Skip to main content
Download PDF

In vitro activity of tigecycline and comparators against carbapenem-susceptible and resistant Acinetobacter baumannii clinical isolates in Italy

Annals of Clinical Microbiology and Antimicrobials volume 7, Article number: 4 (2008) Cite this article

Abstract

Background

In a recent multi-centre Italian survey (2003–2004), conducted in 45 laboratories throughout Italy with the aim of monitoring microorganisms responsible for severe infections and their antibiotic resistance, Acinetobacter baumannii was isolated from various wards of 9 hospitals as one of the most frequent pathogens. One hundred and seven clinically significant strains of A. baumannii isolates were included in this study to determine the in vitro activity of tigecycline and comparator agents.

Methods

Tests for the susceptibility to antibiotics were performed by the broth microdilution method as recommended by CLSI guidelines. The following antibiotics were tested: aztreonam, piperacillin/tazobactam, ampicillin/sulbactam, ceftazidime, cefepime, imipenem, meropenem tetracycline, doxycycline, tigecycline, gentamicin, amikacin, ciprofloxacin, colistin, and trimethoprim/sulphametoxazole. The PCR assay was used to determine the presence of OXA, VIM, or IMP genes in the carbapenem resistant strains.

Results

A. baumannii showed widespread resistance to ceftazidime, ciprofloxacin and aztreonam in more than 90% of the strains; resistance to imipenem and meropenem was 50 and 59% respectively, amikacin and gentamicin were both active against about 30% of the strains and colistin about 99%, with only one strain resistant. By comparison with tetracyclines, tigecycline and doxycycline showed a higher activity. In particular, tigecycline showed a MIC90 value of 2 mg/L and our strains displayed a unimodal distribution of susceptibility being indistinctly active against carbapenem-susceptible and resistant strains, these latter possessed OXA-type variant enzymes.

Conclusion

In conclusion, tigecycline had a good activity against the MDR A. baumannii strains while maintaining the same MIC90 of 2 mg/L against the carbapenem-resistant strains.

Background

Acinetobacter baumannii has emerged as one of the most problematic nosocomial pathogens to eradicate using available antimicrobial agents, and its occurrence has increased especially in patients admitted to intensive care units (ICUs). In a recent Italian survey, this microorganism ranked third among the most relevant pathogens in ICUs and was one of the most resistant microrganisms to all families of antibiotics [1]. The reasons for this emergence in nosocomial settings can be found among: i) its particular characteristics of being a colonizer of multiple body sites of hospitalized patients; ii) its ability to survive for a long time on inanimate surfaces; and iii) its tendency to be intrinsically resistant and to acquire new resistance determinants.

The clinical role of A. baumannii has been very controversial: it was considered a colonizer for a long time but recently, due to the report of severe illness with high associated mortality [2] and occurrence of some severe infections in bacteriemic patients, has been considered – by some clinicians – an indicator of severity, leading to the hypothesis that some changes can take place in this strain i.e. the acquisition of some virulence factors.

Treatment of Acinetobacter spp. infections has been limited to a few broad-spectrum agents including carbapenems, fluoroquinolones, ceftazidime, trimethoprim/sulfamethoxazole, sulbactam, amikacin and some tetracyclines. As resistance to carbapenems and other alternative drugs has emerged [3–7], often conferring a multi-drug-resistance (MDR) phenotype to this microrganism, the popularity of an old class of drugs, i.e. the polymyxin class of agents, has increased. However, colistin-resistant A. baumannii has been recently reported [8, 9], and in spite of documented clinical success, colistin demonstrated dose-dependent nephrotoxicity [10].

In this context, it is mandatory to look at the activity of new antimicrobial agents and numerous reports have indicated that tigecycline, a novel compound belonging to a new class of antimicrobial agents – glycylcyclines -, displays inhibitory activity against Acinetobacter spp. [11–14]. This study sought to determine the in vitro activity of tigecycline and comparators against Italian carbapenem resistant and susceptible A. baumannii strains, isolated throughout Italy during a two-year surveillance study [1]. The presence of carbapenem-resistance genes was also investigated. These data can add new information to the in vitro activity of the most used antibiotics against this sample of epidemiologically representative Italian isolates.

