key: cord-0054793-jnbzon41 authors: Yaghoubi, Sajad; Zekiy, Angelina Olegovna; Krutova, Marcela; Gholami, Mehrdad; Kouhsari, Ebrahim; Sholeh, Mohammad; Ghafouri, Zahra; Maleki, Farajolah title: Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review date: 2021-01-05 journal: Eur J Clin Microbiol Infect Dis DOI: 10.1007/s10096-020-04121-1 sha: cd090ae81c90c27419233904ccf71462fda945aa doc_id: 54793 cord_uid: jnbzon41 Tigecycline is unique glycylcycline class of semisynthetic antimicrobial agents developed for the treatment of polymicrobial infections caused by multidrug-resistant Gram-positive and Gram-negative pathogens. Tigecycline evades the main tetracycline resistance genetic mechanisms, such as tetracycline-specific efflux pump acquisition and ribosomal protection, via the addition of a glycyclamide moiety to the 9-position of minocycline. The use of the parenteral form of tigecycline is approved for complicated skin and skin structure infections (excluding diabetes foot infection), complicated intra-abdominal infections, and community-acquired bacterial pneumonia in adults. New evidence also suggests the effectiveness of tigecycline for the treatment of severe Clostridioides difficile infections. Tigecycline showed in vitro susceptibility to Coxiella spp., Rickettsia spp., and multidrug-resistant Neisseria gonnorrhoeae strains which indicate the possible use of tigecycline in the treatment of infections caused by these pathogens. Except for intrinsic, or often reported resistance in some Gram-negatives, tigecycline is effective against a wide range of multidrug-resistant nosocomial pathogens. Herein, we summarize the currently available data on tigecycline pharmacokinetics and pharmacodynamics, its mechanism of action, the epidemiology of tigecycline resistance, and its clinical effectiveness. The increasing incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacterial pathogens is a major public health concern that poses an economic burden to healthcare system due to prolonged hospital stays and higher morbidity and mortality [1] . Tigecycline is a tetracycline-class antibacterial agent developed for the treatment of polymicrobial MDR infections [2] including both Gramnegative and Gram-positive bacteria. Tigecycline, known as GAR-936, or Tygacil, is the first, unique glycylcycline class of semisynthetic agents which is administered in a parenteral form [3] and was approved by the Food and Drugs Administration (FDA) in 2005 [4] . Later, in 2010, the FDA issued an alert that use of tigecycline in the treatment of severe infections and sepsis was significantly associated with an increased risk for all-cause mortality [5] . Currently, tigecycline has been approved as a monotherapy in adults for three indications including complicated skin and skin structures infections (cSSTI) with the exclusion of diabetes foot infection, complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CAP) [6, 7] , and recent evidence suggests that tigecycline may be effective in the treatment of severe Clostridioides difficile infection [8] . The resistance to tigecycline includes chromosomally or accessory gene-encoded mechanisms. Herein, we summarize the currently available data on tigecycline pharmacokinetics and pharmacodynamics, its mechanism of action, the epidemiology of tigecycline resistance, and its clinical effectiveness. Tigecycline is chemically (4 S, 4 aS,5 aR,12aS)-9-[2-(tertbutylamino) acetami do]-4,7-bis(dimethylamino)l,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-l, ll-dioxo-2-naphthacene-carboxamide [6, 9] . Its chemical formula is C29H39N508 with molecular weight of 585.65 Da [10] . Tigecycline is a chemically modified minocycline (9-tbutylglycylamido derivative of minocycline) [6, 9] . Compared with other tetracyclines, tigecycline's extended, wide-range antibiotic activity is due to a main backbone of minocycline with an N-alkyl-glycylamido side chain addition to the C9 carbon of the "D" tetracycline ring [6, 9] . Due to insufficient absorption from the gut, tigecycline administration is intravenous;~30-60 min every 12 h [6] . The in vitro plasma protein binding of tigecycline at 0.1, 1, and 15 ug/mL was reported as 71, 89, and 96, respectively, and showed nonlinear plasma-protein-binding behavior since the unbound fraction of tigecycline decreased with an increase in the total concentration of tigecycline [11] . Tigecycline has a systemic clearance (from 0.2 to 0.3 L/h/kg), a large volume of distribution (7-10 L/kg), and extensive distribution into various tissues [10] . The recommended standard dosage regimen for tigecycline is an initial dose of 100 mg followed by 50 mg every 12 hrs [12] . The recommended duration of treatment with tigecycline for cSSTI or cIAI and CAP is 5-14 and 7-14 days, respectively [13] . Tigecycline is excreted mainly unchanged in the bile [12] and has a very long half-life (t1/2) in humans (~27-42 h) [12] . Tigecycline achieves therapeutic concentrations by effectively and extensively penetrating body fluids and tissues, such as the lungs, skin, liver, heart, bone, and kidneys [14] [15] [16] . Tigecycline has relatively low mean steady-state serum concentrations of 0.403 mg/L and 0.633 mg/L in patients with cSSTI in the standard dosing [17] . The data on tigecycline pharmacokinetics showed that the ratio of tissue to serum tigecycline concentrations was 38-fold, 8.6-fold, 2.1-fold, 0.35-fold, and 0.58-fold higher in the gall bladder, lungs, colon, bone, and synovial fluid, measured at 4 h after administration of a single 100 mg dose [18] ; a higher ratio of tissue to serum of tigecycline in skin and soft tissue was also found after 1-6 days of standard treatment [15] . The penetration of tigecycline into bones was reported by Bhattacharya et al. (bone: serum ratio; 4.77-fold) [19] . Data from several pharmacokinetic-pharmacodynamic (PK/PD) analyses and clinical trials showed that the ratio for the area under the concentration time curve and minimal inhibitory concentration (AUC/MIC) for serum tigecycline concentrations is a predictor of therapeutic response [20, 21] . Tigecycline does not readily cross the blood-brain barrier. The experimental data suggested that tigecycline exhibits a time-dependent bactericidal activity and has a prolonged postantibiotic effect (PAE) against Gram-positive and Gramnegative pathogens following a 3 mg/kg dose [22] [23] [24] . In comparison to minocycline, tigecycline has a uniformly longer PAE for tested pathogens (3.4-4 h for Staphylococcus aureus and 1.8-2.9 h for Escherichia coli) [22, 23] . Tigecycline is eliminated from the body through biliary excretion in the feces (59%) and urine (22%). Age, sex, and renal function do not appear to interfere with the pharmacokinetics of tigecycline, and no dose adjustment is required for patients with renal impairment (including hemodialysis) [25] [26] [27] . However, clinical caution in the use of tigecycline is needed in patients who have severe hepatic dysfunction (Child Pugh C); an initial dose of 100 mg of tigecycline should be followed by reduced maintenance doses of 25 mg every 12 h [27-29]. Tigecycline is a bacteriostatic, parenteral glycylcycline antibiotic with a stronger (5-fold) binding affinity and structural similarities to the tetracyclines [4, 14, 27] . The main mechanism of action of tigecycline is similar to other tetracyclines in that it acts an inhibitor of bacterial protein translation (i.e., elongation of the peptide chain) via reversible binding to a helical region (H34) on the 30S subunit of bacterial ribosomes. The binding of tigecycline prevents the incorporation of amino acid residues into the elongation of peptide chains and results in the loss of peptide formation and bacterial growth [4, 14, 27] (Fig. 1) . Tigecycline was developed to overcome the main molecular mechanisms of tetracycline resistance, such as tetracycline-specific efflux pump acquisition [e.g., tet(A)] and ribosomal protection [e.g., tet(M)], through the addition of a glycyclamide moiety to the 9-position of minocycline. Antimicrobial susceptibility testing to tigecycline Alterations to the tetracycline structure resulted in an expansion of tigecycline's spectrum of an antibacterial activity against a wide spectrum of Gram-positive and Gram-negative pathogens [ Antibacterial activity was also observed against Coxiella burnetii derived from patients with acute Q fever [46] . The flow cytometry assay data suggest that tigecycline has antibacterial activity [(IC50) 0.71 × 10-3 μg/mL] against Orientia tsutsugamushi and that it may be a therapeutic option for the Some pathogens, such as P. aeruginosa, Proteus spp. Providencia spp., and Morganella spp., are intrinsically resistant to tigecycline [51-53] and the development of acquired resistance to tigecycline has been described in several bacterial species such as Acinetobacter baumannii, Klebsiella pneumonia, Enterobacter spp., and Bacteroides fragilis [49]. In the last decades, the emergence of tigecycline resistance has been reported worldwide [49, 54, 55] though there are relatively few data available regarding the molecular basis for resistance to tigecycline. As shown in vitro, the Tet proteins [e.g., Tet(X), Tet(A), Tet(K) and Tet(M)] have the potential to acquire mutations leading to a reduced susceptibility (i.e,. increased MICs) to tigecycline [56] possibly through the horizontal transfer of mobile genetic elements carrying several resistance genes. In addition, the mobile tigecycline-resistance tet(X) gene variants are newly emerging tigecycline resistance mechanisms in humans and animals [57] . The Tet(X) is a flavin-dependent monooxygenase that originated from Bacteroides spp. and was detected in Enterobacteriaceae and some Acinetobacter spp. isolates [58] [59] [60] . In Gram-negative bacteria, the chromosomally encoded, overexpression of resistance-nodulation division (RND) efflux pumps such as AdeABC, AdeFGH, AdeIJK, MexXY, and AcrAB are important molecular mechanisms in the resistance of bacteria to tigecycline [61-63]. The occurrence of increased MICs and resistance to tigecycline among Acinetobacter spp. was associated with the EUCAST -- EUCAST European Committee on Antimicrobial Susceptibility Testing, FDA Food and Drug Administration, BSAC British Society for Antimicrobial Chemotherapy, S sensitive, R:Resistance upregulation of AdeABC, AdeFGH, AdeIJK, AbeM, and AdeDE pumps and also the presence of the tetX gene [64, 65] although some studies noted that additional efflux pumps or different molecular mechanisms might contribute to tigecycline resistance [58, 66, 67] . The nucleotide and amino acid alterations in the AdeRS two-component system may lead to adeABC overexpression and tigecycline resistance [68] . Besides it was found that the BaeSR system positively regulates the expression of adeA and adeB and stimulated tigecycline-resistant strains [69] . Additional mechanisms of decreased susceptibility to tigecycline, such as a novel RND pump, the presence of tet(X1) or tetA genes, a mutation in the trm gene encoding S-adenosyl-L-methionine (SAM)-dependent methyltransferase, and a frameshift mutation in the plsC gene that encodes for 1-acylsn-glycerol-3-phosphate acyltransferase, have been detected in the clinical A. baumannii isolates [69] [70] [71] . The intrinsic resistance to tigecycline in Enterobacteriaceae has been described in Morganella morganii and Proteus mirabilis and was attributed to the constitutive upregulation of the multidrug AcrAB efflux pump [50] . The AcrAB efflux pumps and their regulatory genes also play a role in the decreased susceptibility to tigecycline in E. coli and Klebsiella spp. [55, 62, [72] [73] [74] . Currently, SoxS, MarA, RamA, and Rob have been characterized as global regulators of the AcrAB pump in Enterobacteriaceae [75] although the exact mechanism of AcrAB pump overexpression has not been clarified [76, 77] . Tigecycline is a possible substrate for the AcrAB and AcrEF pumps in E. coli [78] . The physiological role of the AcrAB pump in E. coli is critical, and it excretes a diversity of lipophilic and amphiphilic antibiotics as substrates [79] . MarA, SoxS, and Rob have been suggested as regulators involved in the MDR phenotype in E. coli [80] . One of the major mechanisms involved in the E. coli MDR phenotype is mediated by the mar regulon that stimulates the downregulation of the OmpF outer membrane porin and also stimulates the upregulation of the AcrAB efflux pump [81, 82] . In E. coli, MarA (controlled by the local repressor MarR) acts as a positive regulator of the AcrAB-TolC efflux pump [83] . Additionally, in some E. coli strains that have high tigecycline MICs, a frameshift mutation (insertion of a cytosine at position 355) has been described in marR (one of the targets for reduced susceptibility to tigecycline) that led to the overexpression of MarA and AcrAB pumps [83] . Linkevicius et al. [84] selected tigecycline-resistant E. coli mutants in vitro and evaluated their biological fitness and cross-resistance. A relatively low-level resistance and a high fitness cost were identified in isolates with mutations of efflux regulatory network genes (lon, acrR, and marR) and related lipopolysaccharide core biosynthesis pathway genes (lpcA, rfaE, rfaD, rfaC, and rfaF). Remarkably, the fitness cost of mutations in E. coli under tigecycline exposure may decrease the ability of mutants to trigger a successful infection [84] . The reduced fitness and virulence in clinical isolates when acrA and tolC were inactivated have already been described, implying that the AcrAB pump may also play a role in adaptation and host virulence [85] . However, more in vivo