Tigecycline (DB00560): A Comprehensive Monograph on a Last-Resort Glycylcycline Antibiotic

Section 1: Introduction to Tigecycline

1.1 A First-in-Class Agent for a Resistant Era

Tigecycline represents the first clinically available member of the glycylcycline class of antibiotics, a novel therapeutic category derived from the well-established tetracyclines.[1] Developed by Wyeth Pharmaceuticals (now part of Pfizer) and marketed under the brand name Tygacil, its creation was a direct and necessary response to the escalating global public health crisis of antimicrobial resistance (AMR).[3] The primary impetus for its development was the urgent need for new agents with activity against a growing list of multidrug-resistant (MDR) pathogens, most notably methicillin-resistant

Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Gram-negative organisms producing extended-spectrum β-lactamases (ESBLs).[5] Its expedited approval by the U.S. Food and Drug Administration (FDA) underscored the critical gap in the therapeutic armamentarium that Tigecycline was designed to fill.[3]

1.2 The Central Paradox: Potency vs. Peril

The clinical story of Tigecycline is defined by a central paradox: the juxtaposition of its remarkable in-vitro potency against its significant in-vivo limitations and safety concerns. By virtue of a key structural modification, Tigecycline was rationally designed to overcome the two principal mechanisms of tetracycline resistance—efflux pumps and ribosomal protection—granting it a broad spectrum of activity against many pathogens that had become resistant to older antibiotics.[7] However, this molecular success is sharply contrasted by a U.S. FDA Black Box Warning, issued due to an observed increase in all-cause mortality in patients treated with Tigecycline compared to comparator antibiotics.[10] This elevated risk is not believed to be from direct drug toxicity but rather from lower efficacy in certain severe infections, a finding that points to challenging pharmacokinetic properties.[10] This complex profile of potency and peril has relegated Tigecycline to the status of a last-resort agent, a powerful but flawed tool to be reserved for specific clinical scenarios where alternative treatments are unsuitable.[11]

1.3 Scope of the Monograph

This report provides a comprehensive and exhaustive monograph on Tigecycline. It will systematically analyze the drug's chemical and pharmacological properties, its spectrum of activity, its pharmacokinetic profile, the evidence supporting its clinical use, and its detailed safety profile. Furthermore, it will explore the evolving mechanisms of resistance that threaten its utility and provide expert recommendations for its judicious application in modern infectious disease management.

Section 2: Chemical Identity and Pharmaceutical Formulation

2.1 Chemical Nomenclature and Structure

Tigecycline is a semi-synthetic antibiotic belonging to the glycylcycline class.[1] Its chemical foundation is minocycline, a tetracycline derivative, but it is distinguished by a unique structural modification that defines its pharmacological properties.[8]

The key structural feature of Tigecycline is the substitution of a glycylamido moiety—specifically, an N-tert-butylglycylamido group—at the C-9 position of the tetracycline's D-ring.[3] This substitution pattern is not present in any naturally occurring or other semi-synthetic tetracyclines and is directly responsible for the drug's ability to overcome common tetracycline resistance mechanisms.[2] Its formal IUPAC name is (4S,4aS,5aR,12aR)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide.[16] The molecular formula is

C29​H39​N5​O8​, corresponding to a molecular weight of approximately 585.65 g/mol.[17]

2.2 Physicochemical Properties and Formulation

Tigecycline is supplied for clinical use as an orange-colored, sterile, lyophilized powder or cake in a single-dose vial.[15] Each 50 mg vial also contains 100 mg of lactose monohydrate as an excipient.[15] It is intended for reconstitution and subsequent dilution for intravenous infusion only. The product demonstrates solubility in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) up to 100 mM and 30 mg/mL, respectively, and is also soluble in phosphate-buffered saline (PBS) at pH 7.2.[16] For long-term storage, the lyophilized powder should be kept at -20°C, where it is stable for at least 12 months.[16]

Table 1: Key Identifiers and Physicochemical Properties of Tigecycline

Identifier Type	Value	Source(s)
Common Name	Tigecycline	1
Brand Name	Tygacil, Tigecycline Accord	1
IUPAC Name	(4S,4aS,5aR,12aR)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide	16
CAS Number	220620-09-7	4
DrugBank ID	DB00560	3
UNII	70JE2N95KR	4
InChIKey	FPZLLRFZJZRHSY-HJYUBDRYSA-N	4
Molecular Formula	C29​H39​N5​O8​	16
Molecular Weight	585.65 g/mol	3
Appearance	Orange lyophilized powder or cake	15

Section 3: Molecular Pharmacology and Mechanism of Action

3.1 Primary Target: The Bacterial Ribosome

The primary mechanism of action for Tigecycline is the inhibition of bacterial protein synthesis, a process vital for bacterial growth and replication.[7] Like its tetracycline predecessors, Tigecycline exerts its effect by targeting the bacterial ribosome. It binds with high affinity and reversibility to the 30S ribosomal subunit.[3] More specifically, its binding site is located within the A-site (aminoacyl-tRNA site) of the ribosome.[3] By occupying this critical location, Tigecycline creates a steric blockade that prevents aminoacyl-tRNA molecules from docking correctly. This interference effectively halts the addition of new amino acids to the growing polypeptide chain, thereby arresting protein elongation and ultimately leading to a bacteriostatic effect.[7]

3.2 Overcoming Tetracycline Resistance: A Structural Masterclass

A key triumph of Tigecycline's design is its ability to circumvent the two most prevalent mechanisms of acquired resistance to older tetracyclines. This capability is a direct consequence of the bulky N-tert-butylglycylamido side chain at the C-9 position of its molecular structure.

