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Bacteremia and meningitis caused by OXA-23-producing Acinetobacter baumannii – molecular characterization and susceptibility testing for alternative antibiotics

Abstract

Background:

Carbapenem-resistant Acinetobacter baumannii infection is a concern in developing countries due to high incidence, few therapeutic options, and increasing costs.

Objective:

Characterize and analyze the antibiotic susceptibility patterns of carbapenem-resistant A. baumannii isolates and evaluate clinical data of meningitis and bacteremia caused by this microorganism.

Methods:

Twenty-six A. baumannii isolates from 23 patients were identified by MALDI-TOF and automated methods and genotyped using pulsed field genotyping electrophoresis. Clinical data and outcomes were evaluated. Susceptibility of isolates to colistin, tigecycline, meropenem, imipenem, and doxycycline was determined.

Results:

Mortality due to A. baumannii infections was 73.91%; all patients with meningitis and 7/8 patients with ventilator-associated pneumonia died. All isolates were susceptibility to polymyxin (100%; MIC50, MIC90: 1 µg/mL, 1 µg/mL) and colistin (100%; MIC50, MIC90: 2 µg/mL, 2 µg/mL), and 92% were susceptible to tigecycline (MIC50, MIC90: 1 µg/mL, 1 µg/mL) and doxycycline (MIC50, MIC90: 2 µg/mL, 2 µg/mL). bla OXA-23 was identified in 24 isolates. Molecular typing showed 8 different patterns: 13 isolates belonged to pattern A (50%).

Conclusion:

Carbapenem-resistant A. baumannii infections mortality is high. Alternative antimicrobial therapy (doxycycline) for selected patients with carbapenem-resistant A. baumannii infection should be considered.

Keywords
Acinetobacter baumannii; Oxacillinases; Carbapenem; Multidrug resistance; Doxycycline

Introduction

Acinetobacter baumannii healthcare associated infections (HAIs) are considered a serious public health problem owing to their prevalence and mortality in developing countries.11 Climaco EC, Oliveira ML, Pitondo-Silva A, et al. Clonal complexes 104, 109 and 113 playing a major role in the dissemination of OXA-carbapenemase-producing Acinetobacter baumannii in Southeast Brazil. Infect Genet Evol. 2013;19:127-133.,22 Fournier PE, Richet H. The epidemiology and control of Acinetobacter baumannii in health care facilities. Clin Infect Dis. 2006;42(5):692-699. The susceptibility of A. baumannii to the most commonly used antibiotics has decreased.33 Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 2008;46(8):1254-1263.

The treatment of carbapenem-resistant A. baumannii (CR-AB) has been a challenge because carbapenem is the first option in most hospitals for empirical treatment of HAI. Consequently, older drugs with increased toxicity, including polymyxins and aminoglycosides, have been used based solely on empirical evidence.44 Fernandez-Cuenca F, Tomas-Carmona M, Caballero-Moyano F, et al. [In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp.: multicenter national study GEIH-REIPI-Ab 2010]. Enferm Infec Microbiol Clin. 2013;31(1):4-9. Doxycycline is an oral tetracycline with activity against A. baumannii and this drug can achieve therapeutic levels in cerebrospinal fluid when adequate dosage is used.55 Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother. 1996;40(5):1104-1107. Tigecycline is another option approved for intra-abdominal and soft tissue infections that has also been used extensively for the treatment of multidrug resistant infections at other anatomic locations. Unfortunately, clinical and antimicrobial susceptibility data are rarely evaluated together, so the true efficacy of non-carbapenem antibiotics against CR-AB is unknown. The aims of this study were to characterize the molecular types of A. baumannii isolates from cerebrospinal fluid and blood culture and to evaluate clinical data and susceptibility patterns of these isolates to treatment with polymyxin, colistin, tigecycline, doxycycline, meropenem, and imipenem.