Methods

Bacterial strains

One hundred and seven strains of A. baumannii were collected from 9 out of the 45 centres included in the 2002–2003 Italian surveillance study on microrganisms responsible for severe infections [1]. The first isolate of each patient was included in this study. These isolates were responsible for documented bloodstream and lower respiratory tract infections (82 strains), 15 strains were isolated from complicated Skin and Skin Structure Infections (cSSSI) and 3 strains from Intra-abdominal Infections (IAIs). The remaining 7 strains were isolated from urinary catheters. Species identification was centrally performed as previously described and reconfirmed by conventional methods using the API 20NE (Bio Merieux – SA- Marcy l'Etoile – France). Isolates were stored in Mueller-Hinton broth with 15% glycerol and frozen at -80°C prior to experiments.

Antimicrobial agents and MIC determinations

MIC determinations were performed by broth microdilution in cation-adjusted Mueller-Hinton broth in accordance with CLSI guidelines [15]. MICs were interpreted with category designations according to CLSI criteria [15]. Breakpoints for tigecycline susceptibility were interpreted according to the FDA breakpoint of 2 mg/L.

Laboratory-grade standard reference powders of the following antimicrobials were obtained and reconstituted according to the manufacturers' instructions: tigecycline (Wyeth Research, PA, USA); amikacin, aztreonam, doxycycline, gentamicin, ciprofloxacin, cotrimoxazole, ceftazidime, tetracycline (Sigma Chemical Company, St. Louis, MO, USA), cefepime (Bruno Farmaceutici SpA Milan, Italy), ampicillin/sulbactam (Pfizer Italy), piperacillin/tazobactam (Wyeth Research, PA, USA), imipenem (Merck & Company, Rathway, NJ, USA), meropenem (Astra Zeneca, Waltham, MA, USA), and colistin (MP Biomedicals, Solon, Ohio, USA). Solutions of tigecycline were freshly prepared on the day of the experiments to avoid known degradation problems. All other antibiotics were freshly prepared as stock solutions and frozen at -20°C until their use.

Time-kill studies

Five isolates (three imipenem-susceptible and two resistant strains) were chosen for time-kill studies: organisms were grown on Mueller-Hinton broth for 4 h (log phase of growth) and were further diluted in 20 ml of the same medium to yield a concentration of approximately 5 × 105 CFU/ml. Wells containing tigecycline at concentrations corresponding to the MIC and two and four times the MIC were tested for each strain. Aliquots (0.1 ml of broth) were removed from each well and serial dilutions were plated onto blood-agar plates after 0, 2, 4, 8 and 24 h of incubation. Colony counts were performed after 24 h of incubation at 36°C. Bactericidal activity was defined as a ≥3 log10 reduction compared with the initial inoculum [16].

PCR of carbapenem resistance genes

PCR assays were carried out by using previously published primers and, in particular, for MBL-encoding genes bla- IMP, and bla- VIM we followed the protocol published by Pagani L. et al [17], and for amplification of genes encoding oxacillinases (bla- OXA23-like, bla-OXA24-like, bla-OXA51-like and bla- OXA58-like) the protocol published by Woodford N. et al [18] was used. The PCR assays were performed directly on colonies. PCR products were purified and sequenced (BMR Bio Molecular Research, Italy).

Results

The 107 strains included in the study were collected from 9 centres in Italy, mainly located in the Central-South area of the country. Lungs and blood were the most common sources of the isolates (41.6% of all isolated came from lower respiratory tract infections, and 20.3% were isolated from blood cultures). In this survey, A. baumannii was also isolated from urinary catheters, complicated skin and skin structure (both 13.8%), and intra-abdominal infections (2.7%).

The results of the in vitro susceptibility testing, expressed as distribution, MIC50, MIC90 and percentage of resistance are presented in Table 1. The vast majority of strains of A. baumannii showed a multi-drug resistant phenotype (MDR), in particular, 53 strains were simultaneously resistant to three antibiotics, namely fluoroquinolones, ceftazidime and aminoglycosides or imipenem, while 44 strains were resistant to four antibiotics, the above three including carbapenems. 17% of strains were resistant also to ampicillin/sulbactam. More than 90% of strains were simultaneously resistant to ciprofloxacin, trimethoprim/sulphametoxazole, aztreonam, and ceftazidime; around 70% of strains were also resistant to gentamicin, amikacin, and tetracycline, while resistance to carbapenems was 50% for imipenem and 59% for meropenem. Among the tetracyclines, the unimodal distribution of susceptibility of tigecycline was comparable with that of doxycycline (93 and 94% susceptible, respectively). In our sample of strains colistin was active (106 out of 107 strains were susceptible). One strain was resistant to this drug, with a MIC of 16 mg/L.