research is needed to determine how these different mutation types are involved in bacterial virulence. In K. pneumoniae, tigecycline resistance is related extensively to the overexpression of RamA [86, 87] . There is a positive association between the upregulation of ramA with an overexpression of AcrAB [75, [87] [88] [89] . Nevertheless, no association between the upregulation of ramA and AcrA expression has been described [90] . RarA is a new AraC-type global regulator that acts via the control of AcrAB and OqxAB efflux pump expression and is mediated by the MDR phenotype in K. pneumoniae [62, 88, 91] . However, He et al. have reported no marked correlation between OqxAB and tigecycline resistance [73] . Sheng et al. [92] have also proposed that RamA may be a positive regulator of the OqxAB pump since variants in ramR have been suggested as a mechanism of acrAB downregulation and tigecycline resistance [77, 92, 93] . IS5 element integration in the new efflux pump operon kpgABC is correlated with a novel mechanism for the rapid in vivo development of tigecycline non-susceptibility [94] . Villa et al. [77] highlighted the role of the ribosomal S10 protein mutation (a mutation in the rpsJ gene that has already been reported to reduce tigecycline susceptibility in both Gram-negative and positive bacteria) in conferring tigecycline resistance. In addition, an alternative pathway involved in K. pneumoniae resistance to tigecycline is the overexpression of marA that is associated with AcrAB upregulation overexpression [62, 88] . The failure of tigecycline treatment in patients with carbapenem-resistant K. pneumoniae (CRKP) strains that harbor the tetA gene has been reported [95] . Additional tigecycline resistance mechanisms conferred by Tet proteins (mainly Tet(X)) have been published, [96] . In a recent study conducted in China [97] , mutations in the ramR and tet(A) efflux genes were found to be the major tigecycline resistance mechanisms among the studied tigecycline-and carbapenem-resistant K. pneumoniae isolates. The upregulation of the SdeXY-HasF efflux pump (a part of the RND efflux pump family) has been associated with tigecycline resistance in S. marcescens [98] . The upregulation of the SdeXY-HasF efflux system that confers resistance to tigecycline is also active against ciprofloxacin and cefpirome. On the other hand, in an experimental mutant strain, the insertional independent inactivation of the sdeY and hasF genes also led to a reduced sensitivity to ciprofloxacin, cefpirome, and tetracycline [98] . Enterobacter spp. In Enterobacter spp., the ramA-mediated mechanisms involving AcrAB efflux pump regulation are the primary mechanisms of tigecycline resistance [62, 99] . In E. aerogenes and E. cloacae, the nucleotide mutations include frameshifts, deletions, and amino acid variations in ramR (mainly in the ligand-binding domain) that lead to the overexpression of ramA and tigecycline resistance [62] . However, the other probable alternative mechanisms of tigecycline resistance that have been reported in E. cloacae include ramA overexpression without any ramR alterations; rarA overexpression and upregulation of the OqxAB pump; and upregulation of the AcrAB through SoxS, RobA, and RamA [62, 85] . Further in vivo and in vitro investigations are needed to characterize fully the probable other efflux pumps and/or regulators involved in tigecycline resistance mechanisms in Enterobacteriaceae [73, 75, 90, 100] . In S. enterica, a positive correlation between the upregulation of ramA (via an inactivating mutation in ramR) and the consecutive overexpression of AcrAB with tigecycline resistance have been reported [101] [102] [103] , although how ramA is controlled in bacteria other than Salmonella spp. is currently unknown. Similar to tigecycline resistance in carbapenemresistant K. pneumoniae isolates, the combination of mutations in ramR and tet(A) genes was also reported in tigecycline-resistant S. enterica [61, 97, 104] . Currently, several Resistance-Nodulation-Division (RND) efflux pumps including MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM have been suggested as mechanisms for drug resistance in P. aeruginosa [105] [106] [107] [108] [109] [110] . Dean et al. suggested the overexpression of MexXY-OprM as a drug efflux-mediated tigecycline resistance mechanism [110, 111] . In addition, the overexpression of the SdeXY pump frequently underlies tigecycline intrinsic resistance in P. aeruginosa [110] . In addition, the expression of other efflux pumps in MDR P. aeruginosa isolates has also been reported [112, 113] . Relatively few data on tigecycline resistance in gram-positive bacteria are available. Overexpression of the multi-antimicrobial extrusion protein (MATE) family efflux pump MepA has been suggested as mechanism of decreased susceptibility to tigecycline in Staphylococcus aureus but does not confer resistance [52, 114, 115] . More recently, Fiedler et al. confirmed that overexpression of two tetracycline-resistance determinants, a tet(L)encoded Major facilitator superfamily (MFS) pump and a tet(M)-encoded ribosomal protection protein, confer tigecycline resistance in Enterococci spp. [116] . The mechanisms of resistance to tigecycline are shown in Fig. 1 . In September 2010, the FDA Adverse Event Reporting System (FAERS) reported [117] an increased risk of mortality with tigecycline (4%; 150/3788) compared with other antibiotics (3%; 110/3646) used to treat similar infections. However, data from a prospective, multicenter, noninterventional study demonstrated the efficacy and safety of tigecycline in a population of severely ill patients with complicated infections [118] . In a retrospective observational study, Kwon et al. [119] evaluated the efficacy and safety profile of tigecycline in comparison with colistin in XDR A. baumannii-positive patients. No difference was observed between both antibiotic groups in terms of treatment success and mortality rates. Serum creatinine elevation and nephrotoxic prevalence cases were observed more commonly in the colistin group (p = 0.028). On the other hand, the excess mortality of 16.7% (60.7 vs. 44%, 95% confidence interval 0.9-32.4%, p = 0.04) was reported in 294 of subjects treated with tigecycline versus colistin for the treatment of pneumonia caused by the multidrug-resistant A. baumannii [120] . In September 2013, FAERS analyzed the data from 10 clinical trials conducted only for FDA-approved uses (cSSSI, cIAI, CABP) [121] . This analysis showed a higher risk of mortality among subjects treated with tigecycline compared with comparators: 2.5 (66/2640) vs. 1.8% (48/2628), respectively. In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions. In a meta-analysis [122] of 5 trials, comparing tigecycline monotherapy versus combination therapy for the treatment of patients