Material and methods

Study setting

A transversal study was carried out at Hospital Universitario Evangelico de Curitiba (HUEC), a tertiary-care, trauma reference hospital, in Southern Brazil, with a total number of 660 beds. The study included patients admitted from April 2010 through April 2013. This study was approved by the Ethics Committee of FEPAR and FPP (311.769).

Clinical data

Data were collected from medical charts and/or hospital computer system databases. The clinical data evaluated included age, gender, site of infection, comorbidities, admission at intensive care unit, antimicrobial therapy, and outcome. Antimicrobial therapy was included in the analysis when it was started within 72 h of infection diagnosis. Infections where classified according to CDC criteria.66 Emori TG, Culver DH, Horan TC, et al. National nosocomial infections surveillance system (NNIS): description of surveillance methods. Am J Infect Control. 1991;19(1):19-35. Thirty-day mortality was also analyzed.

Microbiological studies

Twenty-six isolates of A. baumannii from 23 patients admitted at HUEC from April 2010 through April 2013 were evaluated. Nineteen isolates were obtained from blood culture and 7 from cerebrospinal fluid culture. All isolates were identified using the Vitek2® Compact System (bioMérieux, Durham, USA) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) using Biotyper 2.0 software (Bruker151 Daltonik Inc, Bremen, Germany).

Antibiotic susceptibility tests

Minimal inhibitory concentration (MIC) of colistin, doxycycline, imipenem, meropenem, polymyxin B and tigecycline was estimated by the agar dilution method according to the CLSI, M7-A9 approved standard.77 CLSI (Clinical and Laboratory Standards Institute). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Tenth Edition (M07-A9). Clinical and Laboratory Standard Institute; 2012. Polymyxin B and colistin were also tested by a broth microdilution method according to CLSI M7-A9.88 CLSI. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Tenth Edition (M07-A10). Clinical and Laboratory Standard Institute; 2015. Interpretation of MIC was performed according to CLSI, M100-S24,99 CLSI (Clinical and Laboratory Standards Institute). Performance Standards for Antimicrobial Susceptibility Testing. Approved Standard M100-S24. Clinical and LaboratoryStandard Institute; 2014. except for tigecycline.1010 Marchaim D, Pogue JM, Tzuman O, et al. Major variation in MICs of tigecycline in Gram-negative bacilli as a function of testing method. J Clin Microbiol. 2014;52(5):1617-1621. The MIC50 and MIC90 were calculated for both the agar and broth methods. We also compared broth and agar dilution for colistin and polymyxin using a concordance level of ±≤1 log2.1111 Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol. 2001;39(1):183-190.

Molecular detection of oxacillinase genes

To determine oxacillinase-encoding genes, polymerase chain reaction (PCR) was performed for all isolates by using the following primers: blaOXA-23 (F-5′ GATCGGATTGGAGAACCAGA 3′; R-5′ ATTTCTGACCGCATTTCCAT 3′), blaOXA-51 (F-5′ TAATGCTTTGATCGGCCTTG 3′; R-5′ TGGATTGCACTTCATCTTGG 3′), blaOXA-58 (F-5′ AAGTATTGGGGCTTGTGCTG 3′; R-5′ CCCCTCTGCGCTCTACATAC 3′), blaOXA-143 (F-5′ TGGCACTTTCAGCAGTTCCT 3′; R-5′ TAATCTTGAGGGGGCCAACC 3′). PCR was performed in a final volume of 25 µL with a final DNA concentration of 100 ng/mL. The amplification conditions were 94 °C for 25 s, followed by 52 °C for 40 s and 72 °C for 50 s.1212 Woodford N, Ellington MJ, Coelho JM, et al. Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents. 2006;27(4):351-353.

