Infections caused by metallo-β-lactamase (MBL)-producing Enterobacterales and Pseudomonas are increasingly reported worldwide and are usually associated with high mortality rates (>30%). Neither ...standard therapy nor consensus for the management of these infections exist. Aztreonam, an old β-lactam antibiotic, is not hydrolyzed by MBLs. However, since many MBL-producing strains co-produce enzymes that could hydrolyze aztreonam (e.g., AmpC, ESBL), a robust β-lactamase inhibitor such as avibactam could be given as a partner drug. We performed a systematic review including 35 in vitro and 18 in vivo studies on the combination aztreonam + avibactam for infections sustained by MBL-producing Gram-negatives. In vitro data on 2209 Gram-negatives were available, showing the high antimicrobial activity of aztreonam (MIC ≤ 4 mg/L when combined with avibactam) in 80% of MBL-producing Enterobacterales, 85% of Stenotrophomonas and 6% of MBL-producing Pseudomonas. Clinical data were available for 94 patients: 83% of them had bloodstream infections. Clinical resolution within 30 days was reported in 80% of infected patients. Analyzing only patients with bloodstream infections (64 patients), death occurred in 19% of patients treated with aztreonam + ceftazidime/avibactam. The combination aztreonam + avibactam appears to be a promising option against MBL-producing bacteria (especially Enterobacterales, much less for Pseudomonas) while waiting for new antimicrobials.
Ceftazidime/avibactam (CAZ-AVI), approved in 2015, is an important first-line option for Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC-E). Although still uncommon, resistance to ...CAZ-AVI has emerged and may represent a serious cause of concern.
We performed a systematic literature review of clinical and microbiological features of infections and colonisations by CAZ-AVI-resistant KPC-E, focused on the in vivo emergence of CAZ-AVI resistance in different clinical scenarios.
Twenty-three papers were retrieved accounting for 42 patients and 57 isolates, mostly belonging to K. pneumoniae ST258 harbouring D179Y substitution in the KPC enzyme. The USA, Greece and Italy accounted for 80% of cases. In one-third of isolates resistance was not associated with previous CAZ-AVI exposure. Moreover, 20% of the strains were colistin-resistant and 80% were extended-spectrum β-lactamase (ESBL)-producers. The majority of infected patients had severe underlying diseases (39% cancer, 22% solid-organ transplantation) and 37% died. The abdomen, lung and blood were the most involved infection sites. Infections by CAZ-AVI-resistant strains were mainly treated with combination therapy (85% of cases), with meropenem being the most common (65%) followed by tigecycline (30%), gentamicin (25%), colistin (25%) and fosfomycin (10%). Despite the emergence of resistance, 35% of patients received CAZ-AVI.
Taken together, these data highlight the need for prompt susceptibility testing including CAZ-AVI for Enterobacterales, at least in critical areas. Resistance to CAZ-AVI is an urgent issue to monitor in order to improve both empirical and targeted CAZ-AVI use as well as the management of patients with infections caused by CAZ-AVI-resistant strains.
We investigated the colistin resistance mechanism in an Escherichia coli strain (LC711/14) isolated in Italy in 2014, from an urinary tract infection, which was previously shown to express a colistin ...resistance mechanism different from mcr-1. LC711/14 was found to carry a novel mutation in the pmrB gene, resulting in a leucine to proline amino acid substitution at position 10 of the PmrB sensor kinase component of the PmrAB signal transduction system. The role of this substitution in colistin resistance was documented by expression of the wild-type and mutated alleles in a pmrB deletion derivative of the E. coli reference strain MG1655, in which expression of the mutated allele conferred colistin resistance and upregulation of the endogenous pmrHFIJKLM lipid A modification system. Complementation of LC711/14 with the wild-type pmrB allele restored colistin susceptibility and decreased expression of pmrHFIJKLM, confirming the role of this PmrB mutation. Substitution of leucine at position 10 of PmrB with other amino acids (glycine and glutamine) resulted in loss of function, underscoring a key role of this residue which is located in the cytoplasmic secretion domain of the protein. This work demonstrated that mutation in this domain of the PmrB sensor kinase can be responsible for acquired colistin resistance in E. coli strains of clinical origin.
Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase ...inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.
Speeding up identification and antimicrobial susceptibility testing (AST) is of foremost importance in the management of blood cultures. Here, we describe a simple, rapid, and standardized approach ...based on a very short-term incubation on solid medium from positive blood cultures followed by MALDI-TOF mass spectrometry identification and automated AST. The aim of the study was to evaluate the impact in the laboratory practice of this new procedure with respect to that previously used (standard method) by comparing TAT and cumulative percentage of final reports to clinicians.
Compared with the standard method, the new procedure gave correct organism identification at genus or species level in 98.4% of monomicrobial samples. AST resulted in 97.7% essential agreement and 98.1% categorical agreement, with 0.9% minor errors, 1.0% major error, and 1.5% very major errors. The mean turnaround time to identification and AST was 61.4 h by using the new method compared to 83.1 h by using standard procedure. Concerning cumulative percentages of final reports, approximately a third of results were available at 48 h from the check-in of the sample when using the new procedure, whereas no final reports were ready at the same time with the standard method.
The new procedure allows faster and reliable results using a simple and standardized approach. Thus, it represents an important tool for a more rapid management of blood cultures when molecular methods are not available in the laboratory.
