Article Figures & Data
Figures
- 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.
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.
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
- TABLE 1.
Breakpoints used to determine susceptible, intermediate, and resistant categories for H. influenzae based on PK/PD, BSAC, and CLSI interpretative breakpoints
Antimicrobial Breakpoint (μg/ml) based ona: PK/PD BSAC CLSI S R S I R S I R Parenteral agents Ampicillin ≤2 ≥4 ≤1 - ≥2 ≤1 2 ≥4b Ampicillin-sulbactam ≤2 ≥4 - - - ≤2 - ≥2 Piperacillin-tazobactam ≤8 ≥16 - - - ≤1 - ≥2 Cefuroxime sodium ≤4 ≥4 ≤1 - ≥2 ≤4 8 ≥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 ≤0.5 1-8 ≥16 - - - Clarithromycin ≤0.25 ≥0.5 ≤0.5 1-16 ≥32 ≤8 16 ≥32 Azithromycin ≤0.12 ≥0.25 ≤0.25 0.5-4 ≥8 ≤4 - - Doxycycline ≤0.25 ≥0.5 - - - - - - Trimethoprim-sulfamethoxazolee ≤0.5/9.5 ≥1/19 ≤1.6/30.4 - ≥32/60.8 ≤0.5/9.5 1/19-2/38 ≥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 - - Rifampin ND ND - - - ≤1 2 ≥4 Chloramphenicol ≤4 ≥8 ≤2 - ≥4 ≤2 4 ≥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 ≤8 16 ≥32 Cefuroxime axetil ≤1 ≥2 ≤1 - ≥2 ≤4 8 ≥16 Cefixime ≤1 ≥2 - - - ≤1 - - Cefprozil ≤1 ≥2 - - - ≤8 16 ≥32 Cefdinir ≤0.5 ≥1 - - - ≤1 - - Cefpodoxime ≤0.5 ≥1 - - - ≤2 - - Telithromycin ≤0.5f ≥1f ≤0.5 1-2 ≥4 ≤4 8 ≥16 Tetracycline ≤2g ≥4g ≤1 - ≥2 ≤2 4 ≥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
Antimicrobial MIC50 (μg/ml) MIC90 (μg/ml) % S by PK/PD CLSI % S % R Ampicillin 0.25 >16 NA 81.9 17.0 Amoxicillin 0.5 >16 81.6 83.2 16.8 Amoxicillin-clavulanate, lower dose 0.5 1 98.1 99.6 0.4 Amoxicillin-clavulanate, higher dose 0.5 1 99.6 NA NA Cefaclor 4 16 1.4 89.7 3.6 Cefuroxime axetil 1 2 83.6 98.1 0.7 Cefixime 0.03 0.06 99.8 99.8 NA Ceftriaxone ≤0.004 0.008 100 100 NA Cefprozil 2 8 22.3 92.5 2.6 Cefdinir 0.25 0.5 92.0 97.6 NA Erythromycin 4 8 <0.5 NA NA Clarithromycin 8 16 <0.3 79.6 0.9 Azithromycin 1 2 <1.2 99.5 NA Chloramphenicol 0.5 1 98.1 97.9 1.9 Doxycycline 0.5 1 28.9 NA NA Trimethoprim-sulfamethoxazole 0.12 >4 78.3 78.3 17.0 Ciprofloxacin 0.015 0.03 99.9 99.9 NA Ofloxacin 0.03 0.06 99.9 99.9 NA Gemifloxacin 0.004 0.015 99.9 NA NA Levofloxacin 0.015 0.015 99.9 99.9 NA Gatifloxacin 0.008 0.015 99.9 99.9 NA Moxifloxacin 0.015 0.03 99.8 99.8 NA ↵ 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
Gene Gene 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 type n MIC (μg/ml) 50% 90% Range Ampicillin BLNAS 155 0.25 0.5 0.031-0.5 BLPAR (TEM-1) 68 8 16 2-64 L-BLNAR 189 1 2 0.5-2 BLNAR 138 2 4 1-16 BLPACR-I 59 16 32 2-64 BLPACR-II 12 32 64 16-64 Cefotaxime BLNAS 0.0016 0.0031 0.004-0.063 BLPAR (TEM-1) 0.0016 0.0031 0.008-0.063 L-BLNAR 0.063 0.125 0.031-0.25 BLNAR 0.5 1 0.125-2 BLPACR-I 0.063 0.125 0.016-0.25 BLPACR-II 0.5 1 0.125-1 Meropenem BLNAS 0.031 0.063 0.008-0.125 BLPAR (TEM-1) 0.063 0.063 0.031-0.063 L-BLNAR 0.125 0.25 0.031-0.5 BLNAR 0.125 0.25 0.031-0.5 BLPACR-I 0.125 0.25 0.031-0.5 BLPACR-II 0.125 0.25 0.063-0.25 ↵ 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
Drug MIC result (μg/ml) for strain type: TEM-1 ROB-1 β-Lactamase negative 50% 90% Range 50% 90% Range 50% 90% Range Ampicillin ≥32 ≥32 2-≥32 ≥32 ≥32 8-≥32 0.25 0.50 0.12-≥32 Amoxicillin-clavulanate 1 2 0.12-≥8 0.5 1.0 0.25-2.0 0.5 1 0.12-≥8 Cefaclor 4 16 0.5-≥128 16 64 2.0-≥128 2 8 0.5-≥128 Cefpodoxime 0.06 0.12 ≤0.015-2.0 0.06 0.06 ≤0.015-0.25 0.06 0.12 ≤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: 337 350 352 357 368 377 385 389 437 443 449 490 501 502 511 517 526 528 532 547 562 569 586 Rd A D S S A M S L A T I G R A V R N Y T V V N A Ubukatab I (9) N N I T S H S II (12) N N V K S III (4) N N I T F K L S Straker (14)c V N N T I A L/H T/V A H K H S Kubota (20)d N F N I T F A K I L S S Dabernate I (7) N N T H IIa (5) K IIb (56) N N L S E V K IIc (25) N T 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 N T I S V E T/V H K
- 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