Pulsed field gel electrophoresis (PFGE)

All 26 isolates were genotyped by PFGE and DNA was prepared as described previously.1313 Kaufmann ME. Pulsed-field gel electrophoresis. In: Woodford N, Johnson AP, eds. Molecular Bacteriology: Protocols and Clinical Applications. Vol 15. Humana Press; 1998:33–51. The entire chromosomal DNA of the strains was digested with 30 U of ApaI (Fermentas – Life Science, Glen Burnie, MD). PFGE was performed by using a clamped homogeneous electric field electrophoresis (CHEF) DRIII apparatus (Bio-Rad Laboratories, Hercules, USA). The conditions employed were as follows: temperature of 12 °C, voltage of 6 V/cm, run time of 30 h, and switch time of 5–35 s. The pattern of bands was interpreted according to previously described criteria.1414 Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol. 1995;33(9):2233-2239. PFGE clustering was determined by using the unweighted-pair group method with arithmetic averages (UPGMA) and by using Dice's coefficient. The tolerance was set at 1%. Identical isolates were assigned the same capital letter. Those with 80% similarity were assigned as a subtype of the major type, followed by an Arabic number (e.g. A1, A2, A3, A4).

Results

Patient data

Twenty-six isolates from 23 patients were evaluated. The median age of patients was 42 years (10–60 years). All patients were hospitalized in the intensive care unit when clinical samples were collected. Isolates were obtained from blood culture or cerebrospinal fluid. Samples from other body sites (sputum or bronchoalveolar lavage, urine or tissue biopsy) were not evaluated. Clinical characteristics are presented in Table 1.

Table 1
Clinical and laboratorial data from 23 patients with Acinetobacter baumannii causing infection.

Meningitis

Six patients presented with nosocomial meningitis. The median age was 33 years (15–56 years) with 3 females and 3 males. All patients presented with meningitis secondary to external ventricular shunt due to head trauma or neoplasm with a mortality rate of 100%. All strains in these patients were susceptible to polymyxins (colistin and polymyxin) and doxycycline. When bacterial susceptibility to polymyxins was taken into account, 3 patients received the correct treatment. The 3 remaining patients were treated with carbapenems, and the MIC of this antibiotic was determined to be >32 mg/L in all strains isolated from these patients. There was no clonality shared among the meningitis cases. In one patient with A. baumannii meningitis, the clone isolated from cerebrospinal fluid was identical to one found in blood culture and another cerebrospinal fluid sample that was obtained 5 days later (Clone A).

Bacteremia

Seventeen patients presented with A. baumannii bacteremia, 4 of them primary and 13 of them secondary to infection at another site. Ventilator-associated pneumonia (VAP) with secondary bacteremia was the most common infection (9 cases), followed by secondary bacteremia caused by skin and soft tissue infection (3 cases) and urinary tract infection (1 case). The median age of patients was 50 years (10–60 year), with 14 males and 3 females. There was no clonal association with a specific site of infection. Considering the therapeutic and microbiological aspect of bacteremic patients, 7 patients received correct therapy within 72 h (41.17%). The mortality of patients with A. baumannii bacteremia was 64.70%; specifically, 7 of 9 patients with VAP, and 1 of 3 with skin-soft tissue infections died. There was no correlation of survival with correct antibiotic therapy within first hours of culture sample. There was no clonality among cases of A. baumannii bacteremia.

Antimicrobial susceptibility

More than 90% of isolates were resistant to carbapenem (MIC50 and MIC90 > 32 µg/mL).

Isolates were susceptibility to polymyxin and colistin (MIC50 and MIC90 = 1 µg/mL for polymyxin; MIC50 = 0.5 µg/mL and MIC90 = 1 µg/mL for colistin). Broth and agar dilutions for colistin and polymyxin susceptibility showed a high concordance level (100%).

Bacterial isolates also had susceptibility to tigecycline and doxycycline (MIC50 and MIC90 = 1 µg/mL for tigecycline; MIC50 and MIC90 = 2 µg/mL for doxycycline). Only two samples were resistant to these drugs.

PCR amplified bla OXA-51 in all isolates. The bla OXA-23 gene was amplified in all 24 isolates resistant to carbapenem, but was not detected in the two isolates susceptible to carbapenem.