• Evading Efflux Pumps: Tetracycline resistance is often mediated by membrane-bound efflux pumps, such as those encoded by the tet(A-E) genes, which actively expel the antibiotic from the bacterial cell, preventing it from reaching its ribosomal target. The large glycylamido moiety on Tigecycline makes it a very poor substrate for these pumps. The steric hindrance created by this group prevents the pump from recognizing and transporting the drug, allowing Tigecycline to accumulate to effective intracellular concentrations.[3]
• Evading Ribosomal Protection: The second major resistance mechanism involves ribosomal protection proteins (RPPs), such as those encoded by tet(M) and tet(O). These proteins bind to the ribosome and induce a conformational change that dislodges bound tetracycline molecules. The same glycylamido side chain that confers protection from efflux also significantly enhances Tigecycline's binding affinity for the ribosome, reported to be up to five times stronger than that of tetracycline or minocycline.[8] This tighter binding makes it much more difficult for RPPs to displace Tigecycline from the A-site, thus preserving its inhibitory activity even in the presence of these protective proteins.[7]

This direct structure-activity relationship, where a specific chemical modification leads to the circumvention of two distinct resistance pathways, is the defining feature of the glycylcycline class and a prime example of successful rational drug design aimed at combating AMR.

3.3 Pharmacodynamic Characteristics

In general, Tigecycline is considered a bacteriostatic agent, meaning it primarily inhibits bacterial replication rather than causing rapid cell death.[3] Its antibacterial activity is best described as time-dependent, and the key pharmacodynamic index predictive of its efficacy is the ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (

AUC24​/MIC).[8] Tigecycline also exhibits a prolonged post-antibiotic effect (PAE), a phenomenon where bacterial growth remains suppressed for a period even after drug concentrations have fallen below the MIC. Studies have shown this PAE to be longer for Tigecycline than for minocycline against key pathogens like

S. aureus (3.4–4 hours) and E. coli (1.8–2.9 hours), contributing to the effectiveness of its twice-daily dosing schedule.[8]

Section 4: Clinical Pharmacokinetics and Pharmacodynamics (PK/PD)

The clinical utility and limitations of Tigecycline are fundamentally dictated by its unique pharmacokinetic profile. Understanding its absorption, distribution, metabolism, and excretion (ADME) is essential to appreciating why it is effective for some infections but associated with poor outcomes in others.

4.1 Absorption

Tigecycline has poor oral bioavailability and therefore must be administered exclusively by intravenous (IV) infusion.[1] The standard administration involves an infusion over approximately 30 to 60 minutes.[8]

4.2 Distribution: The Key to Understanding Tigecycline's Limitations

The most defining, and paradoxical, pharmacokinetic feature of Tigecycline is its distribution.

• Large Volume of Distribution (Vd​): Tigecycline exhibits an exceptionally large volume of distribution, averaging 7 to 10 L/kg, which translates to a total volume of 500 to 700 L in an average adult.[5] This indicates that after administration, the drug rapidly and extensively partitions out of the bloodstream and into peripheral tissues.[5]
• High Tissue Concentrations: As a consequence of its large Vd​, Tigecycline achieves high concentrations in various tissues. Animal and human studies have demonstrated that concentrations in bone, liver, lung, colon, and skin are several-fold higher than those achieved in the serum.[8] This property makes it well-suited for treating deep-seated, contained tissue infections.
• Low Serum Concentrations: The direct and critical consequence of this extensive tissue distribution is that steady-state concentrations of Tigecycline in the plasma remain low. Following the standard dosing regimen, peak serum concentrations (Cmax​) are typically only around 0.6 to 0.9 µg/mL.[8] This pharmacokinetic characteristic is the primary liability of the drug and the likely driver of its poor performance in infections where the pathogen resides primarily in the bloodstream, such as bacteremia or certain types of pneumonia.
• Protein Binding: Tigecycline's binding to plasma proteins is concentration-dependent, ranging from approximately 71% to 89% within the range of concentrations observed in clinical studies.[3]

4.3 Metabolism

Tigecycline undergoes very limited metabolism in the body.[9] In-vitro studies using human liver preparations have shown that only trace amounts of metabolites are formed. The primary metabolites identified are a glucuronide conjugate, an N-acetyl metabolite, and a tigecycline epimer, with each accounting for less than 10% of the administered dose.[9] Importantly, Tigecycline does not significantly interact with the major cytochrome P450 (CYP) enzyme isoforms, indicating a low potential for clinically relevant metabolic drug-drug interactions.[15]

4.4 Excretion

The primary route of elimination for Tigecycline is through the biliary system into the feces.[8] Approximately 59% of an administered dose is excreted via the biliary/fecal route, largely as unchanged drug.[23] Renal excretion is a minor pathway, with only about 22% of the dose eliminated in the urine.[5] This predominantly non-renal clearance means that no dosage adjustment is necessary for patients with renal impairment, including those with end-stage renal disease requiring hemodialysis.[23] Tigecycline has a long terminal elimination half-life (

t1/2​), averaging approximately 42 hours in adults, which supports a convenient twice-daily dosing regimen.[8]

4.5 Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship

The extensive tissue distribution and resulting low serum concentrations create a critical PK/PD challenge. The efficacy of Tigecycline is predicted by the AUC24​/MIC ratio.[8] In contained tissue infections where the drug concentrates, this target can be readily achieved locally. However, in bloodstream infections (bacteremia) or infections where the vascular space is the primary site (e.g., hospital-acquired pneumonia), the low serum AUC makes it difficult to achieve the target

AUC24​/MIC. This suboptimal exposure can lead to inadequate bacterial killing, clinical failure, and an increased risk of mortality, providing a clear pharmacologic explanation for the drug's black box warning.

