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Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections Matthew E. Falagas a,b,c,∗ , Konstantinos Z. Vardakas a,b , Konstantinos P. Tsiveriotis a , Nikolaos A. Triarides a,b , Giannoula S. Tansarli a a

Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece Department of Internal Medicine – Infectious Diseases, Mitera Hospital, Hygeia Group, Athens, Greece c Tufts University School of Medicine, Boston, MA, USA b

a r t i c l e

i n f o

Article history: Received 14 January 2014 Accepted 15 January 2014 Keywords: Acinetobacter MDR PDR XDR Enterobacteriaceae Intensive care unit

a b s t r a c t Here we review the effectiveness and safety of high-dose tigecycline (200 mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100 mg every 12 h (q12 h) group and 69.6% (16/23) in the 75 mg q12 h group (P = 0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P > 0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200 mg and 150 mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100 mg q12 h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50 mg q12 h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction New classes of antibiotics against Gram-negative bacteria are not available and resistance to the currently available antibiotics is spreading. Furthermore, recent studies showed that higher minimum inhibitory concentrations (MICs) within the susceptible range both for Gram-positive and Gram-negative bacteria were associated with higher mortality [1,2]. Tigecycline was approved in 2005 by the US Food and Drug Administration (FDA) for complicated skin and soft-tissue infections, complicated intra-abdominal infections (IAIs) and community-acquired pneumonia and since then has been used as a last-resort treatment option against severe

∗ Corresponding author at: Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel.: +30 694 61 10 000; fax: +30 210 68 39 605. E-mail address: [email protected] (M.E. Falagas).

infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter spp. [3,4] and Enterobacteriaceae [5–7]. In addition, the combination of tigecycline with another antimicrobial agent is considered even in the treatment of nosocomial pneumonia due to pandrug-resistant Acinetobacter baumannii infections [8]. Tigecycline was approved for administration at a loading dose of 100 mg followed by 50 mg twice daily [9]. However, high percentages of treatment failure and higher mortality among patients treated with the standard dose of tigecycline were documented [10–14]. Studies in healthy volunteers showed that a dose increase improved the pharmacokinetic/pharmacodynamic (PK/PD) properties of tigecycline at the expense of more gastrointestinal adverse events [15]. A phase 2 randomised controlled trial (RCT) in patients with nosocomial pneumonia was conducted comparing two different higher than approved doses [16].

0924-8579/$ – see front matter © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006

Please cite this article in press as: Falagas ME, et al. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006

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In this systematic review, we aimed to evaluate the available evidence regarding the effectiveness and safety of higher than approved doses of tigecycline. 2. Methods

the outcomes of patients receiving low-dose tigecycline. In addition, the percentage of patients treated with high-dose tigecycline was not reported in three studies [25–27], whilst this percentage was very small in the remaining study [24]. These studies were therefore excluded from the review (Table 1).

2.1. Literature search

3.1. Randomised controlled trial

A systematic search was performed in PubMed and Scopus databases in September 2013. The search term applied to both databases was the following: ‘(tigecycline) AND (received OR administered OR dose) AND (mortality OR survival OR died OR survived OR cure OR failure OR success OR response)’. Abstracts presented at scientific conferences (Interscience Conference on Antimicrobial Agents and Chemotherapy, European Congress of Clinical Microbiology and Infectious Diseases, and International Symposium on Intensive Care Unit and Emergency Medicine) or at conferences and meetings of the Infectious Diseases Society of America, International Society for Infectious Diseases, International Society for Chemotherapy, and European Society of Intensive Care Medicine were also searched to find further potentially eligible studies. Finally, the bibliographies of all relevant articles were hand-searched. Articles published in a language other than English, German, French, Spanish, Italian or Greek were not evaluated.

