options. Tigecycline was subsequently recommended for managing carbapenem- and colistin-resistant K. pneumoniae (C-C-RKP) infections, as it was considered one of the last-resort antibiotics. However, a growing number of tigecycline-resistant cases have since been recorded.³

Pharmacokinetics and Pharmacodynamics

Tigecycline is an IV-administered antibiotic, dosed every 12 hours due to its poor oral absorption. It exhibits nonlinear plasma protein binding (71%-96%), an extensive volume of distribution (7-10 L/kg), and a prolonged half-life (27-42 hours), with a clearance rate of 0.2-0.3 L/h/kg. Tigecycline is mainly excreted through bile (59% feces, 22% urine). Treatment periods range between 5 - 14 days for soft tissue infections (cSSTI) or severe skin and intra-abdominal infections (cIAI), and 7 - 14 days for community-acquired pneumonia (CAP). The recommended dosage is 100 mg initially, followed by 50 mg every 12 hours. Tigecycline demonstrates good tissue penetration, particularly in the lungs, liver, and bones; however, it has poor blood-brain barrier permeability. Dosage adjustment based on age, or gender is not required. However, in severe hepatic impairment (Child-Pugh C), the maintenance dose should be reduced to 25 mg every 12 hours after the initial 100 mg dose. Its efficacy depends on achieving a favorable AUC/MIC ratio.³ 

Mechanism of Action

Tigecycline is a parenteral glycylcycline antibiotic with bacteriostatic activity. It is structurally similar to tetracyclines, with a five-fold higher binding affinity. Tigecycline inhibits bacterial protein translation, or elongation of the peptide chain, by reversibly binding to a helical area (H34) on the 30S subunit of bacterial ribosomes. The mechanism of action is similar to the other essential tetracyclines. By preventing the elongation of chains with the addition of amino acid residues, tigecycline binding inhibits bacteria from producing peptides, thereby suppressing its growth. Tigecycline is synthesized by adding a glycyclamide group to the minocycline 9-position. This modification was an attempt to bypass the fundamental molecular mechanisms of tetracycline resistance: ribosome protection and tetracycline specific efflux pump acquisition.^1,4

Antibacterial Activity

The antibacterial spectrum of tetracycline was broadened by modifying its skeletal structure against a variety of Gram-positive and Gram-negative organisms. It is used as a last resort in the treatment of MDR bacterial infections, particularly carbapenem-resistant Enterobacteriaceae, due to its efficacy. Tigecycline indicated significant efficacy against methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, and PRSP. Furthermore, Tigecycline demonstrated potent activity against Neisseria gonorrhoeae, Haemophilus influenzae, Moraxella catarrhalis, and Stenotrophomonas maltophilia. It has also been demonstrated that tigecycline is active against Rickettsia rickettsii and Coxiella burnetii, isolated from patients with acute Q fever. Clinical data show that tigecycline, used either as monotherapy or in combination with oral vancomycin and intravenous metronidazole is effective in treating patients with severe C.difficile infection (CDI). A.baumannii, K.pneumoniae, Enterobacter spp., Bacteroides fragilis, and other bacteria have been documented to develop acquired resistance to tigecycline. However, some bacteria, including Morganella spp., Providencia spp., P. aeruginosa, and Proteus spp. exhibit inherent resistance to tigecycline.¹

Mechanisms of Tigecycline Resistance

Tigecycline resistance has been reported in the recent years from different parts of the world and a few studies have delved into understanding its resistance mechanism.

Acinetobacter baumannii

Although certain studies suggested that additional efflux pumps or other molecular mechanisms might be responsible for tigecycline resistance, the overexpression of AdeABC, AdeFGH, AdeIJK, AbeM, and AdeDE pumps along with the presence of tetX gene was associated with the development of high resistance and greater minimum inhibitory concentrations (MICs) to tigecycline in Acinetobacter spp. The change in nucleotide and amino acid in the AdeRS two-component system might result in overexpression of adeABC and tigecycline resistance. Further, the BaeSR system was shown to cause tigecycline-resistant strains and function as a positive regulator of adeA and adeB expresses. Other mechanisms contributing to decreased tigecycline susceptibility include the emergence of a new RND pump, the presence of tet(X1) or tetA genes, and mutations in the trm gene, which is involved in the S-adenosyl-L-methionine (SAM)-dependent methyltransferase process. Additionally, the clinical isolates of A. baumannii have been found to carry a frameshift mutation in the plsC gene, which codes for 1-acylsn-glycerol-3-phosphate acyltransferase.