Table 1 Distribution of MIC, MIC50, MIC90 (mg/l) for 107 isolates of Acinetobacter baumannii (MIC50 and MIC90 values are reported in BOLD cells and UNDERLINED numbers, respectively).
Full size table

The molecular characterization of the carbapenem-resistance gene content of the 58 isolates that were resistant to meropenem is shown in Table 2. The blaOXA51 and blaOXA58-like, were the most diffused genes: 43 strains carried both these determinants and 14 strains carried the blaOXA51-like gene. In our sample of carbapenem-resistant strains, only one carried the blaoxa23-like together with the blaoxa51 gene; all strains were negative for MBL (blaVIM and blaIMP) enzymes (table 2). Six out of the 14 strains carrying the blaOXA-51-like gene, demonstrated a susceptible or intermediate level of resistance to imipenem while they were resistant to meropenem, suggesting that other mechanisms can be responsible for carbapenem resistance in these strains. In the 43 strains carrying the blaOXA51 and blaOXA58-like genes there is an association between the presence of the OXA-58 enzyme and resistance to carbapenems.

Table 2 Tigecycline in carbapenem-resistant isolates carrying different OXA-like genes
Full size table

A preliminary observation on the level of resistance to carbapenems demonstrated that meropenem is a more hydrolysable substrate with respect to imipenem, and in all cases, tigecycline remained active in all carbapenem-resistance-strains.

Time-kill studies with increasing concentrations of tigecycline above the MIC, demonstrated that this antibiotic has a maximal killing effect near the MIC, without any increased rate at multiples of the MIC (Table 3). Its bacteriostatic activity was similar in all strains tested irrespective of their resistance to other antibiotics such as carbapenems.

Table 3 Time kill results, expressed as average reduction of log10 of CFU/ml, of tigecycline against five A. baumannii strains with different susceptibilities to carbapenems.
Full size table

Discussion

Acinetobacter baumannii is one of the most important nosocomial pathogens, able to cause severe infections, occurring principally in immunosuppressed patients, in patients with serious underlying diseases, or subjected to invasive procedures and treatment with broad-spectrum antibiotics [19]. This microorganism is also able to spread in high-risk wards, causing outbreaks. Nevertheless, until recently, carbapenems represented a viable choice for treating infections caused by this organism due to a diffused sensitivity to both imipenem and meropenem. In Italy, until 2000, very few strains were resistant [20], and only few genotypes appeared to occur in multiple hospitals causing outbreaks [21–26]. The recent Italian survey previously cited [1] demonstrated that A. baumannii was the third pathogen for severity in high-risk wards, frequently derived from nosocomial pneumoniae (VAP) or bacteremia. In our experience, nosocomial isolates of this microorganism were also co-pathogens in cSSSI and a few strains also came from IAIs. Approximately half of the 107 single isolates were MDR to three or four classes of antibiotics, including carbapenems, while they were almost fully susceptible to tigecycline, doxycycline and colistin. In our results, tigecycline is active, with a MIC90 of 2 mg/L against 93% of strains with maximum killing at the MIC concentrations.

The activity of tigecycline in our Italian isolates is comparable with that of many other national and global studies [12, 27–29], including the worldwide program T.E.S.T.(Tigecycline Evaluation and Surveillance Trial, [12] that reported a MIC90 value of 1 mg/L for a large number of A. baumannii isolates (4353) worldwide. The same study reported the isolation of 14.8% imipenem-resistant strains. Our data are also in line with the results obtained in other European studies [30, 31] in which tigecycline demonstrated its activity with MIC90 of 2 mg/L against strains showing a multiple resistance phenotype.

A. baumannii isolates resistant to various classes of antibiotics are emerging worldwide, and the recent resistance or reduced susceptibility to carbapenems, is considered a serious clinical problem due to the role of first choice therapy that these drugs have had until now.