The only RCT included in the review was a multicentre, phase 2, double-blind RCT including 105 patients with hospitalacquired pneumonia [the scope was to enrol mainly patients with ventilator-associated pneumonia (VAP)] due to Gram-negative or Gram-positive bacteria [16]. The trial was terminated early because of inability to recruit patients up to the scheduled 210 patients, mainly those with VAP. The enrolled patients were randomised to receive one of the following antibiotic regimens: tigecycline 200 mg loading dose followed by 100 mg q12 h (35 patients); tigecycline 150 mg loading dose followed by 75 mg q12 h (36 patients); or imipenem/cilastatin 1 g every 8 h (q8 h) (34 patients). Empirical treatment with ceftazidime 2 g q8 h and tobramycin 7 mg/kg of body weight daily or amikacin 20 mg/kg daily and vancomycin placebo were administered to patients receiving tigecycline at the start of treatment when Pseudomonas aeruginosa or meticillinresistant Staphylococcus aureus (MRSA) infection was suspected. However, patients with confirmed P. aeruginosa infection were eventually excluded from the study. Patients with late-onset nosocomial pneumonia (80%) were mainly enrolled; 39% of patients had VAP. There were no differences in demographic characteristics and mean age between patients in the 200 mg and 150 mg daily groups. Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score, Clinical Pulmonary Infection Score (CPIS) and late-onset nosocomial pneumonia were also similar. Significantly more patients in the 200 mg daily group had treatment failures prior to tigecycline administration. Treatment duration and administration of adjunctive antibiotics were similar in the two groups. Clinical response in the clinically evaluable patients at the test-of-cure visit was 85.0% (17/20) in the group receiving 200 mg daily and 69.6% (16/23) in the group receiving 150 mg daily. The difference in clinical response between the two groups was not statistically significant (P = 0.4). In patients with VAP, higher APACHE II score, higher CPIS or prior antibiotic failure, the clinical response was numerically higher with tigecycline 200 mg daily than tigecycline 150 mg daily (85.7% vs. 71.4%, 100% vs. 33.3%, 80% vs. 54.5% and 83.3% vs. 33.3%, respectively). Three (8.6%) and 7 (19.4%) patients died in the 200 mg and 150 mg daily dose groups, respectively. None of the reported deaths was related to tigecycline. With regard to safety of the tigecycline regimens, the incidence of diarrhoea, treatment-related nausea and vomiting was 14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8% in the group treated with 200 mg daily versus 150 mg daily, respectively (P > 0.05 for all comparisons). Most of the treatment-related adverse events were mild or moderate in severity. In addition, 25.7% and 33.3% of patients, respectively, receiving 200 mg or 150 mg daily experienced serious adverse events, but the percentage of patients with treatment-related serious adverse events was not reported. Comparable numbers of patients in all treatment groups discontinued treatment because of adverse events.

2.2. Study selection Studies comparing clinical outcomes between patients treated with high-dose tigecycline with those treated with lower doses as well as cohort studies reporting on the outcomes of patients receiving high-dose tigecycline were considered eligible for inclusion in the review. Case reports and case series as well as unpublished abstracts presented at scientific conferences were also eligible. Clinical studies reporting on PK/PD outcomes were excluded from the review. 2.3. Data extraction and outcomes The extracted data consisted of the name of the first author of the study, year of publication, study period and design, number of patients, site of infection, causative pathogen, dosing regimen of tigecycline and concomitant antibiotic treatment administered. In addition, mortality, clinical cure and adverse events according to tigecycline dose were recorded. The scope of the review was to evaluate all-cause mortality, clinical cure (as assessed by the investigators of each study) and adverse events occurring during high-dose tigecycline treatment [100 mg every 12 h (q12 h), with or without a 200 mg loading dose]. 3. Results A total of 670 articles were retrieved during the systematic search process in the electronic databases (134 from PubMed and 536 from Scopus). The detailed study selection process is depicted in Fig. 1. In total, five studies and three case reports (263 patients; 274 episodes) were included from PubMed, Scopus, manual searching of bibliographies, and scientific conferences and meetings [16–23]. One study was an RCT [16], two were prospective cohort studies [17,21], two were retrospective cohort studies [20,23] and three were case reports [18,19,22]. Among the included studies, two were unpublished posters presented at scientific conferences [17,20]. Apart from the included studies, administration of high-dose tigecycline was also reported in four other studies [24–27] but the outcomes of patients receiving high-dose tigecycline were not presented separately from