PFGE

Molecular typing with PFGE revealed 8 distinct patterns with 80% similarity (see dendrogram, Fig. 1). Thirteen isolates belong to pattern A (50%), including 11 subtypes. Other patterns (B, C, D, E, F, G and H) were found in 1, 3, 1, 2, 4, 1 and 1 samples, respectively. Both isolates of carbapenem-susceptible A. baumannii showed 70.3% similarity (patterns G and H)

Fig. 1
Dendrogram of 26 isolates from 23 patients with Acinetobacter baumannii causing infection. See Table 1 to correlation of isolates and site of infection.

Discussion

Carbapenem-resistant A. baumannii infections are severe and result in high mortality in critically ill patients. All patients with meningitis ultimately died despite adequate therapy, a mortality rate previously described by our group.1515 Tuon FF, Penteado-Filho SR, Amarante D, Andrade MA, Borba LA. Mortality rate in patients with nosocomial Acinetobacter meningitis from a Brazilian hospital. Braz J Infect Dis. 2010;14(5):437-440. The outcome is not different for bacteremia, although previous studies have shown that delay in the adequate therapy can reduce the mortality.1616 Tuon FF, Rymsza AM, Penteado-Filho SR, Pilonetto M, Arend LN, Levin AS. Should polymyxin be used empirically to treat infections in patients under high risk for carbapenem-resistant Acinetobacter?. J Infect. 2011;62(3):246-249. Carbapenem-resistant A. baumannii is becoming increasingly prevalent in Brazil, and more than 60% of strains in some areas are resistant. OXA-23 carbapenemase has been described as endemic since 2003 in Southern Brazil1717 Schimith Bier KE, Luiz SO, Scheffer MC, et al. Temporal evolution of carbapenem-resistant Acinetobacter baumannii in Curitiba, southern Brazil. Am J Infect Control. 2010;38(4):308-314. and was identified in all carbapenem-resistant A. baumannii in other publications.1818 Cieslinski JM, Arend L, Tuon FF, et al. Molecular epidemiology characterization of OXA-23 carbapenemase-producing Acinetobacter baumannii isolated from 8 Brazilian hospitals using repetitive sequence-based PCR. Diagn Microbiol Infect Dis. 2013;77(4):337-340. The current study confirms that this oxacillinase is prevalent and probably the main mechanism of carbapenem resistance. However, isolates from some hospitals have a different carbapenemase profile, including a low prevalence of OXA-23 in A. baumannii.1919 Werneck JS, Picao RC, Girardello R, et al. Low prevalence of blaOXA-143 in private hospitals in Brazil. Antimicrob Agents Chemother. 2011;55(9):4494-4495, author reply 5.

Out of 26 isolates, 24 were susceptible to doxycycline and two isolates showed intermediate resistance. Timurkaynak et al. found a similar doxycycline susceptibility pattern in A. baumannii,2020 Timurkaynak F, Can F, Azap OK, Demirbilek M, Arslan H, Karaman SO. In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int J Antimicrob Agents. 2006;27(3):224-228. this drug has a bactericidal effect against A. baumannii in some isolates, including carbapenem-resistant strains.2121 Bantar C, Schell C, Posse G, Limansky A, Ballerini V, Mobilia L. Comparative time-kill study of doxycycline, tigecycline, sulbactam, and imipenem against several clones of Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2008;61(3):309-314. Although minocycline has been more potent against Acinetobacter, this tetracycline is not available in Brazil.

In our study, there was a high concordance between susceptibility to colistin and polymyxin, but we did not test resistant isolates. Similar results were described by Gales et al., who reported 94.3% concordance in susceptibility to these drugs.1111 Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol. 2001;39(1):183-190. Furthermore, among the 26 isolates of A. baumannii, 5 showed skipped well phenomena for colistin and 8 for polymyxin (data not shown). This phenomenon occurs when these drugs are tested in broth microdilution and is associated with hetero-resistance.2222 Hawley JS, Murray CK, Griffith ME, et al. Susceptibility of acinetobacter strains isolated from deployed U.S. military personnel. Antimicrob Agents Chemother. 2007;51(1):376-378.