Table 2: Summary of Key Pharmacokinetic Parameters in Adults

Parameter	Mean Value (with range or CV%)	Clinical Significance	Source(s)
Peak Concentration (Cmax​)	0.63 - 0.87 µg/mL	Low serum levels limit efficacy in bacteremia.	8
Area Under the Curve (AUC0−24h​)	4.70 µg·h/mL (36% CV)	Key component of the PK/PD efficacy index (AUC/MIC).	8
Volume of Distribution (Vd​)	7 - 10 L/kg (500 - 700 L)	Extensive tissue penetration; responsible for low serum levels.	5
Systemic Clearance (CL)	0.2 - 0.3 L/h/kg	Primarily non-renal clearance.	5
Elimination Half-life (t1/2​)	~42 hours (83% CV)	Long half-life allows for twice-daily (q12h) dosing.	8
Plasma Protein Binding	71% - 89% (concentration-dependent)	Moderate to high binding.	3

Section 5: In-Vitro Spectrum of Antimicrobial Activity

Tigecycline exhibits a broad spectrum of in-vitro activity, encompassing a wide range of clinically important Gram-positive, Gram-negative, anaerobic, and atypical bacteria, including many MDR strains.

5.1 Gram-Positive Pathogens

Tigecycline demonstrates excellent potency against Gram-positive cocci. This includes activity against:

• Staphylococcus aureus, including both methicillin-susceptible (S. aureus, MSSA) and methicillin-resistant (S. aureus, MRSA) isolates, as well as some strains with reduced susceptibility to glycopeptides.[1]
• Enterococcus species, notably including strains resistant to vancomycin, such as Enterococcus faecalis and Enterococcus faecium (VRE).[1]
• Streptococcus species, such as Streptococcus pneumoniae (including penicillin-resistant strains, PRSP), Streptococcus pyogenes (Group A Streptococcus), and Streptococcus agalactiae (Group B Streptococcus).[1]

5.2 Gram-Negative Pathogens

The activity of Tigecycline extends to many challenging Gram-negative organisms. It is active against:

• Many species of Enterobacterales, including Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Citrobacter freundii. Crucially, this activity is often retained against strains that produce ESBLs and some carbapenem-resistant Enterobacterales (CRE).[1]
• Acinetobacter baumannii, a notoriously difficult-to-treat nosocomial pathogen.[28]
• Stenotrophomonas maltophilia.[1]

5.3 Anaerobic and Atypical Pathogens

Tigecycline possesses reliable activity against a broad range of anaerobic bacteria, including the Bacteroides fragilis group, which is important for treating polymicrobial intra-abdominal infections.[1] It is also active in vitro against

Clostridioides difficile.[1] Its spectrum covers atypical pathogens responsible for pneumonia, such as

Legionella pneumophila, Chlamydia pneumoniae, and rapidly growing nontuberculous mycobacteria.[1]

5.4 Intrinsic and Notable Resistance

Despite its broad spectrum, there are several important pathogens against which Tigecycline has no clinically useful activity. This intrinsic resistance is primarily observed in:

• Pseudomonas aeruginosa
• Proteus species (P. mirabilis, P. vulgaris)
• Providencia species
• Morganella morganii

This lack of activity is often attributed to the constitutive high-level expression of endogenous, non-specific RND-type efflux pumps in these organisms, which effectively prevent the drug from reaching its target.[1]

Table 3: In-Vitro Activity of Tigecycline against Key Clinical Pathogens

Pathogen	Category	MIC$_{50}$ (µg/mL)	MIC$_{90}$ (µg/mL)	Source(s)
Staphylococcus aureus (MRSA)	Gram-Positive Aerobe	0.12 - 0.25	0.25 - 0.5	1
Enterococcus faecalis (VRE)	Gram-Positive Aerobe	0.06	0.12 - 0.25	1
Streptococcus pneumoniae	Gram-Positive Aerobe	≤0.06	0.12	1
Escherichia coli	Gram-Negative Aerobe	0.25	0.5 - 1	1
Klebsiella pneumoniae	Gram-Negative Aerobe	0.5	1 - 2	1
Acinetobacter baumannii	Gram-Negative Aerobe	0.5 - 1	2	28
Bacteroides fragilis	Anaerobe	0.5	2	1
Pseudomonas aeruginosa	Gram-Negative Aerobe	>8	>16	1

Note: MIC values are representative and can vary based on geographic region and surveillance period.

Section 6: Clinical Efficacy in Approved Indications

The clinical development of Tigecycline led to its approval for three specific indications in adults, based on data from large, randomized, double-blind, non-inferiority trials.