3.2. Non-randomised studies 3.2.1. Comparative One study, reported as a conference abstract, reported outcomes on 100 intensive care unit (ICU) patients with severe infections due to A. baumannii and Klebsiella pneumoniae [20]. The compared groups did not differ significantly with regard to age, severity of

Please cite this article in press as: Falagas ME, et al. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006

Study design, period; country

No. of patients receiving TIG; site of infection and causative pathogen

Comparative studies (high-dose versus low-dose) 100 ICU patients; severe SC, retrospective De Pascale (2013) [20] cohort (poster), infections due to 2009–2011; Acinetobacter baumannii and Italy Klebsiella pneumoniae Di Carlo (2013) [21]

Balandin Moreno (2011) [17]

Rationale for using high-dose TIG

Concomitant antibiotic treatment

NRb

200 mg LD + 100 mg q12 h vs. 100 mg LD + 50 mg q12 h 200 mg LD + 100 mg q12 h vs. 150 mg LD + 75 mg q12 h

To treat severe intra-abdominal abscesses

1/12 (8.3%) vs. 11/18 (61.1%); P = 0.005d

Lower cure rates with standard-dose TIG than imipenem/cilastatin in a previous study on patients with HAP

i.v. colistin 5 mg/kg in three equal daily doses i.v. ceftazidime 2 g q8 h + i.v. tobramycin 7 mg/kg or amikacin 20 mg/kg + i.v. vancomycin placebof Carbapenems (16), colistin (12), ␤-lactams (10), quinolones (5), other (4)

44 episodes (37 ICU patients) due to Enterobacteriaceae or non-fermentative Gram-negative bacillig

100 mg q12 h vs. 50 mg q12 hh

To analyse their experience with high-dose TIG in ICU patients

26 episodes (22 patients) trauma ICU patients; KPC K. pneumoniae infectionsi

100 mg q12 h

NR

i.v. gentamicin, i.v. colistin, i.v. fosfomycinj

49-year-old male; bacteraemia due to KPC K. pneumoniae 42-year-old male; meningitis due to XDR K. pneumoniae Elderly male; UTI due to MDR K. pneumoniae and Enterobacter aerogenes

100 mg q12 h

NR

100 mg q12 h

Due to severity of illness and MDR profile of the organism Successful previous experience with bacteraemia due to K. pneumoniae with high-dose TIG

Colistin (i.v. and inhaled), amikacin No

Case report, NR; USA

Dandache (2009) [19] Cunha (2007) [18]

Case report, NR; USA Case report, NR; USA

VAP subpopulation, 19/33 (57.6%) vs. 10/30 (33.3%); P = 0.08 NR

NRa

SC, prospective cohort (poster), 2009–2010; Spain

Humphries (2010) [22]

Clinical cure

To evaluate potential benefits of higher doses of TIG

30 ICU patients with severe IAIs due to XDR KPC-3 K. pneumoniae ST258 clone

Single-arm studies (only high-dose) Sbrana (2013) SC, retrospective cohort, [23] 2011–2012; Italy

Mortality 100 mg q12 h vs. 50 mg q12 h

SC, prospective case series, 2001–2012; Italy MC, phase 2, DB RCT, 2008–2011; Europe, Asia, America, Australia

71 patients/episodes with nosocomial pneumoniae

Effectiveness (high-dose vs. low-dose)

200 mg q24 h

No

Adverse events (high-dose vs. low-dose)