with hospital-acquired pneumonia, no significant difference was observed in the development of the mortality rate from two prospective cohort studies (OR = 2.22, 95% CI 0.79-6.20 p = 0.13). In a systematic review and meta-analysis [123] , including 24 controlled studies, tigecycline-induced secondary bacteremia was found in 4.6% (91/1961) of patients with bloodstream infections. All-cause mortality and clinical cure rates for tigecycline were relatively similar to control antibiotic agents. Tigecycline, in combination with other antimicrobial agents, was suggested as a suitable choice for at-risk patients with BSI. However, tigecycline is not superior to comparator agents for the treatment of serious infections [2] . Due to the rise of multidrug-resistant infections, tigecycline has been used for non-approved indications. In a Spanish university hospital, one-third of tigecycline prescriptions were non-approved mainly as a rescue therapy and concomitantly with other antibiotics in patients with nosocomial pneumonia [124] ; and in an Argentinean hospital, it was 79%, especially in ventilator-associated pneumonia due to MDR Acinetobacter spp. [125] . In a Taipei Veterans' General Hospital, tigecycline was used for non-Food and Drug Administration-approved indications, to treat healthcare-associated pneumonia (38, 57.6%), bacteremia (3, 4.5%), catheter-related infections (3, 4.5%), urinary tract infection (4, 6.1%), osteomyelitis (4, 6.1%), and others (2, 3%) [126] . In a Turkish university hospital, tigecycline was used in the intensive care unit for patients infected with carbapenem-resistant Acinetobacter baumannii [127] . A study carried out in a Lebanese tertiary-care hospital reported 81% of tigecycline non-approved indications in critically ill patients with non-inferior outcome to that of FDAapproved indications [128] . In a pediatric population, tigecycline is not recommended in children and adolescents below 18 years of age. However, clinical studies reported the efficacy of a tigecycline therapy combined with other antimicrobial agents in the treatment of multidrug-resistant infection, i.e., nosocomial infections in newborn infants [129] [130] [131] and carbapenem-resistant gramnegative bacteria infections in liver transplant recipients [132] . Recently, tigecycline was used as a treatment in a case of ventriculoperitoneal shunt-related meningitis in a 5-monthold infant [133] . Available evidence from 15 randomized controlled trials (RCTs), including a recent meta-analysis [134] , assessed the available data with regard to the effectiveness and safety of tigecycline in comparison to other antimicrobials in the treatment of 7689 adult patients with infectious diseases. Adverse events and all-cause mortality were frequent in the tigecycline group. Twelve of the 15 RCTs (6292/7689) described various adverse events with tigecycline use. The adverse events rate was considerably higher in the tigecycline group compared with the comparator drug group (OR = 1.49, 95% CI = 1.23 to 1.80, p < 0.0001). Based on the results from the preclinical animal safety studies, tigecycline was not thought to be teratogenic [27] ; however, in rats and dogs a decrease of white and red blood cells, bone marrow hypocellularity, reductions in fetal weights, and an increased incidence of fetal loss and minor skeletal abnormalities were reported [27, 135] . Now, tigecycline is categorized as teratogenic effect class D and should be used with caution in specific populations, including nursing mothers, pregnant women, pediatrics, and patients with severe hepatic impairment [4, 13, 27, 135, 136] . In addition, the use of tigecycline may affect tooth development particularly if used during the last half of pregnancy and in children under the age of 8 as it can cause permanent tooth discoloration [137] . The human clinical trial studies and the FAERS [138] reported that the most common side effects following tigecycline administration, especially in adults aged between 18 and 50 years, and which were more likely in women, are gastrointestinal (GI) symptoms, i.e., nausea, vomiting, and diarrhea. Further reported side effects relevant to tigecycline administration were pancreatitis, acute generalized exanthematous pustulosis, local reaction at the i.v. site, increased hepatic function, thrombophlebitis, pruritus, fever, mitochondrial dysfunction-associated acute metabolic acidosis abdominal pain, headache, cholestatic, jaundice, and Steven-Johnson syndrome [2, [139] [140] [141] [142] [143] [144] . Clinical studies showed a significant higher (~> 4-fold) incidence of nausea and vomiting induced by tigecycline in patients treated for cSSSI compared with patients treated with vancomycin/aztreonam. However, in patients with cIAI, the incidence of nausea and vomiting occurred equally often in patients treated with imipenem/cilastatin as it did in patients treated with tigecycline (25%/20% for tigecycline and 21%/ 15% for imipenem/cilastatin group, respectively). In community-acquired bacterial pneumonia, the occurrence of GI symptoms was higher in the group of patients treated with tigecycline than the group treated with levofloxacin [138] . The mechanism of action of tigecycline-associated nausea and vomiting remains uncertain and their incidence is dose-related [145] . Whether it is preventable by the pre-emptive use of antiemetics as concomitant drugs (metoclopramide. ondasetron, prochlorperazine, sucralfate, and trimethobenzamide) is unclear [146, 147] . From 2514 patients, the total discontinuation rate was 7% during tigecycline treatment and discontinuation was most frequently associated with nausea (1%) and vomiting (1%) [138] . The phase III clinical trials evaluated tigecycline tolerability and efficacy in patients receiving tigecycline (i.e., 100-mg IV loading dose followed by 50 mg IV q12h) [2, [148] [149] [150] [151] . The difference in the incidence of nausea and vomiting between tigecycline and the comparators (vancomycin+aztreonam or imipenem/cilastatin) was statistically significant (p < 0.05) in ≥ 2 of the 4 Phase III trials. [198] Clinical and pharmacokinetic literature outcomes stated that co-administration of tigecycline with food led to an improvement in the gastrointestinal adverse events; however it did not change the drug's pharmacokinetics [152] . In pancreatitis, the data from all phase 3 and 4 clinical trials found no significant difference in the incidence of pancreatitis between patients treated with tigecycline and patients treated with comparators [153] . On the other hand, a significantly higher rate of pancreatitis of 20% (cases = 10) was observed in a French study [154] . The exact mechanism of tigecycline-induced pancreatitis is unclear; however, some suggested mechanisms are hypertriglyceridemia and toxic metabolite formation that