6.1 Regulatory Approval History

Tigecycline was first granted fast-track and priority review status by the U.S. FDA, culminating in its initial approval on June 17, 2005.[3] The initial indications were for the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal infections (cIAI).[30] The European Medicines Agency (EMA) followed with approval in 2006.[31] In March 2009, the FDA expanded the approved indications to include community-acquired bacterial pneumonia (CAP) in adults.[30]

6.2 Complicated Skin and Skin Structure Infections (cSSSI)

The efficacy of Tigecycline for cSSSI was established in two pivotal Phase III trials that compared it to a standard combination regimen of intravenous vancomycin and aztreonam.[1] In pooled analyses of these studies, Tigecycline demonstrated non-inferiority to the comparator, achieving comparable clinical cure rates in the clinically evaluable and modified intent-to-treat populations.[1] A significant limitation was noted, however, in a subsequent trial focused on diabetic foot infections, where Tigecycline failed to demonstrate non-inferiority. Consequently, it is explicitly not indicated for the treatment of diabetic foot infections.[34]

6.3 Complicated Intra-abdominal Infections (cIAI)

For cIAI, the primary evidence comes from two large Phase III trials comparing Tigecycline monotherapy to the broad-spectrum combination of imipenem and cilastatin, a standard of care for severe intra-abdominal infections.[1] The results of these trials showed that Tigecycline was as efficacious as imipenem/cilastatin, meeting the pre-specified criteria for non-inferiority in achieving clinical cure.[1] This established its role as a potential monotherapy agent for these complex, often polymicrobial infections.

6.4 Community-Acquired Bacterial Pneumonia (CAP)

The approval for CAP was based on two Phase III trials that compared Tigecycline to levofloxacin, a widely used respiratory fluoroquinolone.[1] These studies demonstrated that Tigecycline was non-inferior to levofloxacin for the treatment of hospitalized patients with CAP caused by susceptible pathogens, including

Streptococcus pneumoniae (including cases with concurrent bacteremia), Haemophilus influenzae, and Legionella pneumophila.[34]

The pattern of successful trials for Tigecycline reinforces the importance of its pharmacokinetic profile. Its approved indications—cSSSI, cIAI, and CAP—are infections seated within well-perfused tissues (skin, abdominal cavity, lung parenchyma) where the drug is known to concentrate effectively. In contrast, its failure in diabetic foot infections, which often involve compromised vascular supply, and its poor outcomes in hospital-acquired pneumonia, which has a higher incidence of bacteremia, highlight a consistent theme: Tigecycline's clinical success is directly tied to its ability to reach the site of infection in adequate concentrations.

Table 4: Summary of Pivotal Phase III Clinical Trials for Approved Indications

Indication	Trial Comparator(s)	Primary Endpoint	Tigecycline Outcome	Comparator Outcome	Conclusion	Source(s)
cSSSI	Vancomycin + Aztreonam	Clinical Cure Rate	~86.5%	~88.6%	Non-inferiority met	1
cIAI	Imipenem/Cilastatin	Clinical Cure Rate	~80.6%	~82.4%	Non-inferiority met	1
CAP	Levofloxacin	Clinical Cure Rate	~89.7%	~86.3%	Non-inferiority met	1

Section 7: Safety Profile, Tolerability, and Risk Management

The use of Tigecycline is governed by a significant safety profile, headlined by a black box warning that necessitates careful patient selection and risk-benefit assessment.

7.1 The FDA Black Box Warning: Increased All-Cause Mortality

In 2010, and updated in 2013, the U.S. FDA issued a prominent boxed warning for Tigecycline regarding an increased risk of death.[10] This warning was based on a meta-analysis of 13 Phase 3 and 4 clinical trials that showed a small but statistically significant increase in all-cause mortality in patients treated with Tigecycline compared to those receiving comparator antibiotics. The absolute risk difference was 0.6% (95% CI 0.1, 1.2).[11]

Crucially, the cause of this excess mortality has not been attributed to a specific drug-induced toxicity but rather to lower cure rates and progression of the underlying infection in the Tigecycline arm, particularly in patients with severe infections.[10] The mortality imbalance was most apparent in trials for hospital-acquired pneumonia (HAP), especially ventilator-associated pneumonia (VAP), an unapproved indication where Tigecycline-treated patients had both higher mortality and lower cure rates.[10] This finding directly links the safety warning to the drug's suboptimal pharmacokinetics in bloodstream-dependent infections. As a result of this warning, the FDA advises that Tigecycline should be reserved for use in situations when alternative treatments are not suitable.[11]

7.2 Common Adverse Drug Reactions

The most frequently reported adverse effects of Tigecycline are gastrointestinal in nature, a characteristic shared with the tetracycline class.

• Nausea and Vomiting: Nausea is very common, occurring in up to 30% of patients, while vomiting affects up to 20%. These effects are a primary reason for treatment intolerance.[21]
• Diarrhea: Diarrhea is also a common side effect.[38]
• Other common effects include headache, dizziness, fever, and local injection site reactions such as pain and phlebitis.[38]

7.3 Serious and Less Common Adverse Events

Beyond the common tolerability issues, Tigecycline is associated with several potentially serious adverse events that require clinical monitoring.