NRc

No adverse events

3/35 (8.6%) vs. 7/36 (19.4%); P = NS

At TOC, 17/20 (85.0%) vs. 16/23 (69.6%); P = NS

Diarrhoea 14.3% vs. 2.8%; nausea 8.6% vs. 2.8%; vomiting 5.7% vs. 2.8%; (P = NS for all comparisons)

7/27 (26%) vs. 1/13 (8%); P = NS

NR

NR

All-cause, 3/26 (11.5%); infectionrelated, 2/26 (7.7%) Survived

24/26 (92.3%)

Cured

No adverse events in 25 episodes where TIG was administered NR

Survived

Cured

NR

Survived

Cured

NR

i.v., intravenous; SC, single centre; ICU, intensive care unit; q12 h, every 12 h; NR, not reported; VAP, ventilator-associated pneumonia; NS, non-significant; IAI, intra-abdominal infection; XDR, extensively drug-resistant; KPC, Klebsiella pneumoniae carbapenemase; ST, sequence type; LD, loading dose; MC, multicentre; DB, double-blind; RCT, randomised controlled trial; HAP, hospital-acquired pneumonia; q8 h, every 8 h; TOC, test of cure; UTI, urinary tract infection; MDR, multidrug-resistant; q24 h, every 24 h. a No significant differences in terms of rate of concomitant other active antibiotic use were observed between the two groups. b No significant differences in terms of ICU mortality between the groups (P = 0.8). c The rate of abnormal laboratory measurements during TIG treatment was similar between the two groups (P = NS). d Kaplan–Meier curve showed that patients treated with high-dose TIG had a significant favourable outcome (log-rank test, P = 0.004). e Due to Acinetobacter calcoaceticus, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Serratia marcescens, Haemophilus spp., Staphylococcus aureus and Streptococcus spp. f When Pseudomonas aeruginosa or meticillin-resistant S. aureus (MRSA) infection was suspected. g Patients with pneumonia (23), UTI (6), IAI (6), bronchitis (5), catheter-related bacteraemia (2) and other (2). There was a higher percentage of pneumonia in the group treated with 100 mg q12 h than in the group treated with 50 mg q12 h (59% vs. 23%; P = 0.03). h In four episodes the patients received sequential 100 mg q12 h and 50 mg q12 h. i VAP (11), VAP + bacteraemia (5), bloodstream infection (7), UTI (2) and peritonitis (1). j Colistin + gentamicin combination was administered to one patient, and TIG alone to another patient.

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Ramirez (2013) [16]

i.v. TIG dosing regimen

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Table 1 Characteristics and outcomes of studies reporting on patients who received high-dose tigecycline (TIG) regimens.

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Articles identified and screened in PubMed database (N = 134)

Articles identified and screened in Scopus database (N = 536)

Articles excluded due to irrelevant content of the abstract (N = 613)

Full-text articles assessed (N = 19)

Full-text articles assessed (N = 38)

Articles excluded (N = 54) • • • •

• •

Duplicates (N= 18) Studies reporting only on low-dose tigecycline (N= 24) Studies not reporting the dose (N= 7) Studies not distinguishing outcomes between high- and low-dose treated patients (N= 3) Ineligible comparison (N= 1) Not found (N= 1)

Articles included from conference proceedings (N = 2)

Articles included from handsearching (N = 3)

Articles included in the systematic review (N = 8) Fig. 1. Flow diagram of the systematic search and study selection process.