might be involved in the development of tigecyclineinduced pancreatitis [153] [154] [155] . Several studies also reported tigecycline-induced coagulopathy [156, 157] . The impact of a recommended dose of tigecycline, 50 mg q12h and/or a higher dose of 100 mg q12h, on coagulation parameters in 50 patients with severe infection was evaluated in a Chinese retrospective analysis [158] . A considerable decrease in the levels of plasma fibrinogen (p < 0.001) and a significant increase in the mean values of prothrombin time (PT) and activated partial thromboplastin time (aPTT) (p ≤ 0.002) were observed. In another study, non-anion gap acute metabolic acidosis (NAGAMA), developed through mitochondrial toxicity, was observed after an unusually high dose of 100 mg, twice daily following a single 200 mg loading dose of tigecycline administration; however, the mechanism of NAGAMA is unclear [34] . The routine monitoring of pancreatitis, NAGAMA, and coagulation parameters may be a necessity when administering tigecycline to critically ill patients. The coadministration of tigecycline and warfarin (25 mg single dose) to healthy volunteers resulted in a 40 and 23% decrease in the clearance of R-warfarin and S-warfarin and their AUC, from time zero extrapolated to infinity, was increased by 68 and 29%, respectively [159] . The prothrombin time, or any other suitable anticoagulation test, should be used if tigecycline is administered with warfarin. The prevalence of tigecycline resistance by continent A summary of tigecycline resistance studies according to the individual countries worldwide are shown in Table 2 and Table 3 . In Asia, the occurrence of tigecycline resistance was reported in different bacterial species ranging from 0.% to 66% with a different distribution within the individual Asian countries ( Table 2) . The most frequently reported species, regarding tigecycline resistance, was A. baumannii [174] with a high resistance rate of 66% revealed in Israel [150] . In Enterobacteriaceae, a tigecycline resistance of 11% was reported for NDM-1-positive isolates from Pakistan and, a resistance of 37.9% was reported for tigecycline nonsusceptible Metallobeta-lactamases producing isolates from Taiwan [167] ; the prevalence of tigecycline-resistant K. pneumoniae was found to be 1.3% [183] . The reports of tigecycline-resistant K. pneumoniae came from Saudi Arabia [160, 169, 173] , Taiwan [144] , and Lebanon [169] ; further tigecycline resistance was reported for Escherichia coli, Enterobacter cloacae, and S. marcescens [194, 217] . In other gram-negatives, tigecycline resistance was reported in S. maltophilia from Taiwan and China [165, 166, 181] and in 90% of Pseudomonas aeruginosa isolates from India [163] . For gram-positive pathogens, a tigecycline resistance rate of 3% in MRSA isolates [49, 218] was reported from India by Veeraraghavan et al. and in the study of Sharma et al.; 53.5% (n = 68) of S. aureus isolates showed non-susceptibility to tigecycline [179] . In recent years, the trend of increasing minimal inhibitory concentrations to tigecycline and linezolid was observed in Taiwan; however, strains with resistance to these agents were rare [219] . Interestingly, a 2% tigecycline resistance rate was reported in S. pneumoniae isolates gathered between 2004 and 2010 from the Asia-Pacific region, while in 2015, all S. pneumoniae isolates investigated were susceptible to tigecycline [220] . Tigecycline resistance i s frequently stu died i n Enterobacteriaceae in Europe (Table 2 ). In ESBL producing Enterobacteriaceae, tigecycline resistance was reported in Italy, Belgium, Turkey, and France [187, 194, 195, 207] . Sader et al. reported that 11.4% of European carbapenem-resistant Enterobacteriaceae are not susceptible to tigecycline [192] . In France, cephalosporin-resistant Enterobacteriaceae were shown to be not susceptible to tigecycline in 23.8% of isolates [190] . For other gram-negative pathogens, resistance to tigecycline was reported in Acinetobacter baumannii [185, [221] [222] [223] [224] , as well as S. marcescens [211] and H. influenzae [211] . In grampositive pathogens, tigecycline resistance was reported in two and three MRSA isolates from the Netherlands [225] . In Spain, tigecycline resistance was identified in E. faecium, E. faecalis and viridans streptococci [186] and in Germany, in E. faecalis [197] . In anaerobes, tigecycline resistance was investigated in the B. fragilis group in a Europe-wide study involving 13 countries, and a resistance rate of 1.7% was detected [226] . In the USA, high resistance rates to tigecycline were reported in K. pneumoniae (9.2%), E. aerogenes (20.8%), K. oxytoca (38.5%), E. cloacae (25.4%), and S. marcescens (20.0%) [202] . Sporadic cases were detected in A. baumannii [148, 150, [227] [228] [229] and B. fragilis [201] . ESBL-producing Enterobacteriaceae were shown to be tigecycline-resistant in the USA and Latin America [206] . In gram-positive pathogens, tigecycline resistance was reported in 9% of S. aureus in Mexico [207] . The tigecycline resistance rates in isolates collected between 2004-2016 in Africa were 5.8% ( 37/642) lower than in Europe (37.4%; 240/642) and North America (36.8%; 236/ 642) [49] . In the study of Seifert et al., 1.1% of Enterobacter spp. and 1.3% of S. marcescens isolates were tigecyclineresistant [183] . In the South of the continent, resistance to tigecycline was reported in A. baumannii, K. pneumoniae, Enterobacter spp., C. freundii, P. aeruginosa, and S. marcescens [198, [230] [231] [232] [233] [234] . Tigecycline is a unique glycylcycline class of semisynthetic agents designed to overcome the main tetracycline resistance mechanisms. Although tigecycline was approved for cSSTI, cIAI, and CAP in adults, its therapeutic potential is undoubtedly wider. Its antimicrobial activity against anaerobes and its greater penetration into tissues is advantageous for the treatment of inflammatory lesions and granulomas. Recently available clinical data support the use of tigecycline in severe C. difficile infections. In vitro antimicrobial susceptibility testing showed the susceptibility of a number of pathogens to tigecycline including those MDR pathogens associated with healthcare infections. However, the bacteriostatic activity of tigecycline is probably associated with a higher mortality risk in patients with sepsis or severe infection. (1) The antibiotic resistance crisis: part 1: causes and threats Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis Oritavancin and tigecycline: investigational antimicrobials for multidrug-resistant bacteria Tigecycline: an update FDA U FDA drug safety communication: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections FDA drug safety communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new boxed warning. US Food and Drug