• Pancreatitis: Cases of acute pancreatitis, some of which have been fatal, have been reported. Patients presenting with compatible symptoms (e.g., severe abdominal pain, nausea, vomiting) should be evaluated for pancreatitis.[12]
• Hepatotoxicity: Tigecycline can cause elevations in liver function tests, including AST, ALT, and total bilirubin.[12] Post-marketing reports include isolated cases of significant hepatic dysfunction, cholestasis, jaundice, and hepatic failure.[12]
• Coagulopathy: The drug can interfere with coagulation, leading to hypofibrinogenemia and prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT). Baseline and regular monitoring of coagulation parameters, including fibrinogen, is recommended during therapy.[24]
• Anaphylaxis: As with many antibiotics, severe, life-threatening anaphylactic/anaphylactoid reactions can occur.[35]
• Photosensitivity: Tigecycline can increase the skin's sensitivity to sunlight, potentially causing exaggerated sunburn reactions. Patients should be counseled to use sunscreen and protective clothing during exposure.[40]
• Tetracycline-Class Effects: Tigecycline carries the risks associated with the tetracycline class, including pseudotumor cerebri (benign intracranial hypertension) and Clostridioides difficile-associated diarrhea (CDAD).[3]

7.4 Contraindications and Use in Specific Populations

• Hypersensitivity: Tigecycline is contraindicated in patients with a known hypersensitivity to the drug or to any other tetracycline-class antibiotic, due to the potential for cross-reactivity.[21]
• Pediatric Use: Use is not recommended in children younger than 8 years old. Like other tetracyclines, Tigecycline can bind to calcium in developing teeth and bones, causing permanent yellow-gray-brown tooth discoloration and potentially inhibiting bone growth.[35] For children aged 8 to 17, its use should be reserved for situations where no suitable alternatives are available.[24]
• Pregnancy and Lactation: Tigecycline can cause harm to a developing fetus, including permanent tooth discoloration. Women of childbearing potential must use effective contraception during treatment.[21] It is not known if Tigecycline is excreted in human milk, and lactating women may be advised to pump and discard breast milk during therapy and for 9 days after the final dose.[35]

7.5 Clinically Significant Drug Interactions

• Warfarin: Tigecycline may enhance the anticoagulant effect of warfarin. Close monitoring of the International Normalized Ratio (INR) is essential when these drugs are co-administered.[3]
• Oral Contraceptives: The efficacy of oral contraceptives may be reduced by Tigecycline. Patients should be advised to use an additional, non-hormonal method of birth control during therapy.[35]
• Retinoic Acid Derivatives: Co-administration with drugs like acitretin or isotretinoin should be avoided due to an increased risk of developing pseudotumor cerebri.[3]
• Calcineurin Inhibitors: Tigecycline may alter the concentrations of tacrolimus or cyclosporine; therapeutic drug monitoring is advised if used concurrently.[35]

Table 5: Clinically Significant Adverse Reactions to Tigecycline

System Organ Class	Adverse Reaction	Frequency/Severity	Clinical Management/Monitoring Note	Source(s)
General	All-Cause Mortality	Black Box Warning	Reserve for use when no alternatives are suitable. Driven by lower efficacy in severe infections.	11
Gastrointestinal	Nausea, Vomiting	Very Common (10-30%)	Symptomatic management. May be dose-limiting.	38
Gastrointestinal	Pancreatitis	Rare but Serious (can be fatal)	Monitor serum amylase/lipase if symptoms occur. Discontinue if diagnosed.	12
Hepatic	Elevated LFTs, Jaundice	Common (LFTs), Rare (Jaundice/Failure)	Monitor LFTs at baseline and periodically. Discontinue if significant dysfunction occurs.	12
Hematologic	Hypofibrinogenemia, Prolonged PT/aPTT	Frequency Not Reported	Monitor coagulation parameters (fibrinogen, PT, aPTT) at baseline and regularly.	24
Immune System	Anaphylaxis/Anaphylactoid Reactions	Rare but Life-Threatening	Immediate discontinuation and emergency medical attention required.	35
Dermatologic	Photosensitivity	Frequency Not Reported	Counsel patients to avoid sun exposure and use sunscreen.	40
Neurologic	Pseudotumor Cerebri	Rare	Monitor for headache, vision changes. Associated with tetracycline class.	3
Pediatric	Tooth Discoloration, Bone Growth Inhibition	Class Effect	Contraindicated in children <8 years old.	35

Section 8: Dosage, Administration, and Use in Special Populations

Correct dosing and administration are critical for optimizing the efficacy and safety of Tigecycline.

8.1 Standard Adult Dosing

The recommended dosage regimen for all approved indications in adults is:

• Loading Dose: A single 100 mg dose administered intravenously.[24]
• Maintenance Dose: 50 mg administered intravenously every 12 hours.[24]

The duration of therapy should be tailored to the specific infection and the patient's clinical response:

• cSSSI and cIAI: 5 to 14 days.[24]
• CAP: 7 to 14 days.[24]

8.2 Preparation and Intravenous Administration

Tigecycline must be reconstituted and diluted prior to IV administration. The lyophilized 50 mg powder should be reconstituted with 5.3 mL of a compatible solution (0.9% Sodium Chloride, 5% Dextrose, or Lactated Ringer's Injection) to yield a concentration of 10 mg/mL. The appropriate volume of the reconstituted solution is then withdrawn and added to a 100 mL IV bag for infusion, ensuring the final concentration in the bag does not exceed 1 mg/mL. The infusion should be administered over 30 to 60 minutes. The reconstituted solution should be yellow to orange; if it is discolored (e.g., green or black), it must be discarded.[24]

8.3 Dosing in Special Populations

• Hepatic Impairment: No dosage adjustment is needed for patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). However, for patients with severe hepatic impairment (Child-Pugh Class C), the maintenance dose should be reduced. After the standard 100 mg loading dose, these patients should receive 25 mg IV every 12 hours and be monitored closely for treatment response.[24]
• Renal Impairment: Due to its primary biliary/fecal elimination, no dosage adjustment is required for patients with any degree of renal impairment, including those on hemodialysis.[23]
• Pediatric Dosing (Reserved for when no alternatives exist):
• Children aged 8 to 11 years: 1.2 mg/kg IV every 12 hours, with a maximum dose of 50 mg every 12 hours.[24]
• Adolescents aged 12 to 17 years: 50 mg IV every 12 hours.[24]