disease, duration of tigecycline treatment or inadequate empirical antimicrobial therapy (P = not significant). MDR A. baumannii and K. pneumoniae were the main pathogens isolated. Pathogens other than A. baumannii and K. pneumoniae were less common in the high-dose group than in the low-dose tigecycline group (P < 0.01). Patients were treated with tigecycline 100 mg q12 h or 50 mg q12 h. Detailed data on concomitant antibiotic treatment were not available in the abstract but it was reported that no significant differences in terms of the rate of concomitant active antibiotic use were observed between the two groups. Infections due to less-susceptible isolates (MIC for tigecycline ≥1 ␮g/mL) were more commonly treated with high-dose tigecycline (P < 0.01). No significant difference in ICU mortality was found between the compared groups (P = 0.8). In the subpopulation of patients with VAP (33 patients received 100 mg q12 h and 30 patients received 50 mg q12 h), clinical cure was 57.6% with high-dose and 33.3% with low-dose tigecycline, but the difference was not statistically

significant (P = 0.08); the corresponding mortality was not reported. In the same population, microbiological eradication was 57.1% and 30.4%, respectively (P = 0.1). Data on other infections were not available. Multivariate analysis in the subpopulation of VAP showed that high-dose tigecycline, adequate empirical antibiotic treatment and Sequential Organ Failure Assessment (SOFA) score were independent predictors for clinical cure. Finally, the rate of abnormal laboratory measurements during treatment was similar between the two groups (P = not significant) and none of the enrolled patients required discontinuation or reduction in tigecycline dose due to adverse events. Another study included 30 ICU patients with severe IAIs due to K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae [21]. In total, 63.3% of patients had solid organ tumour. The mean age of the patients was 56.6 ± 15 years and the APACHE II score on admission was 23.4 ± 1.7. Moreover, 66.7% of patients came from the surgical emergency unit and 50% had been hospitalised in the

Please cite this article in press as: Falagas ME, et al. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006

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previous 2 years. One-half of patients had abscesses, 26.7% had anastomotic leaks, 13.3% had wound infections and 10.0% had peritonitis. Klebsiella pneumoniae was cultured from intra-operative samples, abdominal drain, and wound or percutaneous fluid samples in 46.6%, 26.7% and 26.7% of patients, respectively. It was also cultured from bronchoalveolar lavage (BAL) in 50% of patients. In 50% of patients the infection was polymicrobial. All isolates were XDR and were treated with tigecycline in combination with colistin. The administered regimens were 200 mg loading dose followed by 100 mg q12 h and 100 mg loading dose followed by 50 mg q12 h. Most patients with positive BAL cultures received low-dose tigecycline. The 200 mg daily group included also all five patients in whom the infection’s causative pathogen had a tigecycline MIC of >0.5 ␮g/mL. Significantly lower mortality was observed among patients treated with high-dose tigecycline compared with those treated with low-dose tigecycline [1/12 (8.3%) vs. 11/18 (61.1%); P = 0.005]. Most patients who survived had abscesses, whilst those who died had positive BAL cultures and/or anastomotic leaks. Univariate analyses showed that absence of surgical drainage, high mean APACHE II score, septicaemia, VAP and treatment with lowdose tigecycline were associated with ICU mortality. No adverse events occurred during high-dose tigecycline treatment in this study. Finally, one study reported as a conference abstract included 44 episodes of infections in 37 ICU patients [17]. Among the included patients with a mean age of 52 years, 48.6% were immunocompromised. The mean APACHE II score on admission was 18.7. The most common site of infection was pneumonia (38.6%), followed by urinary tract infections (UTIs) and IAIs (13.6% each). Enterobacteriaceae (61.4%, 59.3% of which were K. pneumoniae) and Gram-negative non-fermentative bacilli (22.7%) were the most commonly isolated pathogens. The infection was polymicrobial in 18% of cases. Tigecycline was administered either as a 200 mg loading dose followed by 100 mg q12 h (27 cases) or as a 100 mg loading dose followed by 50 mg q12 h (13 cases). Four cases received sequential low- to high-dose tigecycline. In 95% of cases tigecycline was administered in combination with other antibiotics: carbapenems (36.4%); colistin (27.3%); ␤-lactams (22.7%); and fluoroquinolones (11.4%). There was a significantly higher percentage of pneumonia in the group treated with 100 mg q12 h than with 50 mg q12 h (59% vs. 23%; P = 0.03) [17]; no other differences were observed between the compared cases. Mortality was 26% (7/27) in patients receiving 100 mg q12 h and 8% (1/13) in patients receiving 50 mg q12 h (P = 0.36). Severe sepsis or septic shock was the main risk factor for mortality in the whole cohort (P = 0.01). 3.2.2. Non-comparative The outcomes of 22 patients (26 episodes) with KPC-producing K. pneumoniae infections in a trauma ICU were assessed in a retrospective study [23]. The mean SOFA and APACHE II scores were 9 ± 3 and 50 ± 15, respectively. None of the included patients had a significant underlying disease but all required mechanical ventilation on admission. The most common infection was VAP, which was found in 61.5% of episodes, followed by bloodstream infection (26.9%); two cases with UTI and one case with peritonitis were also enrolled. Severe sepsis was detected in 84.6% of episodes. All patients received 100 mg tigecycline q12 h. Gentamicin [intravenous (i.v.) 5–7 mg/kg daily] was administered in combination with tigecycline in 19 episodes, whilst colistin methanesulfonate (i.v. 4.5 million International Units q12 h) was administered in combination with tigecycline in 12 episodes. Fosfomycin (i.v. 3 g q8 h) was administered as a third drug in 13 episodes. Etest revealed that 27% of isolates were resistant to tigecycline, 67% were resistant to colistin, 20% to gentamicin and 13% to fosfomycin. Use of combination regimens ensured that all patients received appropriate treatment. Mortality was 11.5%, infection-related mortality