Administration Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis Tigecycline for the treatment of patients with Clostridium difficile infection: an update of the clinical evidence Tigecycline-induced acute pancreatitis: about two cases and review of the literature Antibiotic and chemotherapy e-book Determination of atypical nonlinear plasma-protein-binding behavior of tigecycline using an in vitro microdialysis technique Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases: 2-Volume Set Redefining tigecycline therapy Tigecycline: Alone or in combination? Tigecycline penetration into skin and soft tissue Tissue distribution of GAR-936, a broad spectrum antibiotic in male rats Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose Reassessment of tigecycline bone concentrations in volunteers undergoing elective orthopedic procedures Exposureresponse analyses of tigecycline efficacy in patients with complicated skin and skin-structure infections Exposureresponse analyses of tigecycline efficacy in patients with complicated intra-abdominal infections Tigecycline in the treatment of complicated intra-abdominal and complicated skin and skin structure infections In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria Pharmacokinetics, pharmacodynamics, safety and tolerability of tigecycline Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects enterica serovar Hadar resistant to tigecycline Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes RamA, a transcriptional regulator, and AcrAB, an RND-type efflux pump, are associated with decreased susceptibility to tigecycline in Enterobacter cloacae Effect of proton pump inhibitors on in vitro activity of tigecycline against several common clinical pathogens Genetic variability of AdeRS two-component system associated with tigecycline resistance in XDR-Acinetobacter baumannii isolates AdeRS combination codes differentiate the response to efflux pump inhibitors in tigecycline-resistant isolates of extensively drug-resistant Acinetobacter baumannii RND-type efflux pumps in multidrug-resistant clinical isolates of Acinetobacter baumannii: major role for AdeABC overexpression and AdeRS mutations A truncated AdeS kinase protein generated by ISAba1 insertion correlates with tigecycline resistance in Acinetobacter baumannii Role of the BaeSR two-component system in the regulation of Acinetobacter baumannii adeAB genes and its correlation with tigecycline susceptibility Decreased susceptibility to tigecycline in Acinetobacter baumannii mediated by a mutation in trm encoding SAMdependent methyltransferase Contribution of efflux pumps, porins, and βlactamases to multidrug resistance in clinical isolates of Acinetobacter baumannii AcrAB efflux pump plays a role in decreased susceptibility to tigecycline in Morganella morganii Tigecycline susceptibility and the role of efflux pumps in tigecycline resistance in KPC-producing Klebsiella pneumoniae Effect of transcriptional activators SoxS, RobA, and RamA on expression of multidrug efflux pump AcrAB-TolC in Enterobacter cloacae Genetic characterisation of clinical Klebsiella pneumoniae isolates with reduced susceptibility to tigecycline: Role of the global regulator RamA and its local repressor RamR Deaths attributable to carbapenem-resistant Enterobacteriaceae infections Genomics of KPC-producing Klebsiella pneumoniae sequence type 512 clone highlights the role of RamR and ribosomal S10 protein mutations in conferring tigecycline resistance Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936) Substrate specificity of the RNDtype multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominately by two large periplasmic loops RamA is an alternate activator of the multidrug resistance cascade in Enterobacter aerogenes Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli Mechanisms and fitness costs of tigecycline resistance in Escherichia coli Involvement of the AcrAB-TolC efflux pump in the resistance, fitness, and virulence of Enterobacter cloacae Real-time PCR and statistical analyses of acrAB and ramA expression in clinical isolates of Klebsiella pneumoniae Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae First emergence of acrAB and oqxAB mediated tigecycline resistance in clinical isolates of Klebsiella pneumoniae pre-dating the use of tigecycline in a Chinese hospital Tigecycline susceptibility in Klebsiella pneumoniae and Escherichia coli causing neonatal septicaemia (2007-10) and role of an efflux pump in tigecycline non-susceptibility Genetic regulation of the ramA locus and its expression in clinical isolates of Klebsiella pneumoniae Elucidating the regulon of multidrug resistance regulator RarA in Klebsiella pneumoniae Mechanisms of tigecycline resistance among Klebsiella Eur J Clin Microbiol Infect Dis pneumoniae clinical isolates ramR mutations in clinical isolates of Klebsiella pneumoniae with reduced susceptibility to tigecycline IS5 element integration, a novel mechanism for rapid in vivo emergence of tigecycline nonsusceptibility in Klebsiella pneumoniae Comparison of polymyxin B, tigecycline, cefepime, and meropenem MICs for KPCproducing Klebsiella pneumoniae by broth microdilution, Vitek 2, and Etest Tygacil®(package insert) Roles of ramR and tet (A) mutations in conferring tigecycline resistance in carbapenemresistant Klebsiella pneumoniae clinical isolates Tigecycline resistance in Serratia marcescens associated with up-regulation of the SdeXY-HasF efflux system also active against ciprofloxacin and cefpirome Emergence of AcrAB-mediated tigecycline resistance in a clinical isolate of Enterobacter cloacae during ciprofloxacin treatment Genome sequencing and genomic characterization of a tigecycline-resistant Klebsiella pneumoniae strain isolated from the bile samples of a cholangiocarcinoma patient ramR mutations involved in efflux-mediated multidrug resistance in Salmonella enterica serovar Typhimurium Decreased fluoroquinolone susceptibility in mutants of Salmonella serovars other than Typhimurium: detection of novel mutations involved in modulated expression of ramA and soxS Ciprofloxacin selects for multidrug resistance in Salmonella enterica serovar Typhimurium mediated by at least two different pathways The tetA gene decreases tigecycline sensitivity of Salmonella enterica isolates Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa Expression in Escherichia coli of a new multidrug efflux pump, MexXY, from Pseudomonas aeruginosa Overexpression of the mexC-mexD-oprJ efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1 Tigecycline: a new glycylcycline for treatment of serious infections Two efflux systems expressed simultaneously in multidrug-resistant Pseudomonas aeruginosa Contribution of multidrug efflux pumps to multiple antibiotic resistance in veterinary clinical isolates of Pseudomonas aeruginosa A novel