Enterobacteriaceae

The Enterobacteriaceae species, including Morganella morganii and Proteus mirabilis, exhibit intrinsic tigecycline resistance due to the constitutive activation of the multidrug efflux pump AcrAB. The genes regulating the AcrAB efflux pumps also assist in the decline of Klebsiella and E. coli susceptibility of the tigecycline. The global regulation mechanism of the AcrAB pump by SoxS, MarA, RamA, and Rob in Enterobacteriaceae remains unknown. The overexpression of the AcrAB pump has no clear explanation.

Escherichia coli

Tigecycline is a potential substrate for the AcrAB and AcrEF efflux pumps in E. coli. The AcrAB pump releases a broad range of lipophilic and amphipathic antibiotics. Rob, SoxS, and MarA regulatory proteins confer the MDR phenotype; here, MarA over-expresses the efflux pump. OmpF porin is down-regulated by AcrAB-TolC. Besides contributing to tigecycline resistance, mutations in the genes encoding the efflux regulatory network (lon, acrR, marR) and lipopolysaccharide biosynthesis (lpcA, rfaE, rfaD, rfaC, rfaF) frequently result in a significant fitness cost that reduces bacterial pathogenicity. This can be achieved through the overexpression of MarA and AcrAB pumps via frameshift mutations, such as the insertion of a cytosine residue at position 355 in marR. However, all these findings require further in vivo studies to establish a relationship between these mutations and the pathogenic nature of the bacteria. 

Serratia marcescens

By raising the RND family's SdeXY-HasF efflux pump, Serratia marcescens develops resistance to tigecycline. Additionally, this mechanism contributes to the development of resistance to cefpirome and ciprofloxacin. In contrast, decreased susceptibility to ciprofloxacin, cefpirome, and tetracycline is the consequence of the independent inactivation of the sdeY and hasF genes.

Enterobacter spp.

Tigecycline resistance is primarily mediated by the activation of the ramA-regulated AcrAB efflux pump. In E. aerogenes and E. cloacae, mutations in ramR, such as frameshifts or deletions/amino acid changes, result in overexpression of ramA. Alternative mechanisms of resistance in E. cloacae include overexpression of ramA alone, rare overexpression of rarA coupled with activation of OqxAB, and overexpression of AcrAB by SoxS, RobA, and RamA. Further studies may detect other efflux pumps and regulators.

Salmonella spp.

The positive link between successive AcrAB overexpression and resistance to tigecycline, as well as activation of the ramA genes through an inactivating mutation in the RamR repressor, has also been documented within S. enterica. Accordingly, it is also unknown how RamA is controlled in bacteria beyond Salmonella species. Although tigecycline resistance in S. enterica suggested the existence of both ramR and tet (A) gene mutations, both C. pneumoniae isolates from carbapenem-resistant patients tested positive for the presence of the tigecycline resistant gene. 

Pseudomonas aeruginosa

Drug resistance in P. aeruginosa has been associated with Resistance-Nodulation-Division (RND) efflux pumps, such as MexAB-OprM, MexCD-OprJ, MexEFOprN, and MexXY-OprM. Overexpression of the SdeXY and MexXY-OprM pumps has been associated with tigecycline resistance. Other efflux pumps have also affected MDR isolates.

Gram-positive bacteria

The limited data available on gram-positive bacteria that are resistant to tigecycline indicate that overexpression of the MATE efflux pump MepA in Staphylococcus aureus reduces susceptibility to tigecycline without the emergence of full resistance. Overexpression of the tet(L)-encoded MFS pump and tet(M)-encoded ribosomal protection protein is associated with resistance to tigecycline in Enterococcus spp.^1,5

Klebsiella pneumoniae resistant to tigecycline, particularly those that are carbapenem and colistin-resistant, is mediated by several mechanisms as discussed below.