5

was 7.7% and favourable response was 92.3%. No adverse events occurred in patients who received tigecycline.

4. Discussion Of eight available reports on the effectiveness and safety of high-dose tigecycline, eight provided data on mortality, six on clinical cure and four on adverse events. As expected, the currently available data on high-dose tigecycline derive mainly from patients receiving ICU care, infected with MDR or even XDR pathogens and/or suffering from severe infections. The conflicting findings of these reports must be interpreted in view of significant limitations regarding the scarcity of evidence (the review could evaluate the outcome of 263 patients/episodes) as well as the quality of the studies that were finally included in the review. In fact, all studies except one [16] were nonrandomised studies, whilst a considerable part of the studied population derived from unpublished cohort studies [17,20]. Furthermore, the available RCT was terminated before recruitment of the scheduled population was achieved and therefore it was underpowered to detect any differences between studied populations. Tigecycline was not administered alone in any of the included studies; instead, antibiotics with overlapping activity against mainly Gram-negative bacteria such as colistin, aminoglycosides, ␤-lactams and fluoroquinolones were also administered. Therefore, the impact of tigecycline treatment alone on the observed effectiveness and safety could not be adequately estimated. Furthermore, the rationale for administration of a higher tigecycline dose was not clearly defined in most of the included studies; however, since most of the studies were conducted after the FDA announcement regarding higher mortality in tigecycline-treated patients, we can assume that a higher dose was used in order to increase the probability of survival. Finally, the effect of tigecycline dose on the outcome was not explored in multivariate analyses in most of the non-randomised studies. In a study that reported a multivariate analysis, high-dose tigecycline was an independent predictor of survival in patients with VAP. Development of resistance with highor low-dose tigecycline was not studied in any of the included studies. The clinical significance of the PK/PD properties of tigecycline has not been studied extensively [28]. The ratio of area under the concentration–time curve to MIC (AUC/MIC) is considered the parameter that describes most accurately the PK/PD properties of tigecycline. A study on healthy subjects who received tigecycline 25 mg, 50 mg, 75 mg and 100 mg q12 h for 19 consecutive doses showed that tigecycline exhibits linear pharmacokinetics; as the dose increased, the AUC increased as well [15]. Accordingly, for a given MIC value, a higher dose of tigecycline should be associated with a higher AUC/MIC and presumably better clinical response. Logistic regression in a study including patients with complicated skin and skin-structure infections showed that steady-state 24-h AUC/MIC ratio (AUC24 /MIC) as a continuous variable was a predictor of microbiological but not clinical response in monomicrobial and polymicrobial staphylococcal and streptococcal infections [29]. In addition, for every unit of AUC24 /MIC increase, the ability of the model to predict microbiological response increased by 17.1%. In this model, an AUC24 /MIC >17.9 was predictive of clinical response; for every unit of AUC24 /MIC increase, the ability of the model to predict clinical response increased by 3.7%. However, AUC24 /MIC was not predictive of either microbiological or clinical response in monomicrobial Gram-negative and mixed Gram-positive and Gram-negative infections. Similar models in patients with IAIs showed that, among other factors, an AUC24 /MIC ratio >3.1 was predictive of clinical success; AUC24 /MIC alone or in combination