Numerous mechanisms, including decreased permeability, efflux pump overexpression, and carbapenemase production, can be responsible for the resistance to carbapenems [7, 32, 33]. Class B (IMP and VIM enzymes) and D (oxacillinases) beta-lactamases are the most important group of enzymes able to hydrolyze carbapenems: although MBLs are not the predominant enzymes in A. baumannii, several IMP-enzymes have been described in various countries [34–37] while VIM-1, first identified in Italy in a strain of P. aeruginosa [38], is now reported in Korea [39], in Poland [40] and, as sporadic isolates, in many other parts of the world. Most worrisome are the carbapenemase-hydrolyzing oxacillinase (OXA) clusters that have been identified in A. baumannii in nine major subgroups [7, 41, 42], including the most diffused throughout the world OXA-23, OXA-24, OXA-51, OXA-58 enzymes and their variants [43]. The significant contribution of these enzymes to carbapenem resistance in A. baumannii has been emphasized, particularly when they are accompanied by ISAba1 and ISAba3 in the naturally occurring plasmid [44], due to the fact that these sequences can provide the promoter required for expression of linked antibiotic-resistance genes. The OXA-51/69-like beta-lactamases are, instead, "naturally occurring" chromosomal enzymes in this species, isolated from four continents, and their expression varies according to the presence of ISAba1 as previously discussed [45]. All these enzymes have been found in different isolates from various countries [24, 46–49]. In our strains, OXA-51 alone or associated with other enzymes was found. As recently suggested [32], these enzymes are very poor carbapenemases and may be natural chromosomally encoded in the vast majority of A. baumannii isolates, regardless of their susceptibility or resistance to carbapenems. OXA-58 enzymes are the most diffused oxacillinases in 43 strains of A. baumannii. As recently demonstrated, these enzymes may contribute to carbapenem resistance [32, 45], although it cannot be excluded that other mechanisms may additionally affect the activity of these drugs.

The recent emergence of high-resistance rates to tigecycline in multiple clones of MDR strains is also cause for concern. Various Authors [50–52] have reported a few cases of high tigecycline-resistance in nosocomial isolates: the involvement of an overexpression of the AdeABC multidrug efflux pump in the decreased susceptibility of tigecycline in these strains was postulated [52, 53]. To date, tigecycline has been approved for the treatment of complicated intra-abdominal and complicated skin and skin structure infections; the well documented activity of this drug against A. baumannii isolates and the high concentration reached by this drug in alveolar cells (77.5 fold higher than serum)[29], have indicated its use in infections sustained by these MDR microorganisms [54], despite the lack of approved clinical indications and criteria for in vitro susceptibility testing. In this situation, due to the importance that tigecycline can have in the treatment of MDR A. baumannii infections, it is absolutely mandatory to monitor isolates for evidence of acquired microbiological resistance, requiring further investigations to understand better all the possible mechanisms underlying this phenomenon.

Conclusion

Our results have shown that the MDR resistance phenotype is very diffused in A. baumannii isolated from severe infections in Italy. We have documented that almost half of the strains are also resistant to carbapenems and, as published by other Authors [55], also colistin has not escaped development of resistance: in fact, we isolated one strain resistant to this drug. Carbapenem-resistance in these strains is due to the presence of three different oxacillinases and the most diffused hydrolytic enzymes are the OXA-51/OXA-58 enzymes, carried in 43 strains. Tigecycline shows a potent antibacterial activity with a unimodal distribution of MIC and a MIC90 of 2 mg/L; the drug has indeed a bacteriostatic effect at the MIC concentration, and its activity is not influenced by the other mechanisms of resistance carried in these microorgansims, including the resistance to carbapenems. Furthermore recent studies demonstrated that tigecycline achieved maximal killing near the MIC in this species and concentration escalation studies demonstrated that this drug needs to approach concentrations higher than those currently achieved in the bloodstream to adequately treat A. baumannii infections [13].

These in vitro results, obtained in a representative sample of Italian isolates – all from documented severe infections – need to be confirmed by the clinical efficacy of this drug from Phase 3 clinical trials regarding the treatment of nosocomial pneumonia and other infections sustained by this microrganism. For the moment, the evaluation of the microbiological and pharmacological profile of tigecycline in each patient and the careful assessment of susceptibility can assist physicians in deciding on tigecycline use.

References

  1. 1.

    Nicoletti GSG, Fadda G, Boros S, Nicolosi D, Marchese A, Spanu T, Pantosti A, Monaco M, Rezza G, Casosne A, Garaci E: Bacterial Isolates from Severe Infections and Their Antibiotic Susceptibility Patterns in Italy: a Nationwide Study in the Hospital Setting. Journal of Chemotherapy. 2006, 18: 589-602.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Wilson SJCK, Zieger M, Gabehart K, Goodman J, Volk H, Sood R: Direct costs of multidrug-resistant Acinetobacter baumannii in the burn unit of a public teaching hospital. American Journal of Infection Control. 2004, 32 (6): 342-344. 10.1016/j.ajic.2004.02.008

    Article  PubMed  Google Scholar 

  3. 3.