MATE family efflux pump contributes to the reduced susceptibility of laboratoryderived Staphylococcus aureus mutants to tigecycline Structural basis for TetMmediated tetracycline resistance Tigecycline resistance in clinical isolates of Enterococcus faecium is mediated by an upregulation of plasmid-encoded tetracycline determinants tet (L) and tet (M) FDA drug safety communication: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections Prospective, non-interventional, multi-centre trial of tigecycline in the treatment of severely ill patients with complicated infections-new insights into clinical results and treatment practice Efficacy and safety profile comparison of colistin and tigecycline on the extensively drug resistant Acinetobacter baumannii Effectiveness of tigecycline-based versus colistin-based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumanniiin a critical setting: a matched cohort analysis Food Administration D (2015) Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND Efficacy and safety of tigecycline monotherapy versus combination therapy for the treatment of hospital-acquired pneumonia (HAP): a metaanalysis of cohort studies The efficacy and safety of tigecycline for the treatment of bloodstream infections: a systematic review and meta-analysis Off-label prescription of tigecycline: clinical and microbiological characteristics and outcomes Late onset ventilator-associated pneumonia due to multidrug-resistant Acinetobacter spp.: experience with tigecycline Infection (2011) Clinical experience with tigecycline as treatment for serious infections in elderly and critically ill patients Outcomes in patients infected with carbapenem-resistant Acinetobacter baumannii and treated with tigecycline alone or in combination therapy Prescription patterns for tigecycline in severely ill patients for non-FDA approved indications in a developing country: A compromised outcome Tigecycline Use in Neonates: 5-Year Experience of a Tertiary Center Safety and efficacy of tigecycline to treat multidrug-resistant infections in pediatrics: an evidence synthesis Effectiveness of tigecycline in the treatment of infections caused by carbapenem-resistant gram-negative bacteria in pediatric liver transplant recipients: A retrospective study Tigecycline therapy in an infant for ventriculoperitoneal shunt meningitis Efficacy and safety of tigecycline for the treatment of severe infectious diseases: an updated meta-analysis of RCTs Organism (no tested)/% susceptible/ antimicrobial agent MIC50 MIC90 Range resistant a Is there a future for tigecycline Tigecycline salvage therapy for critically ill children with multidrug-resistant/extensively drug-resistant infections after surgery Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project Acute generalized exanthematous pustulosis associated with tigecycline Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline) Efficacy and safety of tigecycline: a systematic review and meta-analysis High Dose Tigecycline-Induced Mitochondrial Dysfunction-Associated Acute Metabolic Acidosis: A Retrospective Study Tigecycline-induced acute pancreatitis in a renal transplant patient: a case report and literature review Tigecycline: first of a new class of antimicrobial agents Guideline: appropriate use of tigecycline Tigecycline: an antibiotic for the twenty-first century Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumannii Rapid development of Acinetobacter baumannii resistance to tigecycline A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae Pharmacokinetics (PK), safety and tolerability of GAR-936, a novel glycylcycline antibiotic, in healthy subjects. 39th Interscience Conference on The antibiotic drug tigecycline: a focus on its promising anticancer properties True incidence of tigecycline-induced pancreatitis: how many cases are we missing? Tigecycline in the treatment of patients with necrotizing skin and soft tissue infections due to multiresistant bacteria Hypofibrinogenemia induced by tigecycline: a potentially life-threatening coagulation disorder Tigecycline-induced coagulopathy A Retrospective Analysis of the Effect of Tigecycline on Coagulation Function Evaluation of a potential tigecycline-warfarin drug interaction Evolution of tigecycline resistance in Klebsiella pneumoniae in a single patient Emergence of tigecycline & colistin resistant Acinetobacter baumanii in patients with complicated urinary tract infections in north India Emergence of tigecycline and colistin resistance in Acinetobacter species isolated from patients in Kuwait hospitals Evaluation of tigecycline activity in clinical isolates among Indian medical centers In vitro susceptibilities of clinical isolates of ertapenemnon-susceptible Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other antimicrobial agents A multicenter surveillance of antimicrobial resistance on Stenotrophomonas maltophilia in Taiwan Detection of the Smqnr quinolone protection gene and its prevalence in clinical isolates of Stenotrophomonas maltophilia in China Metallo-β-lactamase-producing Enterobacteriaceae isolates at a Taiwanese hospital: lack of distinctive phenotypes for screening Prevalence of faecal carriage of Enterobacteriaceae with NDM-1 carbapenemase at military hospitals in Pakistan, and evaluation of two chromogenic media Tigecycline in vitro activity against commonly encountered multidrug-resistant Gram-negative pathogens in a Middle Eastern country In-vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii in Taiwan Tigecycline susceptibility report from an Indian tertiary care hospital Differences in phenotypic and genotypic characteristics among imipenem-nonsusceptible Acinetobacter isolates belonging to different genomic species in Taiwan In vitro activity of tigecycline against clinical isolates of multidrug-resistant Acinetobacter baumannii in Siriraj Hospital, Thailand High tigecycline resistance in multidrug-resistant Acinetobacter baumannii Clonal spread of multidrug-resistant Acinetobacter baumannii in eastern Taiwan In vitro activity of tigecycline against colistin-resistant Acinetobacter spp. isolates from Korea Prevalence and diversity of carbapenemases among imipenem-nonsusceptible Acinetobacter isolates in Korea: emergence of a novel OXA-182 Colistin and tigecycline susceptibility among multidrug-resistant Acinetobacter baumannii isolated from ventilator-associated pneumonia Tigecycline Resistance among Clinical Isolates of Staphylococcus aureus from North-east India In-vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii in Taiwan determined by the broth microdilution and disk diffusion methods Frequency and genetic determinants of tigecycline resistance in clinically isolated stenotrophomonas maltophilia in Beijing Tigecycline resistance among carbapenem-resistant Klebsiella pneumoniae: clinical