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with other factors also had the largest impact on the probability of clinical success [30]. Finally, in VAP patients receiving tigecycline 50 mg q12 h, the AUC24 /MIC was 60% lower than the corresponding figure in non-VAP patients [31]. Based on the PK/PD properties of tigecycline, the antibiotic could be tested in extended or continuous infusion. The benefits of extended/continuous infusion have been seen for other antibiotics [32,33]. However, few relevant data have become available until now and therefore safe conclusions cannot be drawn as yet. In particular, a study on healthy subjects showed that the AUC was not statistically different between patients receiving 4-h infusions and those receiving 1-h infusions of tigecycline [15]. In addition, the 4-h infusion of tigecycline did not affect the incidence or severity of treatment-related nausea. In 2010, the FDA announced that tigecycline was associated with an increased risk of death in a pooled analysis of data from the 13 available RCTs [34]. Meta-analyses following this announcement concluded that more adverse events [10,13] and higher mortality [14] were observed in patients treated with tigecycline than in those treated with comparators. Two meta-analyses focused on studies where tigecycline was administered for approved indications and came to different conclusions; different data (fewer deaths were reported in a published RCT than the deaths used in the FDA analysis) and different models were used in these analyses [11,12]. A patient-level meta-analysis was proposed as a mean for further investigation, and the manufacturer published patient-level data a year later [35]. The logistic regression analysis highlighted low albumin and total protein levels, nosocomial pneumonia, older age, high APACHE II score and prior antibiotic therapy as predictors for mortality. Treatment with tigecycline was not a predictor of mortality. Mortality at 30 days and mortality at the first 2 days or 7 days was similar between tigecycline and comparators. In the regression analysis of tigecycline-treated patients, baseline bacteraemia (especially among patients with VAP) was a significant predictor for mortality. The FDA has recently reported that mortality risk was also higher with tigecycline treatment for approved indications [36]. The deaths were due to worsening infections, complications of infection, or other underlying medical conditions. The majority of patients who received treatment with high-dose tigecycline in the included studies were severely or critically ill and were infected by drug-resistant bacteria. Following the reports by the FDA, such patients are probably the most appropriate candidates to receive definitive treatment with tigecycline. Empirical treatment could also be considered in settings where XDR (or possibly MDR) isolates are prevalent. Unless future RCTs show non-inferiority of high-dose tigecycline regimens with comparator antibiotics, these data suggest that more well-designed trials on high-dose tigecycline, especially for severely ill patients, are urgently needed, especially in view of the limited alternative treatment options in such populations due to the emergence of MDR or XDR pathogens. In terms of safety, the RCT showed that the incidence of gastrointestinal adverse events was numerically higher (but not significantly) among patients receiving the high-dose regimen than those receiving lower-dose tigecycline [16]. In addition, serious adverse events did not differ significantly in the compared groups, but these were numerically more common among patients treated with lower-dose tigecycline. The number of patients enrolled in the RCT was small and definitive conclusions cannot be drawn. Meta-analyses have shown that more adverse events and more drug discontinuations due to adverse events occurred with tigecycline than comparator antibiotics [10,13,14]. In healthy subjects, gastrointestinal adverse events such as nausea and vomiting were dose-dependent and increased in frequency with the increase in tigecycline dose [15]. The same study showed that adverse events were reduced when the subjects were fed, providing a possible