PFGE demonstrated a predominant clone (A) with the remaining isolates characterized as related clones. The mechanism of carbapenem resistance was associated with the presence of the gene bla OXA-23, although we cannot exclude combined mechanisms such as pump efflux and porin loss.2323 Zarrilli R, Crispino M, Bagattini M, et al. 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.

The question of whether to use combined therapy to treat Acinetobacter infections remains unanswered. In vitro studies are controversial and clinical studies are comprised of retrospective cohorts with small sample numbers. However, in the context of multidrug-resistant Acinetobacter, few options are available, mainly for hard-to-treat infections, like meningitis. Tigecycline has a low penetration into cerebrospinal fluid.2424 Pallotto C, Fiorio M, D’Avolio A, et al. Cerebrospinal fluid penetration of tigecycline. Scand J Infect Dis. 2014;46(1):69-72. Tigecycline is also contra-indicated for the treatment of primary bacteremia as peak concentration of less than 1 mg/L can be achieved, an insufficient level for treatment of bloodstream infection. Furthermore, sub-therapeutic concentrations are associated with increasing resistance.2525 Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2007;59(4):772-774. Polymyxin is the drug primarily used for treatment of CR-AB. The use of polymyxin B is less reported than that of colistin, although this drug has shown successful results with less acute renal injury than colistin.2626 Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005;40(9):1333-1341. However, to date, there are no reports regarding the penetration of polymyxin B, the most common polymyxin used in Brazil, in the central nervous system. Colistin has been used for the treatment of meningitis with reasonable outcomes.2626 Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005;40(9):1333-1341. Despite the presence of a susceptibility pattern to polymyxins in most of our isolates, these drugs should be cautiously used due to increasing resistance, nephrotoxicity, and neurotoxicity. When these drawbacks are taken into consideration, doxycycline is an attractive alternative for or potential addition to other active drugs to treat nosocomial meningitis.

In summary, A. baumannii infections in our patient cohort resulted in high mortality, and carbapenem resistance was frequent in these severe infections. OXA-23 continues to be the main mechanism of resistance of A. baumannii in this region of the Brazil, with a predominant clonal pattern. Fortunately, alternative drugs are available for use under specific conditions that must be decided by experts.

  • 1
    All authors meet the ICMJE authorship criteria.
  • Ethical approval
    Yes (2014 – 0118)
  • Informed consent
    N/A
  • Funding
    None.

