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Review

Antimicrobial Resistance in Haemophilus influenzae

Stephen Tristram, Michael R. Jacobs, Peter C. Appelbaum
Stephen Tristram
1School of Human Life Science, University of Tasmania, Launceston, Australia
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  • For correspondence: Stephen.Tristram@utas.edu.au
Michael R. Jacobs
2Case Western Reserve University School of Medicine, Cleveland, Ohio
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Peter C. Appelbaum
3Hershey Medical Center, Hershey, Pennsylvania
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DOI: 10.1128/CMR.00040-06
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  • FIG. 1.
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    FIG. 1.

    Correlation between β-lactam resistance mechanisms and susceptibility of H. influenzae to ampicillin, cefotaxime, and meropenem. Data were adapted from Hasegawa et al. (57) and Sanbongi et al. (125). The figure was created by M. Jacobs.

  • FIG. 2.
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    FIG. 2.

    MIC distributions of selected β-lactam antimicrobial agents for H. influenzae. Arrows indicate PK/PD breakpoints. The two arrows shown for amoxicillin and amoxicillin-clavulanate indicate breakpoints applicable to lower (left) and higher (right) dosing regimens. The two arrows shown for cefuroxime indicate breakpoints applicable to oral (left) and parenteral (right) dosing regimens. The figure was created by M. Jacobs.

  • FIG. 3.
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    FIG. 3.

    MIC distributions of selected non-β-lactam antimicrobial agents for H. influenzae. Arrows indicate PK/PD breakpoints. The figure was created by M. Jacobs.

Tables

  • Figures
  • TABLE 1.

    Breakpoints used to determine susceptible, intermediate, and resistant categories for H. influenzae based on PK/PD, BSAC, and CLSI interpretative breakpoints

    AntimicrobialBreakpoint (μg/ml) based ona:
    PK/PDBSACCLSI
    SRSIRSIR
    Parenteral agents
        Ampicillin≤2≥4≤1-≥2≤12≥4b
        Ampicillin-sulbactam≤2≥4---≤2-≥2
        Piperacillin-tazobactam≤8≥16---≤1-≥2
        Cefuroxime sodium≤4≥4≤1-≥2≤48≥16
        Cefotaxime≤2≥4≤1-≥2≤2--
        Ceftriaxone≤2≥4≤1-≥2≤2--
        Cefepime≤4≥8---≤2--
        Ceftazidime≤8≥16≤2-≥4≤2--
        Meropenem≤4≥8≤4-≥8≤0.5--
        Imipenem≤4≥8≤4-≥8≤4--
        Ertapenem≤1≥2≤2-≥4≤0.5--
    Parenteral and oral agents
        Erythromycin≤0.25≥0.5≤0.51-8≥16---
        Clarithromycin≤0.25≥0.5≤0.51-16≥32≤816≥32
        Azithromycin≤0.12≥0.25≤0.250.5-4≥8≤4--
        Doxycycline≤0.25≥0.5------
        Trimethoprim-sulfamethoxazolee≤0.5/9.5≥1/19≤1.6/30.4-≥32/60.8≤0.5/9.51/19-2/38≥4/76
        Ciprofloxacin≤1≥2≤0.5-≥1≤1--
        Ofloxacin≤2≥4≤0.5-≥1≤2--
        Gemifloxacin≤0.25≥0.5≤0.25-≥0.5---
        Levofloxacin≤2≥4≤1-≥2≤2--
        Gatifloxacin≤1≥2≤1-≥2≤1--
        Moxifloxacin≤1≥2≤0.5-≥1≤1--
        RifampinNDND---≤12≥4
        Chloramphenicol≤4≥8≤2-≥4≤24≥8
    Oral agents
        Amoxicillin (1.5 g/day; 45 mg/kg/day)≤2≥4≤1-≥2---
        Amoxicillin (3-4 g/day; 90 mg/kg/day)≤4c≥8c------
        Amoxicillin-clavulanate (1.5 g-250 mg/day; 45-6.4 mg/kg/day)≤2c≥4c≤1-≥2≤4-≥8d
        Amoxicillin-clavulanate (4 g-6.4 mg/day; 45 mg/kg/day)≤4c≥8c------
        Cefaclor≤0.5≥1≤1-≥2≤816≥32
        Cefuroxime axetil≤1≥2≤1-≥2≤48≥16
        Cefixime≤1≥2---≤1--
        Cefprozil≤1≥2---≤816≥32
        Cefdinir≤0.5≥1---≤1--
        Cefpodoxime≤0.5≥1---≤2--
        Telithromycin≤0.5f≥1f≤0.51-2≥4≤48≥16
        Tetracycline≤2g≥4g≤1-≥2≤24≥8
    • ↵ a S, susceptible; I, intermediate; R, resistant; ND, not defined; -, no breakpoint available.