Table 6: Recommended Dosing Regimens for Tigecycline

Patient Population	Loading Dose	Maintenance Dose	Notes	Source(s)
Adults	100 mg IV x 1	50 mg IV q12h	Standard dosing for all approved indications.	24
Pediatric (8-11 years)	None Recommended	1.2 mg/kg IV q12h (Max: 50 mg/dose)	Use only when no alternatives are suitable.	24
Pediatric (12-17 years)	None Recommended	50 mg IV q12h	Use only when no alternatives are suitable.	24
Severe Hepatic Impairment (Child-Pugh C)	100 mg IV x 1	25 mg IV q12h	Monitor treatment response with caution.	24
Any Degree of Renal Impairment (including Hemodialysis)	100 mg IV x 1	50 mg IV q12h	No dosage adjustment required.	23

Section 9: The Evolving Landscape of Tigecycline Resistance

Despite being engineered to overcome established resistance mechanisms, the clinical use of Tigecycline has exerted selective pressure, leading to the emergence of novel resistance pathways, particularly in Gram-negative bacteria.

9.1 Overview of Resistance Emergence

Acquired resistance to Tigecycline, while still relatively uncommon in some surveillance programs, is an increasing global concern.[20] The mechanisms driving this new wave of resistance are distinct from those that Tigecycline was originally designed to defeat. Rather than reactivating classic tetracycline-specific defenses, bacteria have adapted by upregulating broad-spectrum efflux systems or acquiring genes that can enzymatically inactivate the drug.

9.2 Mechanisms in Gram-Negative Bacteria (The Primary Concern)

The predominant mechanism of acquired Tigecycline resistance in Gram-negative pathogens is the overexpression of chromosomally encoded, multidrug Resistance-Nodulation-Division (RND) family efflux pumps.[8] These pumps have broad substrate specificity and can recognize and expel Tigecycline from the bacterial cell.

• In Acinetobacter baumannii, resistance is commonly associated with the upregulation of the AdeABC, AdeFGH, and AdeIJK RND efflux pumps.[8]
• In Klebsiella pneumoniae, Enterobacter spp., and E. coli, the primary system involved is the AcrAB-TolC pump. Overexpression is typically driven by mutations in global regulatory genes that control the pump's expression, such as ramA, ramR, marA, and soxS.[8]
• In Pseudomonas aeruginosa, which is intrinsically resistant, the MexXY-OprM efflux system contributes to its high-level resistance.[8]

9.3 Plasmid-Mediated Resistance: A New Threat

A more recent and alarming development is the emergence and spread of plasmid-mediated Tigecycline resistance genes. The most significant of these are the tet(X) variants (e.g., tet(X3), tet(X4)).[8] Unlike efflux- or ribosomal protection-based mechanisms, the

tet(X) gene encodes a flavin-dependent monooxygenase enzyme that directly modifies and inactivates the Tigecycline molecule.[8] Because these genes are located on mobile genetic elements (plasmids), they can be transferred horizontally between different bacterial species and strains, facilitating the rapid dissemination of high-level resistance. This represents a significant escalation in the AMR arms race against this last-resort antibiotic.

9.4 Mechanisms in Gram-Positive Bacteria

Resistance in Gram-positive bacteria is less common but has been described. In Staphylococcus aureus, overexpression of the MepA efflux pump (a member of the MATE family) can lead to decreased susceptibility.[8] In

Enterococcus species, high-level expression of the tet(L) (efflux) and tet(M) (ribosomal protection) genes, typically associated with tetracycline resistance, can also confer resistance to Tigecycline.[8]

Section 10: Off-Label and Investigational Applications

The potent in-vitro activity of Tigecycline against MDR pathogens has led to its widespread off-label use, alongside emerging research into non-antibacterial applications.

10.1 Widespread Off-Label Use for MDR Infections

Clinicians frequently turn to Tigecycline as a salvage therapy for serious infections caused by MDR organisms when few or no other options exist.[29] This practice is most common for:

• Hospital-Acquired and Ventilator-Associated Pneumonia (HAP/VAP)
• Bacteremia and Sepsis

These infections are often caused by CRE, MDR Acinetobacter baumannii, or other difficult-to-treat Gram-negative pathogens.[28] This off-label use is highly controversial and undertaken with significant risk, given the black box warning and the poor outcomes observed in the HAP/VAP clinical trials, which are directly linked to the drug's inability to achieve adequate serum concentrations.[10]

10.2 Role in Combination Therapy

To mitigate the risks associated with monotherapy, particularly in severe infections, Tigecycline is often used as part of a combination regimen.[28] It has been combined with agents like colistin or carbapenems for treating infections caused by CRAB or CRE. However, evidence supporting synergy is mixed, and in-vitro studies have sometimes shown indifference or even antagonism.[28] A meta-analysis comparing Tigecycline and colistin for MDR infections found no significant difference in overall efficacy but highlighted complex trade-offs: Tigecycline was associated with lower 30-day mortality and significantly less renal toxicity, while colistin was associated with lower in-hospital mortality.[45] These findings underscore the difficult decisions clinicians face when using last-resort agents.