The rise of a new hypervirulent variant of
(hvKp) was recently reported, mainly linked to the ST23 lineage. The hvKp variants can cause severe infections, including hepatic abscesses, bacteremia, and ...meningitis, with a particularly disconcerting propensity to cause community-acquired, life-threatening infection among young and otherwise healthy individuals. The present study aimed to report the clinical characteristics of a hypermucoviscous
strain isolated in Italy and sustaining recurrent meningitis in a patient of Peruvian origin. A further objective was to retrospectively investigate, by means of whole-genome sequencing (WGS) analysis, the genomic features of such an isolate. The hypermucoviscosity phenotype of the strain (sk205y205t) was determined using the string test. Genomic information was obtained by WGS (Illumina) and bioinformatic analysis. Strain sk205y205t was susceptible to most antibiotics, despite the presence of some resistance genes, including
,
,
and
. The isolate belonged to ST65 and serotype K2, and exhibited several virulence factors related to the hvKp variant. Among these, were the siderophore genes
,
,
,
and
; the capsule-regulating genes
and
; and the type 1 and 3 fimbriae
and
, respectively. A further operon, encoding the genotoxin colibactin (
), was also identified. The virulence plasmids pK2044, pRJA166b, and pNDM. MAR were also detected. Phylogenetic investigation showed that this Italian strain is highly similar to a Chinese isolate, suggesting a hidden circulation of this hvKp ST65 K2 lineage.
Infections caused by carbapenem-resistant
(CRAB) have limited therapeutic options. Sulbactam-durlobactam is a combination of two βlactamase inhibitors with activity against CRAB under phase 3 ...clinical investigation. We performed a systematic review on in vitro studies reporting
resistances against sulbactam/durlobactam. We considered "resistant" species to be those with MIC ≥ 8 mg/L. Ten studies were included in the review (9754 tested isolates). Overall, 2.3% of
were resistant to sulbactam/durlobactam, and this percentage rose to 3.4% among CRAB subgroups and to 3.7% among colistin-resistant strains. Resistance was 100% among metallo β-lactamase-producing strains. Overall, in 12.5% of cases, sulbactam/durlobactam resistance was associated with the production of NDM-1, in 31.7% of cases with the substitutions in the PBP3 determinants, and in the remaining cases the resistance mechanism was unknown. In conclusion,
resistance towards sulbactam/durlobactam is limited, except for MBL-producing strains.
Infections sustained by multidrug-resistant (MDR) and pan-resistant Acinetobacter baumannii have become a challenging problem in Intensive Care Units. Tigecycline provided new hope for the treatment ...of MDR A. baumannii infections, but isolates showing reduced susceptibility have emerged in many countries, further limiting the therapeutic options. Empirical combination therapy has become a common practice to treat patients infected with MDR A. baumannii, in spite of the limited microbiological and clinical evidence supporting its efficacy. Here, the in vitro interaction of tigecycline with seven commonly used anti-Acinetobacter drugs has been assessed.
Twenty-two MDR A. baumannii isolates from Intensive Care Unit (ICU) patients and two reference strains for the European clonal lineages I and II (including 3, 15 and 6 isolates that were resistant, intermediate and susceptible to tigecycline, respectively) were tested. Antimicrobial agents were: tigecycline, levofloxacin, piperacillin-tazobactam, amikacin, imipenem, rifampicin, ampicillin-sulbactam, and colistin. MICs were determined by the broth microdilution method. Antibiotic interactions were determined by chequerboard and time-kill assays. Only antibiotic combinations showing synergism or antagonism in both chequerboard and time-kill assays were accepted as authentic synergistic or antagonistic interactions, respectively.
Considering all antimicrobials in combination with tigecycline, chequerboard analysis showed 5.9% synergy, 85.7% indifference, and 8.3% antagonism. Tigecycline showed synergism with levofloxacin (4 strains; 16.6%), amikacin (2 strains; 8.3%), imipenem (2 strains; 8.3%) and colistin (2 strains; 8.3%). Antagonism was observed for the tigecycline/piperacillin-tazobactam combination (8 strains; 33.3%). Synergism was detected only among tigecycline non-susceptible strains. Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for 5 of 7 selected isolates. No antagonism was confirmed by time-kill assays.
This study demonstrates the in vitro synergistic activity of tigecycline in combination with colistin, levofloxacin, amikacin and imipenem against five tigecycline non-susceptible A. baumannii strains, opening the way to a more rationale clinical assessment of novel combination therapies to combat infections caused by MDR and pan-resistant A. baumannii.
Fosfomycin is being increasingly prescribed for multidrug-resistant bacterial infections. In patients with systemic involvement, intravenous fosfomycin is usually administered as a partner drug, as ...part of an antibiotic regimen. Hence, the knowledge of fosfomycin pharmacodynamic interactions (synergistic, additive, indifferent and antagonistic effect) is fundamental for a proper clinical management of severe bacterial infections. We performed a systematic review to point out fosfomycin’s synergistic properties, when administered with other antibiotics, in order to help clinicians to maximize drug efficacy optimizing its use in clinical practice. Interactions were more frequently additive or indifferent (65.4%). Synergism accounted for 33.7% of total interactions, while antagonism occurred sporadically (0.9%). Clinically significant synergistic interactions were mostly distributed in combination with penicillins (51%), carbapenems (43%), chloramphenicol (39%) and cephalosporins (33%) in Enterobactaerales; with linezolid (74%), tetracyclines (72%) and daptomycin (56%) in Staphylococcus aureus; with chloramphenicol (53%), aminoglycosides (43%) and cephalosporins (36%) against Pseudomonas aeruginosa; with daptomycin (97%) in Enterococcus spp. and with sulbactam (75%) and penicillins (60%) and in Acinetobacter spp. fosfomycin-based antibiotic associations benefit from increase in the bactericidal effect and prevention of antimicrobial resistances. Taken together, the presence of synergistic interactions and the nearly total absence of antagonisms, make fosfomycin a good partner drug in clinical practice.
PDF