    • ↵ b CLSI breakpoint used to define BLNAR isolates.

    • ↵ c Breakpoints are expressed as amoxicillin component; testing was performed using a 2:1 ratio of amoxicillin/clavulanic acid.

    • ↵ d Breakpoint used to defined BLPACR isolates.

    • ↵ e Breakpoints are expressed as trimethoprim component; testing was performed using a 1:19 ratio of trimethoprim/sulfamethoxazole.

    • ↵ f Limited information is currently available to determine PK/PD breakpoints.

    • ↵ g The microbiological breakpoint was used in the absence of PK/PD studies (27, 30, 64, 87).

  • TABLE 2.

    Susceptibility of worldwide isolates of H. influenzae (n = 8,523) to 23 antimicrobials and MIC50s and MIC90sa

    AntimicrobialMIC50 (μg/ml)MIC90 (μg/ml)% S by PK/PDCLSI
    % S% R
    Ampicillin0.25>16NA81.917.0
    Amoxicillin0.5>1681.683.216.8
    Amoxicillin-clavulanate, lower dose0.5198.199.60.4
    Amoxicillin-clavulanate, higher dose0.5199.6NANA
    Cefaclor4161.489.73.6
    Cefuroxime axetil1283.698.10.7
    Cefixime0.030.0699.899.8NA
    Ceftriaxone≤0.0040.008100100NA
    Cefprozil2822.392.52.6
    Cefdinir0.250.592.097.6NA
    Erythromycin48<0.5NANA
    Clarithromycin816<0.379.60.9
    Azithromycin12<1.299.5NA
    Chloramphenicol0.5198.197.91.9
    Doxycycline0.5128.9NANA
    Trimethoprim-sulfamethoxazole0.12>478.378.317.0
    Ciprofloxacin0.0150.0399.999.9NA
    Ofloxacin0.030.0699.999.9NA
    Gemifloxacin0.0040.01599.9NANA
    Levofloxacin0.0150.01599.999.9NA
    Gatifloxacin0.0080.01599.999.9NA
    Moxifloxacin0.0150.0399.899.8NA
    • ↵ a Data are from the Alexander Project 1998 to 2000 (64). S, susceptible; R, resistant; NA, not available.

  • TABLE 3.

    Genes and gene products for selected H. influenzae resistance mechanismsa

    GeneGene product and description
    bla TEM TEM type β-lactamase; can be specified, as in blaTEM-1, to signify the gene associated with a specific TEM β-lactamase, such as TEM-1
    bla ROB-1 ROB-1 β-lactamase (although variants of this gene and enzyme have not been described, it is usual to use the suffix-1 with the gene and enzyme)
    ftsI PBP3 (see the text for discussion on PBP3A and PBPB)
    dacA PBP5
    dacB PBP4
    acrA/acrB AcrAB efflux pump
    acrR AcrR (repressor for AcrAB efflux pump)
    tet(B)Tet(B) tetracycline efflux protein
    tet(M), tet(K)Tet(M) and Tet(K) ribosomal protection proteins (reported only from non-H. influenzae Haemophilus spp.)
    cat Chloramphenicol acetyltransferase
    • ↵ a Compiled from references 24, 53, 71, 72, 117, 136, and 149.

  • TABLE 4.