    Giordano A, Varesi P, Bertini A, Villa L, Dionisi AM, Venditti M, Carfagna P, Luzzi I, Mancini C, Carattoli A: Outbreak of Acinetobacter baumannii Producing the Carbapenem-Hydrolyzing Oxacillinase OXA-58 in Rome, Italy. Microbial Drug Resistance. 2007, 13 (1): 37-43. 10.1089/mdr.2006.9995

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Bertini A, Poirel L, Bernabeu S, Fortini D, Villa L, Nordmann P, Carattoli A: Multicopy blaOXA-58 Gene as a Source of High-Level Resistance to Carbapenems in Acinetobacter baumannii. Antimicrob Agents Chemother. 2007, 51 (7): 2324-2328. 10.1128/AAC.01502-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Thean Yen Tan M, Karen Poh, Siew Yong Ng: Molecular Typing of Imipenem-Resistant Acinetobacter baumannii-calcoaceticus Complex in a Singapore Hospital Where Carbapenem Resistance Is Endemic. Infection Control and Hospital Epidemiology. 2007, 28: 941-944. 10.1086/518964.

    Article  PubMed  Google Scholar 

  6. 6.

    Valenzuela JK, Thomas L, Partridge SR, van der Reijden T, Dijkshoorn L, Iredell J: Horizontal Gene Transfer in a Polyclonal Outbreak of Carbapenem-Resistant Acinetobacter baumannii. J Clin Microbiol. 2007, 45 (2): 453-460. 10.1128/JCM.01971-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA: The Global Challenge of Multidrug Resistant (MDR) Acinetobacter baumannii. Antimicrob Agents Chemother. 2007, AAC.01464-01406.

    Google Scholar 

  8. 8.

    Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, Liolios L: Heteroresistance to Colistin in Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006, 50 (9): 2946-2950. 10.1128/AAC.00103-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Urban C, Mariano N, Rahal JJ, Tay E, Ponio C, Koprivnjak T, Weiss J: Polymyxin B-Resistant Acinetobacter baumannii Clinical Isolate Susceptible to Recombinant BPI21 and Cecropin P1. Antimicrob Agents Chemother. 2001, 45 (3): 994-995. 10.1128/AAC.45.3.994-995.2001

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  10. 10.

    Li J, Nation RL, Turnidge , John D, Milne , Robert W, Coulthard , Kingsley , Rayner , Craig R, Patterson , David L: Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. The Lancet Infectious diseases. 2006, 6 (9): 589-601. 10.1016/S1473-3099(06)70580-1

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Livermore DM: Tigecycline: what is it and where should be used. Journal of Antimicrobial Chemotherapy. 2005, 56: 611-614. 10.1093/jac/dki291

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Testsurveillance.com. 2007,http://www.testsurveillance.com

  13. 13.

    Scheetz MH, Qi C, Warren JR, Postelnick MJ, Zembower T, Obias A, Noskin GA: In Vitro Activities of Various Antimicrobials Alone and in Combination with Tigecycline against Carbapenem-Intermediate or -Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007, 51 (5): 1621-1626. 10.1128/AAC.01099-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Song JY, Kee SY, Hwang IS, Seo YB, Jeong HW, Kim WJ, Cheong HJ: In vitro activities of carbapenem/sulbactam combination, colistin, colistin/rifampicin combination and tigecycline against carbapenem-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2007, 60 (2): 317-322. 10.1093/jac/dkm136

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Institute CLSI: Performance Standards for Antimicrobial Susceptibility Testing; Sixteenth Information supplement. Clinical and Laboratory Standard Institute. 2006, 26: 114-116.

    Google Scholar 

  16. 16.

    Swenson JMHJ, Peterson L, : Special phenotypic methods for detecting antibacterial resistance. 1999, Washington DC: ASM Press

    Google Scholar 

  17. 17.

    Pagani L, Colinon C, Migliavacca R, Labonia M, Docquier J-D, Nucleo E, Spalla M, Li Bergoli M, Rossolini GM: Nosocomial Outbreak Caused by Multidrug-Resistant Pseudomonas aeruginosa Producing IMP-13 Metallo-{beta}-Lactamase. J Clin Microbiol. 2005, 43 (8): 3824-3828. 10.1128/JCM.43.8.3824-3828.2005

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  18. 18.

    Neil Woodford MJE, Coelho Juliana, Turton Jane, Elaina Ward M, Brown Susan, Amyes Sebastian, Livermore David: Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. International Journal of Antimicrobial Agents. 2006, 27 (4): 351-353. 10.1016/j.ijantimicag.2006.01.004

    Article  PubMed  Google Scholar 

  19. 19.

    O-LC García-Garmendia, Garnacho-Montero J, Jiménez-Jiménez Francisco-Javier, Pérez-Paredes Carmen, Barrero-Almodóvar Ana, Gili-Miner Miguel: Risk factors for Acinetobacter baumannii nosocomial bacteremia in critically ill patients: a cohort study. Clinical Infectious Diseases. 2001, 33 (936–946):

  20. 20.