References

  • 1
    Climaco EC, Oliveira ML, Pitondo-Silva A, et al. Clonal complexes 104, 109 and 113 playing a major role in the dissemination of OXA-carbapenemase-producing Acinetobacter baumannii in Southeast Brazil. Infect Genet Evol 2013;19:127-133.
  • 2
    Fournier PE, Richet H. The epidemiology and control of Acinetobacter baumannii in health care facilities. Clin Infect Dis 2006;42(5):692-699.
  • 3
    Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis 2008;46(8):1254-1263.
  • 4
    Fernandez-Cuenca F, Tomas-Carmona M, Caballero-Moyano F, et al. [In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp.: multicenter national study GEIH-REIPI-Ab 2010]. Enferm Infec Microbiol Clin 2013;31(1):4-9.
  • 5
    Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother 1996;40(5):1104-1107.
  • 6
    Emori TG, Culver DH, Horan TC, et al. National nosocomial infections surveillance system (NNIS): description of surveillance methods. Am J Infect Control 1991;19(1):19-35.
  • 7
    CLSI (Clinical and Laboratory Standards Institute). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Tenth Edition (M07-A9) Clinical and Laboratory Standard Institute; 2012.
  • 8
    CLSI. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Tenth Edition (M07-A10) Clinical and Laboratory Standard Institute; 2015.
  • 9
    CLSI (Clinical and Laboratory Standards Institute). Performance Standards for Antimicrobial Susceptibility Testing. Approved Standard M100-S24 Clinical and LaboratoryStandard Institute; 2014.
  • 10
    Marchaim D, Pogue JM, Tzuman O, et al. Major variation in MICs of tigecycline in Gram-negative bacilli as a function of testing method. J Clin Microbiol 2014;52(5):1617-1621.
  • 11
    Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol 2001;39(1):183-190.
  • 12
    Woodford N, Ellington MJ, Coelho JM, et al. Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents 2006;27(4):351-353.
  • 13
    Kaufmann ME. Pulsed-field gel electrophoresis. In: Woodford N, Johnson AP, eds. Molecular Bacteriology: Protocols and Clinical Applications Vol 15. Humana Press; 1998:33–51.
  • 14
    Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol 1995;33(9):2233-2239.
  • 15
    Tuon FF, Penteado-Filho SR, Amarante D, Andrade MA, Borba LA. Mortality rate in patients with nosocomial Acinetobacter meningitis from a Brazilian hospital. Braz J Infect Dis 2010;14(5):437-440.
  • 16
    Tuon FF, Rymsza AM, Penteado-Filho SR, Pilonetto M, Arend LN, Levin AS. Should polymyxin be used empirically to treat infections in patients under high risk for carbapenem-resistant Acinetobacter?. J Infect 2011;62(3):246-249.
  • 17
    Schimith Bier KE, Luiz SO, Scheffer MC, et al. Temporal evolution of carbapenem-resistant Acinetobacter baumannii in Curitiba, southern Brazil. Am J Infect Control 2010;38(4):308-314.
  • 18
    Cieslinski JM, Arend L, Tuon FF, et al. Molecular epidemiology characterization of OXA-23 carbapenemase-producing Acinetobacter baumannii isolated from 8 Brazilian hospitals using repetitive sequence-based PCR. Diagn Microbiol Infect Dis 2013;77(4):337-340.
  • 19
    Werneck JS, Picao RC, Girardello R, et al. Low prevalence of blaOXA-143 in private hospitals in Brazil. Antimicrob Agents Chemother 2011;55(9):4494-4495, author reply 5.
  • 20
    Timurkaynak F, Can F, Azap OK, Demirbilek M, Arslan H, Karaman SO. In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int J Antimicrob Agents 2006;27(3):224-228.
  • 21
    Bantar C, Schell C, Posse G, Limansky A, Ballerini V, Mobilia L. Comparative time-kill study of doxycycline, tigecycline, sulbactam, and imipenem against several clones of Acinetobacter baumannii Diagn Microbiol Infect Dis 2008;61(3):309-314.
  • 22
    Hawley JS, Murray CK, Griffith ME, et al. Susceptibility of acinetobacter strains isolated from deployed U.S. military personnel. Antimicrob Agents Chemother 2007;51(1):376-378.
  • 23
    Zarrilli R, Crispino M, Bagattini M, et al. 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.
  • 24
    Pallotto C, Fiorio M, D’Avolio A, et al. Cerebrospinal fluid penetration of tigecycline. Scand J Infect Dis 2014;46(1):69-72.
  • 25
    Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii J Antimicrob Chemother 2007;59(4):772-774.
  • 26
    Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005;40(9):1333-1341.

Edited by

Associate Editor: Afonso Barth

Publication Dates

  • Publication in this collection
    Nov 2018

History

  • Received
    1 Aug 2017
  • Accepted
    3 Apr 2018
  • Published
    24 Apr 2018
Sociedade Brasileira de Microbiologia USP - ICB III - Dep. de Microbiologia, Sociedade Brasileira de Microbiologia, Av. Prof. Lineu Prestes, 2415, Cidade Universitária, 05508-900 São Paulo, SP - Brasil, Ramal USP 7979, Tel. / Fax: (55 11) 3813-9647 ou 3037-7095 - São Paulo - SP - Brazil
E-mail: bjm@sbmicrobiologia.org.br