    MIC distributions for H. influenzae and β-lactam resistance mechanismsa

    Drug and strain typenMIC (μg/ml)
    50%90%Range
    Ampicillin
        BLNAS1550.250.50.031-0.5
        BLPAR (TEM-1)688162-64
        L-BLNAR189120.5-2
        BLNAR138241-16
        BLPACR-I5916322-64
        BLPACR-II12326416-64
    Cefotaxime
        BLNAS0.00160.00310.004-0.063
        BLPAR (TEM-1)0.00160.00310.008-0.063
        L-BLNAR0.0630.1250.031-0.25
        BLNAR0.510.125-2
        BLPACR-I0.0630.1250.016-0.25
        BLPACR-II0.510.125-1
    Meropenem
        BLNAS0.0310.0630.008-0.125
        BLPAR (TEM-1)0.0630.0630.031-0.063
        L-BLNAR0.1250.250.031-0.5
        BLNAR0.1250.250.031-0.5
        BLPACR-I0.1250.250.031-0.5
        BLPACR-II0.1250.250.063-0.25
    • ↵ a Data are from Hasegawa et al. (57). BLNAS, β-lactamase negative ampicillin susceptible; BLPAR, β-lactamase positive ampicillin resistant; L-BLNAR, low-level BLNAR; BLPACR-I, β-lactamase positive amoxicillin-clavulanate resistant (from L-BLNAR); BLPACR-II, β-lactamase positive amoxicillin-clavulanate resistant (from BLNAR).

  • TABLE 5.

    MIC data for β-lactamase-negative and TEM-1- and ROB-1-producing H. influenzae strainsa

    DrugMIC result (μg/ml) for strain type:
    TEM-1ROB-1β-Lactamase negative
    50%90%Range50%90%Range50%90%Range
    Ampicillin≥32≥322-≥32≥32≥328-≥320.250.500.12-≥32
    Amoxicillin-clavulanate120.12-≥80.51.00.25-2.00.510.12-≥8
    Cefaclor4160.5-≥12816642.0-≥128280.5-≥128
    Cefpodoxime0.060.12≤0.015-2.00.060.06≤0.015-0.250.060.12≤0.015-4
    • ↵ a Data are from Farrell et al. (48).

  • TABLE 6.

    Deduced amino acid substitutions in PBP3 for different series of BLNAR strains compared with Rd control

    Strain (n)Amino acid at positiona:
    337350352357368377385389437443449490501502511517526528532547562569586
    RdADSSAMSLATIGRAVRNYTVVNA
    Ubukatab
        I (9) N N ITS H S
        II (12) N N V K S
        III (4) N N I T F K LS
    Straker (14)cVN N TIAL/H T/V AH K HS
    Kubota (20)d N F N I T F A K I L S S
    Dabernate
        I (7)NNT H
        IIa (5) K
        IIb (56)NN L SE V K
        IIc (25)NT T K
        IId (15) V K
    Hasegawaf
        I (9) H
        II (2) I T F H
        III (7) T K
        IV (1) I T K
        V (1) T F K
        VI (35) I T F K
    Fluit (28)g N NTISVE T/V H K
    • ↵ a Boldface type, all strains; underlining, most strains; plain text, some strains.

    • ↵ b Ubukata et al. (149).

    • ↵ c Straker et al. (136).

    • ↵ d Kubota et al. (76).

    • ↵ e Dabernat et al. (31).

    • ↵ f Hasegawa et al. (56).

    • ↵ g Fluit et al. (50).

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Antimicrobial Resistance in Haemophilus influenzae
Stephen Tristram, Michael R. Jacobs, Peter C. Appelbaum
Clinical Microbiology Reviews Apr 2007, 20 (2) 368-389; DOI: 10.1128/CMR.00040-06

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Antimicrobial Resistance in Haemophilus influenzae
Stephen Tristram, Michael R. Jacobs, Peter C. Appelbaum
Clinical Microbiology Reviews Apr 2007, 20 (2) 368-389; DOI: 10.1128/CMR.00040-06
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • SUSCEPTIBILITY TESTING OF H. INFLUENZAE
    • TREATMENT OF H. INFLUENZAE INFECTIONS
    • BASELINE SUSCEPTIBILITY, DEVELOPMENT OF RESISTANCE, AND DEVELOPMENT OF INTERPRETATIVE SUSCEPTIBILITY BREAKPOINTS
    • MECHANISMS OF RESISTANCE
    • CLINICAL SIGNIFICANCE OF RESISTANCE
    • CONCLUSIONS
    • ADDENDUM IN PROOF
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Anti-Bacterial Agents
Drug Resistance, Bacterial
Haemophilus influenzae

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