solution to this problem. Therefore, the concerns that an increase in tigecycline dosage may be associated with even more adverse events are valid. In any case, the benefits with higher doses should outweigh any possible harm. In conclusion, there is limited clinical evidence regarding the effectiveness of high-dose tigecycline-containing regimens. These studies provide conflicting results regarding mortality owing to the heterogeneity of the studied populations and their design. Data on safety are lacking. The available PK/PD studies suggest that higher doses improve the AUC/MIC values, thus providing valid support for their use in clinical practice. Further well-designed studies are required to establish the effectiveness and safety of high-dose tigecycline. Funding: No funding source Competing interests: MEF has participated in advisory boards of Achaogen, Astellas, AstraZeneca, Bayer and Pfizer, has received lecture honoraria from Angelini, Astellas, AstraZeneca, Glenmark, Merck and Novartis, and has received research support from Angelini, Astellas and Rokitan. All other authors declare no competing interests. Ethical approval: Not required. References [1] Falagas ME, Tansarli GS, Rafailidis PI, Kapaskelis A, Vardakas KZ. Impact of antibiotic MIC on infection outcome in patients with susceptible Gramnegative bacteria: a systematic review and meta-analysis. Antimicrob Agents Chemother 2012;56:4214–22. [2] Mavros MN, Tansarli GS, Vardakas KZ, Rafailidis PI, Karageorgopoulos DE, Falagas ME. Impact of vancomycin minimum inhibitory concentration on clinical outcomes of patients with vancomycin-susceptible Staphylococcus aureus infections: a meta-analysis and meta-regression. Int J Antimicrob Agents 2012;40:496–509. [3] Karageorgopoulos DE, Kelesidis T, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. J Antimicrob Chemother 2008;62:45–55. [4] Michalopoulos A, Falagas ME. Treatment of Acinetobacter infections. Expert Opin Pharmacother 2010;11:779–88. [5] Falagas ME, Karageorgopoulos DE, Nordmann P. Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiol 2011;6:653–66. [6] Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother 2013 [Epub ahead of print]. [7] Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies. J Antimicrob Chemother 2008;62:895–904. [8] Jean SS, Hsueh PR. Current review of antimicrobial treatment of nosocomial pneumonia caused by multidrug-resistant pathogens. Expert Opin Pharmacother 2011;12:2145–8. [9] US Food and Drug Administration. Full prescribing information for 2010. http://www.accessdata.fda.gov/drugsatfda docs/label/ Tygacil; 2010/021821s021lbl.pdf [accessed 24.09.13]. [10] Cai Y, Wang R, Liang B, Bai N, Liu Y. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother 2011;55:1162–72. [11] Vardakas KZ, Rafailidis PI, Falagas ME. Effectiveness and safety of tigecycline: focus on use for approved indications. Clin Infect Dis 2012;54:1672–4. [12] Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 2012;54:1699–709. [13] Tasina E, Haidich AB, Kokkali S, Arvanitidou M. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis 2011;11:834–44. [14] Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: a systematic review and meta-analysis. J Antimicrob Chemother 2011;66:1963–71. [15] Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005;49:220–9. [16] Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem–cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother 2013;57:1756–62. [17] Balandin Moreno B, Fernández Simón I, Romera Ortega MA, Alcántara Carmona S, Martinez Alvarez L, Pérez Redondo M, et al. Clinical experience with tigecycline in intensive care unit. In: 24th Annual

Please cite this article in press as: Falagas ME, et al. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006

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Please cite this article in press as: Falagas ME, et al. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.01.006