Efflux Pumps: Tigecycline resistance is mediated by the overexpression or amplification of the AcrAB-TolC efflux pump system. The pump actively expels tigecycline from bacterial cells, reducing the drug's intracellular concentration and thereby diminishing the drug’s effectiveness.

Ribosomal Mutations: Tigecycline acts by inhibiting bacterial ribosomes and therefore is a protein synthesis inhibitor. Mutations in the binding sites of ribosomal proteins decrease the binding affinity of tigecycline to its site and thus enable the bacteria to resist its inhibitory action.

Regulatory Mutations: The upregulation of efflux pumps and other resistance pathways is controlled by mutations in the regulatory genes controlling them, all of which add to tigecycline resistance. Regulatory up-regulation of the AcrAB-TolC-efflux system further contributes to bacterial resistance.

These mechanisms pose significant challenges in the treatment of infections caused by multidrug-resistant K. pneumoniae, underscoring the need for advanced therapeutic strategies and constant vigilance in public health management.³

The study by Luchao et al., identified TMexCD1-TOprJ1, a new plasmid-borne tigecycline resistance found in isolates of K. pneumoniae. This efflux pump gene cluster significantly enhanced tigecycline resistance, reducing its efficacy both in vivo and in vitro. The study emphasized the potential for global dissemination of this resistance mechanism via plasmids, posing a significant threat to public health.⁶

The study by Korczak et al., is a review focused on molecular tigecycline resistance mechanisms in Enterobacter spp. a significant group of Gram-negative pathogens responsible for severe nosocomial infections. It highlights that tigecycline, a last-resort antibiotic, faces increasing resistance due to mechanisms such as efflux pumps, tet genes, and outer membrane porins, which lower antibiotic concentrations and contribute to multidrug resistance. The review discusses the global challenges posed by pathogens already resistant to both carbapenems and colistin, emphasizing the need for better understanding of resistance mechanisms and mitigation strategies.⁷

Jyoti et al., studied 5,258 Gram-negative bacilli (GNB) isolated from clinical samples, of which 2,668 (50.74%) were carbapenem-resistant, and 413 (7.85%) were resistant to both tigecycline and carbapenems. Common resistant organisms included K.pneumoniae (37.04%), Acinetobacter spp. (25.18%), and E.coli (12.59%). The study highlights the increasing resistance to tigecycline, leaving limited treatment options, and advocates for antimicrobial stewardship to prevent the emergence of resistance.⁸

Microbiological Spectrum

Tigecycline has demonstrated broad in vitro activity against a wide spectrum of both aerobic and anaerobic bacteria. It is particularly effective against typical aerobic Gram-positive pathogens such as MRSA, vancomycin intermediate S. aureus, and both penicillin-resistant and vancomycin-resistant enterococci. For Streptococcus pneumoniae, MIC90 values of 0.12 to 0.5 mg/mL have been established. In addition, both tetracycline-sensitive and -resistant strains have exhibited almost similar MIC levels of tigecycline. The FDA's susceptibility breakpoints for Streptococci and Staphylococci were 0.25 and 0.5 mg/mL, respectively, indicating that all of the aforementioned infections would be considered susceptible to tigecycline. Among Gram-negative pathogens, tigecycline has shown activity against Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydophila pneumoniae. However, Legionella spp. tend to exhibit high MIC values for tigecycline. For Enterobacteriaceae, tigecycline's MIC90 values in tetracycline-susceptible strains have ranged from 0.25 to 1 mg/mL. The effectiveness of tigecycline against tetracycline-resistant bacteria has shown considerable variability, despite the fact that the majority of tetracycline-resistant bacteria have comparable tigecycline MIC values.