    Turner PJ, : The activity of meropenem and comparators against Acinetobacter strains isolated from European hospitals, 1997–2000. Clin MicrobiolInfect. 2003, 9: 563-567.

    CAS  Google Scholar 

  21. 21.

    Pagani LMR, Nucleo E, D'Andrea MM, Spalla M, Terulla C, Aquilini E, Labonia M, Li Bergoli M, Rossolini GM: Outbreak of multidrug-resistant Acinetobacter baumannii producing the carbapenem hydrolysing beta-lactamase OXA-58 in a general intensive care unit in Southern Italy. 16th European Congress of Clinical Microbiology and Infectious Diseases. 2006, Nice, France: ESCMID

    Google Scholar 

  22. 22.

    Longo BAP, Luzzi I, Placanica P, Gallo S, Tarasi A, Di Sora F, Monaco M, Dionisi AM, Volpe I, Montella F, Cassone A, Rezza G: An outbreak of Acinetobacter baumannii in an intensive care unit: epidemiological and molecular findings. Journal of Hospital Infection. 2006, 64 (3): 303-305. 10.1016/j.jhin.2006.07.010

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Zarrilli R, Casillo R, Di Popolo A, Tripodi MF, Bagattini M, Cuccurullo S, Crivaro V, Ragone E, Mattei A, Galdieri N: Molecular epidemiology of a clonal outbreak of multidrug-resistant Acinetobacter baumannii in a university hospital in Italy. Clinical Microbiology and Infection. 2007, 13 (5): 481-489. 10.1111/j.1469-0691.2006.01675.x.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Giordano Alessandra PV, Bertini Alessia, Villa Laura, Dionisi Maria Anna, Venditti Mario, Carfagna Paolo, Luzzi Ida, Mancini Carlo, Carattoli Alessandra: Outbreak of Acinetobacter baumannii Producing the Carbapenem-Hydrolyzing Oxacillinase OXA-58 in Rome, Italy. Microbial Drug Resistance. 2007, 13 (1): 37-43. 10.1089/mdr.2006.9995

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Zarrilli R, Crispino M, Bagattini M, Barretta E, Di Popolo A, Triassi M, Villari P: Molecular Epidemiology of Sequential Outbreaks of Acinetobacter baumannii in an Intensive Care Unit Shows the Emergence of Carbapenem Resistance. J Clin Microbiol. 2004, 42 (3): 946-953. 10.1128/JCM.42.3.946-953.2004

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Bertini A, Giordano A, Varesi P, Villa L, Mancini C, Carattoli A: First Report of the Carbapenem-Hydrolyzing Oxacillinase OXA-58 in Acinetobacter baumannii Isolates in Italy. Antimicrob Agents Chemother. 2006, 50 (6): 2268-2269. 10.1128/AAC.00166-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  27. 27.

    Livermore DM: Tigecycline: what is it, and where should it be used?. J Antimicrob Chemother. 2005, 56 (4): 611-614. 10.1093/jac/dki291

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Alvarez J, Picazo JJ: In Vitro Activities of Tigecycline (GAR-936) against Recently Isolated Clinical Bacteria in Spain. Antimicrob Agents Chemother. 2002, 46 (3): 892-895. 10.1128/AAC.46.3.892-895.2002

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  29. 29.

    Pankey GA: Tigecycline. J Antimicrob Chemother. 2005, 56 (3): 470-480. 10.1093/jac/dki248

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Milatovic D, Schmitz FJ, Verhoef J, Fluit AC: Activities of the Glycylcycline Tigecycline (GAR-936) against 1, 924 Recent European Clinical Bacterial Isolates. Antimicrob Agents Chemother. 2003, 47 (1): 400-404. 10.1128/AAC.47.1.400-404.2003

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  31. 31.

    Henwood CJ, Gatward T, Warner M, James D, Stockdale MW, Spence RP, Towner KJ, Livermore DM, Woodford N: Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother. 2002, 49 (3): 479-487. 10.1093/jac/49.3.479

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Heritier C, Poirel L, Lambert T, Nordmann P: Contribution of Acquired Carbapenem-Hydrolyzing Oxacillinases to Carbapenem Resistance in Acinetobacter baumannii. Antimicrob Agents Chemother. 2005, 49 (8): 3198-3202. 10.1128/AAC.49.8.3198-3202.2005

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  33. 33.

    Livermore D: The impact of Curr Opin Investig Drugs. 2002, 3: 218-224.

    Google Scholar 

  34. 34.

