Extended spectrum β-lactamase (ESBL)-producing bacteria are prevalent worldwide and correlated with hospital infections, but they have been evolving as an increasing cause of community acquired ...infections. The spread of ESBL constitutes a major threat for public health, and infections with ESBL-producing organisms have been associated with poor outcomes. Established therapeutic options for severe infections caused by ESBL-producing organisms are considered the carbapenems. However, under the pressure of carbapenem overuse and the emergence of resistance, carbapenem-sparing strategies have been implemented. The administration of carbapenem-sparing antibiotics for the treatment of ESBL infections has yielded conflicting results. Herein, the current available knowledge regarding carbapenem-sparing strategies for ESBL producers is reviewed, and the optimal conditions for the "when and how" of carbapenem-sparing agents is discussed. An important point of the review focuses on piperacillin-tazobactam as the agent arousing the most debate. The most available data regarding non-carbapenem β-lactams (i.e., ceftolozane-tazobactam, ceftazidime-avibactam, temocillin, cephamycins and cefepime) are also thoroughly presented as well as non β-lactams (i.e., aminoglycosides, quinolones, tigecycline, eravacycline and fosfomycin).
The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful ...of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant
(CRPA). Less options are available against carbapenem-resistant
(CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered "panacea" for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only
active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and
, deserves a greater attention. Optimal conditions for monotherapy and the "when and how" of combination treatments integrating the novel agents will be discussed.
Abstract Acinetobacter baumannii ventriculitis/meningitis due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has become a clinical entity of considerable ...importance in recent years. A review of the available literature regarding intraventricular (IVT) or intrathecal (ITH) administration of colistin in MDR and XDR A. baumannii ventriculitis/meningitis was conducted and a total of 83 episodes in 81 patients were identified (71 cases in adults and 10 in children and neonates). Colistin was administered via the IVT and ITH route in 52 and 22 cases, respectively, whilst in 7 cases the exact route was not identified. The median dose of local colistin was 125 000 IU (10 mg) with a range of 20 000 IU (1.6 mg) to 500 000 IU (40 mg) in adults, whilst a dose of 2000 IU/kg (0.16 mg/kg) up to 125 000 IU (10 mg) was used in the paediatric population. The median duration of treatment of IVT/ITH polymyxin E was 18.5 days, whilst the median time to achieve sterilisation of cerebrospinal fluid was 4 days. The rate of successful outcome was 89%, and toxicity related to treatment mainly manifested as reversible chemical ventriculitis/meningitis was reported in nine cases (11%). Nowadays, IVT and ITH colistin represents the last resort treatment of MDR and XDR A. baumannii ventriculitis/meningitis, offering a unique, rather safe and successful mode of therapy.
Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, ...Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel β-lactam-β-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented.
New-generation threaded acetabulum components have been used in total hip arthroplasty (THA) with good outcomes. We have extensively used the EcoFit® SC cup (Implantcast, Buxtehude, Germany) in our ...practice. In this report, we present some major complications related to the use of this implant, as well as insights regarding the surgical technique to avoid such adverse effects. Furthermore, we attempt to describe certain contraindications for using threaded cups in THA, taking into account specific patient anatomy and intraoperative acetabulum preparation. We have observed acetabulum roof and posterior wall fractures, as well as incomplete placement of the component. Ensuring the meticulous preparation of the peripheral rim of the acetabulum is crucial to prevent incomplete placement since threaded components have a larger diameter than that of the reamers used to prepare the acetabulum. Additionally, when dealing with the acetabula where the posterior or anterior walls have thinned, it is advisable to refrain from using a threaded cup to avoid the risk of intraoperative fractures caused by the torque forces exerted during implant insertion.
Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, ...since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen Klebsiella pneumoniae is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and K. pneumoniae carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in K. pneumoniae. In the last decade, the management of severe infections due to KPC-producing K. pneumoniae (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.
KEY MESSAGES
In the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwide
Following the introduction in clinical practice of novel β-lactam/β-lactamase inhibitor combinations and novel β-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolution
Treatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics
To evaluate the in vitro activities of plazomicin and comparator aminoglycosides and elucidate the underlying aminoglycoside resistance mechanisms among carbapenemase-producing K. pneumoniae isolates ...collected during a nationwide surveillance study in Greek hospitals.
Three hundred single-patient carbapenemase-producing K. pneumoniae isolates were studied, including 200 KPC-, 50 NDM-, 21 VIM-, 14 KPC & VIM-, 12 OXA-48-, two NDM & OXA- and one KPC & OXA-producing isolates. Susceptibility testing was performed by broth microdilution, and minimum inhibitory concentrations (MICs) interpreted per EUCAST breakpoints. Carbapenemase-, aminoglycoside modifying enzyme- and 16S rRNA methylase- encoding genes were detected by PCR.
Of 300 isolates tested, 5.7% were pandrug resistant and 29.3% extensively drug resistant. Plazomicin inhibited 87.0% of the isolates at ≤2 mg/L, with MIC
/MIC
of 0.5/4 mg/L. Apramycin (a veterinary aminoglycoside) inhibited 86.7% of the isolates at ≤8 mg/L and was the second most active drug after plazomicin, followed by gentamicin (S, 43%; MIC
/MIC
, 4/> 256) and amikacin (S, 18.0%; MIC
/MIC
, 32/128). Twenty-three (7.7%) isolates (16 KPC-, 6 VIM- and one KPC & OXA-48-producers) exhibited MICs ≥64 mg/L for plazomicin, and harbored rmtB (n = 22) or armA (n = 1). AAC(6')-Іb was the most common aminoglycoside modifying enzyme (84.7%), followed by AAC(3΄)-IIa (25.3%), while those two enzymes were co-produced by 21.4% of the isolates.
Plazomicin retains activity against most carbapenemase-producing K. pneumoniae isolated from Greek hospitals, with MICs consistently lower than those of the other aminoglycosides, even in the presence of aminoglycoside modifying enzymes. Dissemination of 16S- rRNA methylases in 8% of the isolates is an unwelcome event that needs strict infection control measures and rigorous stewardship interventions.
Three ceftazidime-avibactam-resistant KPC-2-producing
Klebsiella pneumoniae
strains of ST39 were isolated in Greece, from rectal swabs of three patients after 10–15 days of treatment. The patients ...were treated with ceftazidime-avibactam as monotherapy or in combination with colistin. Two of these strains harbored a D179Y or a D179V substitution in the Ω loop of KPC-2, corresponding to KPC-33, or to the novel KPC-57, respectively. The third strain had a 15 amino acid insertion after position 259 in the KPC-2, corresponding to KPC-44.
PDF