10.3 Investigational Anti-Neoplastic Activity

An intriguing area of non-antibiotic research is the potential anti-cancer activity of Tigecycline. Pre-clinical studies have shown that it exhibits activity against various malignancies, including acute myeloid leukemia (AML), non-small cell lung cancer, and glioblastoma.[1] This effect is not related to its antibacterial properties but is attributed to its ability to inhibit mitochondrial protein translation. As many cancer cells exhibit an increased dependence on mitochondrial function for energy and proliferation (the Warburg effect), they are uniquely sensitive to this disruption. This remains an active and promising area of investigational research.[1]

Section 11: Synthesis and Expert Recommendations

11.1 Tying it All Together: The Tigecycline Profile

Tigecycline is a potent, broad-spectrum glycylcycline antibiotic whose clinical utility is fundamentally defined and constrained by its pharmacokinetic profile. Its design as a molecule that could evade common tetracycline resistance mechanisms was a triumph of medicinal chemistry, granting it excellent in-vitro activity against many of the most feared MDR pathogens. However, its clinical application revealed that in-vitro potency does not guarantee in-vivo success. The drug's massive volume of distribution is its greatest strength and its most critical weakness. This property allows for excellent penetration into deep tissues, making it an effective agent for contained, tissue-based infections like cIAI and cSSSI. Simultaneously, this same property leads to low, often sub-therapeutic, serum concentrations, rendering it a poor and high-risk choice for bacteremia and other bloodstream-dependent syndromes like HAP/VAP. This PK/PD mismatch is the most plausible and unifying explanation for the increased mortality observed in clinical trials, which ultimately led to its black box warning.

11.2 Recommendations for Judicious Clinical Use

Given its complex profile, the use of Tigecycline must be highly selective, cautious, and evidence-based.

• Patient Selection is Paramount: Tigecycline should be reserved as a last-resort agent. Its use is most appropriate for polymicrobial cIAI and cSSSI caused by documented MDR pathogens for which safer and more effective alternatives are not available or have failed.
• Confirm Susceptibility: Therapy should always be guided by culture and susceptibility data. Empiric use should be a rare exception, reserved for critically ill patients with a high suspicion of infection by a susceptible MDR pathogen, and should be de-escalated or discontinued promptly once definitive microbiological data are available.
• Avoid in Bacteremia and HAP/VAP: In line with the FDA warning and the wealth of PK/PD data, Tigecycline monotherapy should be avoided for the treatment of bacteremia, HAP, and VAP. Its use in these settings represents a significant risk of clinical failure. If it must be used in such a desperate clinical scenario, it should only be as part of a combination regimen, with full awareness of the risks and after a thorough discussion with the patient or their surrogate.
• Dosing Considerations: The standard adult dose (100 mg load, then 50 mg q12h) should be used. While higher, off-label doses (e.g., 100 mg q12h) have been explored to improve PK/PD target attainment in severe infections, this practice is not supported by robust safety and efficacy data and may increase the risk of toxicity.[22] The mandatory dose reduction to 25 mg q12h in patients with severe hepatic impairment (Child-Pugh C) must be strictly followed.
• Vigilant Monitoring: Clinicians must maintain a high index of suspicion for adverse effects. This includes monitoring for gastrointestinal intolerance, signs of pancreatitis (serum amylase/lipase), liver dysfunction (LFTs), and coagulopathy (fibrinogen, PT, INR). Patients should be counseled on the risk of photosensitivity.

11.3 Future Directions

The story of Tigecycline offers critical lessons for the future of antibiotic development. It highlights that optimizing a molecule for potency and resistance evasion is insufficient; a favorable pharmacokinetic profile that ensures adequate drug delivery to the site of infection is equally crucial. The ongoing surveillance for emerging resistance mechanisms, especially plasmid-mediated enzymatic inactivation via tet(X) genes, is essential to preserving the limited utility of this important last-resort antibiotic.