For tetracycline-resistant isolates, most resistant strains exhibit tigecycline MIC values ranging from 2-16 mg/mL. This is particularly true for the majority of Morganella morganii and several Proteus and Providencia species. Studies on these isolates have revealed that they constitutively overexpress multidrug efflux pump systems, including AcrAB, for which tigecycline is a substrate. In most of the studies examining large numbers of isolates, ~ 95% of all the members of Enterobacteriaceae family were observed to be sensitive to tigecycline at the FDA susceptibility breakpoint of 2 mg/mL. The MIC values for strains of both E.coli and Klebsiella species, with or without extended-spectrum β-lactamases (ESBLs), have been shown to be comparable in terms of tigecycline susceptibility and sensitivity rates. Acinetobacter species and Stenotrophomonas maltophilia had the lowest tigecycline MIC values among the nonfermentive Gram-negative bacilli. Although certain strains of Burkholderia cepacia may possess tigecycline MIC values of 2 mg/mL, more than 90% of P.aeruginosa strains will have MIC values of 4 mg/mL and would be considered resistant to tigecycline. Most anaerobic bacteria, including C.difficile, Fusobacterium sp., Prevotella sp., Poryphymonas sp., and the Bacteroides fragilis group, are sensitive to tigecycline. The FDA established susceptibility breakpoint for tigecycline against anaerobes as established is 4 mg/mL, a value that falls well within the MIC distribution observed for anaerobic organisms in clinical trials. Additionally, it demonstrates a high MIC value for minocycline and exhibits strong potency against Neisseria gonorrhoeae, Eikenella corrodens, and rapidly growing mycobacteria such as Mycobacterium chelonae, Mycobacterium abscessus, and the Mycobacterium fortuitum group.⁶ 

Conclusion

Tigecycline has proved to be an essential antibiotic effective against multidrug-resistant infections, showing remarkable efficacy across the spectrum of pathogens and clinical settings. It has shown activity against Gram-positive organisms, such as MRSA and VRE, and against Gram-negative organisms, including K. pneumoniae and E. coli, primarily in cIAIs and cSSTIs. However, this agent is not effective against organisms with intrinsic resistance, such as Proteus mirabilis, Pseudomonas aeruginosa, and Providencia spp. In utility studies, tigecycline has shown effectiveness at a clinical success rate of 70% in lung infections and 88.9% in urinary tract infections, showing its broad-spectrum potential. However, challenges persist with resistance in A. baumannii and carbapenem-resistant K. pneumoniae, with resistance rates ranging from 20% to 50%, limiting its effectiveness in BSIs and VAP.

Combination therapy has been established to improve clinical outcomes of tigecycline significantly. It reduces failure rates significantly when used as a combination therapy with agents such as colistin or carbapenems and lowers 28-day mortality, especially in infections caused by CROs. Despite this promising profile, monotherapy with tigecycline is associated with greater rates of superinfections due to CROs, emphasizing the need for combined regimens. Furthermore, higher dosages of tigecycline, such as 200 mg/day, have been associated with improved outcomes in patients who are critically ill, but are more likely to cause adverse effects, which includes AKI. Additionally, patients with hypertension should avoid the PB-TGC combination due to its higher AKI risk. Treatment with tigecycline may also result in reduced fibrinogen.

Tigecycline, due to its high tissue penetration and long half-life, has proved to be particularly effective in treating cIAIs and cSSTIs. However, plasma concentrations are too low to achieve effective levels in BSIs and VAP, which demand greater systemic exposure. Resistance mechanisms, including overexpression of efflux pumps such as AdeABC in A. baumannii and genetic mutations such as ramR in K. pneumoniae, complicate its utility, making susceptibility testing and dosing optimization necessary.

Tigecycline plays a crucial role in antibiotic stewardship programs, particularly given its potential to target multidrug-resistant organisms. Its efficacy against ESBL-producing and carbapenemase-producing Gram-negative bacteria makes it a last-resort antibiotic. However, tigecycline resistance emphasizes the need for judicious use, stringent measures in infection control, and combination therapy approaches to maintain its effectiveness. In the rising tide of global antibiotic resistance, tigecycline remains a crucial weapon, particularly when used as part of a comprehensive stewardship and resistance mitigation program.

Conflict of Interest

Nil