    Chu YW, Afzal-Shah M, Houang ET, Palepou MI, Lyon DJ, Woodford N, Livermore DM: IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998. Antimicrob Agents Chemother. 2001, 45 (3): 710-714. 10.1128/AAC.45.3.710-714.2001

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  35. 35.

    Tognim MC, Gales AC, Penteado AP, Silbert S, Sader HS: Dissemination of IMP-1 metallo-beta-lactamase-producing Acinetobacter species in a Brazilian teaching hospital. Infect Control Hosp Epidemiol. 2006, 27 (7): 742-747. 10.1086/504356

    Article  PubMed  Google Scholar 

  36. 36.

    Walsh TR, Toleman MA, Poirel L, Nordmann P: Metallo-beta-lactamases: the quiet before the storm?. Clinical microbiology reviews. 2005, 18 (2): 306-325. 10.1128/CMR.18.2.306-325.2005

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  37. 37.

    Nishio H, Komatsu M, Shibata N, Shimakawa K, Sueyoshi N, Ura T, Satoh K, Toyokawa M, Nakamura T, Wada Y: Metallo-beta-lactamase-producing gram-negative bacilli: laboratory-based surveillance in cooperation with 13 clinical laboratories in the Kinki region of Japan. Journal of clinical microbiology. 2004, 42 (11): 5256-5263. 10.1128/JCM.42.11.5256-5263.2004

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  38. 38.

    Lauretti L, Riccio ML, Mazzariol A, Cornaglia G, Amicosante G, Fontana R, Rossolini GM: Cloning and characterization of blaVIM, a new integron-borne metallo-beta-lactamase gene from a Pseudomonas aeruginosa clinical isolate. Antimicrob Agents Chemother. 1999, 43 (7): 1584-1590.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. 39.

    Yum JH, Yi K, Lee H, Yong D, Lee K, Kim JM, Rossolini GM, Chong Y: Molecular characterization of metallo-beta-lactamase-producing Acinetobacter baumannii and Acinetobacter genomospecies 3 from Korea: identification of two new integrons carrying the bla(VIM-2) gene cassettes. The Journal of antimicrobial chemotherapy. 2002, 49 (5): 837-840. 10.1093/jac/dkf043

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Wroblewska MM, Towner KJ, Marchel H, Luczak M: Emergence and spread of carbapenem-resistant strains of Acinetobacter baumannii in a tertiary-care hospital in Poland. Clin Microbiol Infect. 2007, 13 (5): 490-496. 10.1111/j.1469-0691.2007.01694.x

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Queenan AM, Bush K: Carbapenemases: the versatile beta-lactamases. Clinical microbiology reviews. 2007, 20 (3): 440-458. table of contents 10.1128/CMR.00001-07

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  42. 42.

    Walther-Rasmussen J, Hoiby N: Class A carbapenemases. The Journal of antimicrobial chemotherapy. 2007, 60 (3): 470-482. 10.1093/jac/dkm226

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Afzal-Shah M, Livermore DM: Worldwide emergence of carbapenem-resistant Acinetobacter spp. The Journal of antimicrobial chemotherapy. 1998, 41 (5): 576-577. 10.1093/jac/41.5.576

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Marque S, Poirel L, Heritier C, Brisse S, Blasco MD, Filip R, Coman G, Naas T, Nordmann P: Regional occurrence of plasmid-mediated carbapenem-hydrolyzing oxacillinase OXA-58 in Acinetobacter spp. in Europe. Journal of clinical microbiology. 2005, 43 (9): 4885-4888. 10.1128/JCM.43.9.4885-4888.2005

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  45. 45.

    Poirel L, Nordmann P: Carbapenem resistance in Acinetobacter baumannii: mechanisms and epidemiology. Clin Microbiol Infect. 2006, 12 (9): 826-836. 10.1111/j.1469-0691.2006.01456.x

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Tsakris A, Ikonomidis A, Spanakis N, Pournaras S, Bethimouti K: Identification of a novel bla(OXA-51) variant, bla(OXA-92), from a clinical isolate of Acinetobacter baumannii. Clin Microbiol Infect. 2007, 13 (3): 348-349. 10.1111/j.1469-0691.2006.01598.x

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Valenzuela JK, Thomas L, Partridge SR, van der Reijden T, Dijkshoorn L, Iredell J: Horizontal gene transfer in a polyclonal outbreak of carbapenem-resistant Acinetobacter baumannii. Journal of clinical microbiology. 2007, 45 (2): 453-460. 10.1128/JCM.01971-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  48. 48.