Works cited

1. Tigecycline - Wikipedia, accessed August 3, 2025, https://en.wikipedia.org/wiki/Tigecycline
2. Tigecycline (Tygacil): The First in the Glycylcycline Class of Antibiotics - ResearchGate, accessed August 3, 2025, https://www.researchgate.net/publication/7169912_Tigecycline_Tygacil_The_First_in_the_Glycylcycline_Class_of_Antibiotics
3. DT-Web: DB00560 - Unict, accessed August 3, 2025, https://alpha.dmi.unict.it/dtweb/search.php?query=DB00560
4. Tigecycline - PubChem, accessed August 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Tigecycline
5. Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects - PMC, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC538906/
6. Tigecycline: A Critical Analysis | Clinical Infectious Diseases | Oxford ..., accessed August 3, 2025, https://academic.oup.com/cid/article/43/4/518/390728
7. What is the mechanism of Tigecycline? - Patsnap Synapse, accessed August 3, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-tigecycline
8. Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7785128/
9. Tigecycline: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 3, 2025, https://go.drugbank.com/drugs/DB00560
10. The role of tigecycline in the treatment of infections in light of the new black box warning, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/24597542/
11. TYGACIL® (tigecycline) Boxed Warning | Pfizer Medical - US, accessed August 3, 2025, https://www.pfizermedicalinformation.com/tygacil/boxed-warning
12. Tigecycline - LiverTox - NCBI Bookshelf, accessed August 3, 2025, https://www.ncbi.nlm.nih.gov/books/NBK547888/
13. Molecular mechanisms of tigecycline-resistance among Enterobacterales - Frontiers, accessed August 3, 2025, https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1289396/full
14. Efficacy and safety of tigecycline: a systematic review and meta-analysis - Oxford Academic, accessed August 3, 2025, https://academic.oup.com/jac/article/66/9/1963/766876
15. NDA 21-821/S-010 Page 3 TYGACIL ... - accessdata.fda.gov, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021821s010lbl.pdf
16. Tigecycline, Glycylcycline antibiotic (CAS 220620-09-7) (ab142000) | Abcam, accessed August 3, 2025, https://www.abcam.com/en-us/products/biochemicals/tigecycline-glycylcycline-antibiotic-ab142000
17. Tigecycline | C29H39N5O8 | CID 54686904 - PubChem, accessed August 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/54686904
18. TYGACIL® (tigecycline) Description | Pfizer Medical - US, accessed August 3, 2025, https://www.pfizermedical.com/tygacil/description
19. Tigecycline (GAR 936, Glycylcycline, CAS Number: 220620-09-7) | Cayman Chemical, accessed August 3, 2025, https://www.caymanchem.com/product/15026/tigecycline
20. Mechanisms of tigecycline resistance in Gram-negative bacteria: A narrative review - PMC, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11610970/
21. Tigecycline - Infectious Diseases - MSD Manual Professional Edition, accessed August 3, 2025, https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/tigecycline
22. Population Pharmacokinetics of Tigecycline: A Systematic Review - PMC - PubMed Central, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9211078/
23. Pharmacokinetic and Pharmacodynamic Profile of Tigecycline ..., accessed August 3, 2025, https://academic.oup.com/cid/article/41/Supplement_5/S333/289231
24. TYGACIL® (tigecycline) Dosage and Administration | Pfizer Medical ..., accessed August 3, 2025, https://www.pfizermedical.com/tygacil/dosage-admin
25. Population pharmacokinetics of tigecycline in critically ill patients - Frontiers, accessed August 3, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1083464/full
26. The Pharmacokinetic and Pharmacodynamic Profile of Tigecycline - E-lactancia, accessed August 3, 2025, https://www.e-lactancia.org/media/papers/Tigeciclina-FQ-Clin_Infect_Dis-2005.pdf
27. Tigecycline - Infectious Diseases Management Program at UCSF, accessed August 3, 2025, https://idmp.ucsf.edu/content/tigecycline
28. Efficacy of tigecycline monotherapy versus combination therapy with other antimicrobials against carbapenem-resistant Acinetobacter baumannii sequence type 2 in Heilongjiang Province - Annals of Palliative Medicine, accessed August 3, 2025, https://apm.amegroups.org/article/view/32184/26849
29. Evaluation of Tigecycline Utilization and Trends in Antibacterial ..., accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9938701/
30. Tygacil (tigecycline) FDA Approval History - Drugs.com, accessed August 3, 2025, https://www.drugs.com/history/tygacil.html
31. Prescription Patterns for Tigecycline in Severely Ill Patients for Non-FDA Approved Indications in a Developing Country: A Compromised Outcome, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5366332/
32. Efficacy of Tigecycline for Secondary Acinetobacter Bacteremia and Factors Associated with Treatment Failure | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed August 3, 2025, https://journals.asm.org/doi/abs/10.1128/aac.04987-14
33. Tigecycline: an evidence-based review of its antibacterial activity an | CE, accessed August 3, 2025, https://www.dovepress.com/tigecycline-an-evidence-based-review-of-its-antibacterial-activity-and-peer-reviewed-fulltext-article-CE
34. TYGACIL® (tigecycline) Indications and Usage | Pfizer Medical - US, accessed August 3, 2025, https://www.pfizermedical.com/tygacil/indications-usage
35. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TIGECYCLINE FOR INJECTIO - accessdata.fda.gov, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/205645s013lbl.pdf
36. A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744] - PubMed Central, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1277826/
37. Tygacil (tigecycline) - Molina Healthcare, accessed August 3, 2025, https://www.molinahealthcare.com/-/media/Molina/PublicWebsite/PDF/Providers/common/pa-criteria/Tygacil-tigecycline-C14555-A.pdf
38. Tigecycline Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 3, 2025, https://www.drugs.com/sfx/tigecycline-side-effects.html
39. Tygacil (tigecycline) dosing, indications, interactions, adverse effects, and more, accessed August 3, 2025, https://reference.medscape.com/drug/tygacil-tigecycline-342527
40. Tigecycline Uses, Side Effects & Warnings - Drugs.com, accessed August 3, 2025, https://www.drugs.com/mtm/tigecycline.html
41. www.mayoclinic.org, accessed August 3, 2025, https://www.mayoclinic.org/drugs-supplements/tigecycline-intravenous-route/description/drg-20072556#:~:text=Tigecycline%20may%20cause%20your%20skin,skin%2C%20or%20a%20severe%20sunburn.
42. Tygacil, INN-Tigecycline - EMA, accessed August 3, 2025, https://www.ema.europa.eu/en/documents/product-information/tygacil-epar-product-information_en.pdf
43. Tigecycline (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 3, 2025, https://www.mayoclinic.org/drugs-supplements/tigecycline-intravenous-route/description/drg-20072556
44. Tygacil Dosage Guide - Drugs.com, accessed August 3, 2025, https://www.drugs.com/dosage/tygacil.html
45. Efficacy and Safety of Colistin versus Tigecycline for Multi-Drug ..., accessed August 3, 2025, https://www.mdpi.com/2079-6382/11/11/1630