characteristics and expression levels of efflux pump genes In vitro activity of tigecycline and comparators (2014-2016) among key WHO 'priority pathogens' and longitudinal assessment (2004-2016) of antimicrobial resistance: a report from the TEST study Antimicrobial susceptibility of Bacteroides fragilis group isolates in Europe: 20 years of experience In vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii and Stenotrophomonas maltophilia Susceptibility to tigecycline of isolates from samples collected in hospitalized patients with secondary peritonitis undergoing surgery Study on in-vitro susceptibility of ESBL-positive Escherichia coli isolated from urine specimens. Le infezioni in medicina: rivista periodica di eziologia, epidemiologia, diagnostica Susceptibility of Klebsiella spp. to tigecycline and other selected antibiotics In vitro activity of tigecycline against m ultidrug-resistant Enterobacteriaceae isolates from a Belgian hospital Tigecycline: CMI 50/90 towards 1766 Gram-negative bacilli (3rd generation cephalosporins resistant Enterobacteriaceae), Acinetobacter baumannii and Eur J Clin Microbiol Infect Dis Bacteroides fragilis group Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin Tigecycline activity tested against carbapenemresistant Enterobacteriaceae from 18 European nations: results from the SENTRY surveillance program In vitro activity of tigecycline against 2423 clinical isolates and comparison of the available interpretation breakpoints Antimicrobial susceptibility of gram-negative and gram-positive bacteria collected from countries in Eastern Europe: results from the Tigecycline Evaluation and Surveillance Trial (TEST) 2004-2010 A longitudinal assessment of antimicrobial susceptibility among important pathogens collected as part of the Tigecycline Evaluation and Surveillance Trial (TEST) in France between Emergence of an Enterobacter hormaechei strain with reduced susceptibility to tigecycline under tigecycline therapy Tigecycline-resistant Enterococcus faecalis strain isolated from a German intensive care unit patient In vitro activity of tigecycline against clinical isolates of carbapenem resistant Acinetobacter baumannii complex in Pretoria, South Africa Antimicrobial resistance surveillance in the South African public sector Antimicrobial resistance surveillance in the South African private sector report for 2016 Multi-drug resistant Bacteroides fragilis recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan Regional variations in multidrug resistance among Enterobacteriaceae in the USA and comparative activity of tigecycline, a new glycylcycline antimicrobial Rates of antimicrobial resistance in Latin America (2004-2007) and in vitro activity of the glycylcycline tigecycline and of other antibiotics Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance Trial (TEST) Susceptibility of important Gram-negative pathogens to tigecycline and other antibiotics in Latin America between Update on antimicrobial susceptibility rates among gram-negative and gram-positive organisms in the United States: results from the Tigecycline Evaluation and Surveillance Trial (TEST) Prevalence of multidrug-resistant bacteria at a tertiarycare teaching hospital in Mexico: special focus on Acinetobacter baumannii Analysis of 3789 in-and outpatient Escherichia coli isolates from across Canada-results of the CANWARD 2007-2009 study Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing Enterobacteriaceae Global assessment of the activity of tigecycline against multidrugresistant Gram-negative pathogens between 2004 and 2014 as part of the Tigecycline Evaluation and Surveillance Trial Global assessment of antimicrobial susceptibility among Gram-negative organisms collected from pediatric patients between 2004 and 2012: results from the Tigecycline Evaluation and Surveillance Trial Comprehensive assessment of tigecycline activity tested against a worldwide collection of Acinetobacter spp In vitro activity of tigecycline and comparator agents against a global collection of Gram-negative and Gram-positive organisms: tigecycline Evaluation and Surveillance Trial Global in vitro activity of tigecycline and comparator agents: Tigecycline Evaluation and Surveillance Trial Tigecycline activity tested against antimicrobial resistant surveillance subsets of clinical bacteria collected worldwide Antimicrobial susceptibility among gram-negative isolates collected from intensive care units in North America In vitro susceptibilities of clinical isolates of ertapenem-nonsusceptible Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other antimicrobial agents In-vitro activity of tigecycline and comparator agents against common pathogens: Indian experience Trends in the susceptibility of methicillin-resistant Staphylococcus aureus to nine antimicrobial agents Antimicrobial activity among gram-positive and gram-negative organisms collected from the Asia-Pacific region as part of the Tigecycline Evaluation and Surveillance Trial: Comparison of 2015 results with previous years In vitro activity of tigecycline against multidrug-resistant Acinetobacter baumannii clinical isolates. Le infezioni in medicina: rivista periodica di eziologia, epidemiologia, diagnostica In vitro activity of tigecycline against multidrug-resistant Acinetobacter baumannii Failure of tigecycline to treat severe Clostridium difficile infection First description of colistin and tigecyclineresistant Acinetobacter baumannii producing KPC-3 carbapenemase in Portugal In vitro activity of tigecycline against methicillin-resistant Staphylococcus aureus, including livestock-associated strains Antimicrobial susceptibility of Bacteroides fragilis group isolates in Europe: 20 years of experience Tigecycline for the treatment of Acinetobacter infections: a case series Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report Antimicrobial susceptibility of extended-spectrum β-lactamase producers and multidrug-resistant Acinetobacter baumannii throughout the United States and comparative in vitro activity of tigecycline, a new glycylcycline antimicrobial The molecular epidemiology and genetic environment of carbapenemases detected in Africa Current state of resistance to antibiotics of last-resort in South Africa: a review from a public health perspective NDM-1 imported from India-first reported case in South Africa Colistin and tigecycline resistance in carbapenemase-producing Gramnegative bacteria: emerging resistance mechanisms and detection methods Molecular epidemiology of carbapenem, colistin and tigecycline resistant Enterobacteriaceae in Durban Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Acknowledgments We thank the Dr. Abazar Pournajaf for scientific reviewing and kind support.Availability of data and material All the data in this review are included in the manuscript.