    Zhou H, Pi BR, Yang Q, Yu YS, Chen YG, Li LJ, Zheng SS: Dissemination of imipenem-resistant Acinetobacter baumannii strains carrying the ISAba1 blaOXA-23 genes in a Chinese hospital. Journal of medical microbiology. 2007, 56 (Pt 8): 1076-1080. 10.1099/jmm.0.47206-0

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Ruiz M, Marti S, Fernandez-Cuenca F, Pascual A, Vila J: High prevalence of carbapenem-hydrolysing oxacillinases in epidemiologically related and unrelated Acinetobacter baumannii clinical isolates in Spain. Clin Microbiol Infect. 2007, 13 (12): 1192-1198. 10.1111/j.1469-0691.2007.01825.x

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Navon-Venezia S, Leavitt A, Carmeli Y: High tigecycline resistance in multidrug-resistant Acinetobacter baumannii – authors' response. J Antimicrob Chemother. 2007, 60 (1): 178-179. 10.1093/jac/dkm188.

    CAS  Article  Google Scholar 

  51. 51.

    Reid Gail ESAG, Aldeza Christine, Janda William, Clark Nina: Rapid Development of Acinetobacter baumannii Resistance to Tigecycline. Pharmacotherapy. 2007, 27 (8): 1198-1201. 10.1592/phco.27.8.1198

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Peleg AY, Adams J, Paterson DL: Tigecycline Efflux as a Mechanism for Nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother. 2007, 51 (6): 2065-2069. 10.1128/AAC.01198-06

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  53. 53.

    Ruzin A, Keeney D, Bradford PA: AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus-Acinetobacter baumannii complex. J Antimicrob Chemother. 2007, 59 (5): 1001-1004. 10.1093/jac/dkm058

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Curcio D, Fernandez F: Acinetobacter spp. susceptibility to tigecycline: a worldwide perspective. J Antimicrob Chemother. 2007, 60 (2): 449-450. 10.1093/jac/dkm202

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL: Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006, 6 (9): 589-601. 10.1016/S1473-3099(06)70580-1

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The Authors are indebted to the following Italian laboratories that sent the strains included in the study: A.O. G. Moscati (Avellino), University of Bari (BA), A.O. Policlinico University of Naple – Federico II (NA), A.O. Cardarelli (NA), University of Naple I (NA), A.O. Civico e Benfratelli Palermo (PA), A.O. Bianchi Melacrino Morelli Reggio Calabria (RC), A.O. Careggi Firenze (FI), Policlinico Gemelli Roma (RM). This work was supported by a grant from Wyeth-Italy (to S.S.) and by FIRB-2005 grant (to G.N. and S.S) from the Ministry of Education and Universities (MIUR, Rome, Italy).

Author information

Affiliations

  1. Department of Microbiological and Gynaecological Sciences, University of Catania, Italy

    Maria Lina Mezzatesta, Giusi Trovato, Floriana Gona, Vito Mar Nicolosi, Daria Nicolosi, Giuseppe Nicoletti & Stefania Stefani

  2. Istituto Superiore di Sanità, Roma, Italy

    Alessandra Carattoli

  3. Department of Microbiology, Policlinico Gemelli Roma, Italy

    Giovanni Fadda

Authors
  1. Maria Lina Mezzatesta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giusi Trovato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Floriana Gona
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vito Mar Nicolosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daria Nicolosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandra Carattoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giovanni Fadda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giuseppe Nicoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefania Stefani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefania Stefani.

Additional information

Competing interests

GN and SS received funding from Wyeth – Italy.

Authors' contributions

MML participated in the study design, interpretation of the results, and co-drafted the manuscript; TG participated in the study design, co-performing MIC and killing curves, analysis and interpretation of data; GF participated in the study design, co-performing DNA extractions and PCR experiments; NMV and ND participated in design and provided the strains for the study; CA, FG and GN participated in design, in the coordination of the study and in the revision of the manuscript; SS participated in the design the study, interpretation of the data, co-drafted the manuscript and participated in the final revision

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mezzatesta, M.L., Trovato, G., Gona, F. et al. In vitro activity of tigecycline and comparators against carbapenem-susceptible and resistant Acinetobacter baumannii clinical isolates in Italy. Ann Clin Microbiol Antimicrob 7, 4 (2008). https://doi.org/10.1186/1476-0711-7-4

Download citation

Keywords

  • Ceftazidime
  • Imipenem
  • Meropenem
  • Colistin
  • Carbapenems

Annals of Clinical Microbiology and Antimicrobials

ISSN: 1476-0711

Contact us