Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with in vitro activity against CRE; and eravacycline, which is a tetracycline class antibacterial with in vitro activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.

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Community-onset S. maltophilia infection deserves attention. Patients with community-onset SMBSI have reduced disease severity and lower mortality rate when compared to HA SMBSI. Underlying structural/mechanical abnormalities, especially those caused by malignancies, are common in SMBSI cases and should be investigated when bacteremia occurs.

The spread of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae has become a major public health threat worldwide. Area covered: A thorough systematic literature review describing the current evidence and future prospects of therapeutic options for infections caused by ESBL-producing Enterobacteriaceae. Expert commentary: The methods of detecting ESBLs have been evolving. The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing lowered the MIC breakpoints of cephalosporins against ESBL-producing Enterobacteriaceae in 2010. Phenotypic testing for ESBLs is no longer recommended. Instead, the selection of appropriate antimicrobial agents largely depends on the report of minimum inhibitory concentrations (MICs). To date, therapeutic options for these multidrug-resistant organisms remain limited. The clinical efficacy of piperacillin/tazobactam and cefepime on in vitro-susceptible ESBL-producing Enterobacteriaceae remains a concern. Many studies found an in vitro-in vivo discordance based on current breakpoints. Carbapenems are the most reliable antibiotics for severe infections caused by ESBL-producing Enterobacteriaceae. However, their overuse has led to a serious problem of increasing drug resistance. Recently, ceftolozane/tazobactam and ceftazidime/avibactam have been approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. The introduction of these new β-lactam/β-lactamase inhibitor combinations offers new carbapenem-sparing options for the treatment of ESBL infections.

Purpose This study aimed to investigate the resistance mechanisms and molecular epidemiology of carbapenem-nonsusceptible Escherichia coli (CnsEC) in Taiwan. Patients and methods From 2012 to 2015, 237 E. coli isolates with minimum inhibitory concentrations of imipenem or meropenem >1 μg/mL were collected in a nationwide surveillance and subjected to polymerase chain reaction (PCR) for carbapenemase, AmpC-type β-lactamase, and extended spectrum β-lactamase (ESBL) genes. We evaluated outer membrane proteins (OmpF and OmpC) loss and conducted multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Isolates that were resistant to all carbapenems were designated as pan-carbapenem-resistant E. coli (pCREC) in this study. Results The predominant resistance mechanism of CnsEC in Taiwan was the CMY-2 β-lactamase in combination with OmpF and OmpC loss. Sequence type 131 was the most prevalent type (29.2%). Among 237 CnsEC isolates, 106 (44.7%) isolates were pCREC and 18 (7.59%) produced carbapenemase. The prevalence of carbapenemases increased from 6% in 2012 to 11.36% in 2015. Various carbapenemases including KPC-2, IMP-8, NDM-1, NDM-5, VIM-1, OXA-48, and OXA-181 were identified, with NDM-1 being the most common (38.9%) carbapenemase. Comparison between pCREC and non-pCREC among the non-carbapenemase-producing CnsEC isolates revealed SHV, CMY, co-carriage of SHV and CTX-M and concurrent loss of both OmpF and OmpC were more commonly detected in the pCREC group. PFGE revealed no nationwide clonal spread of carbapenemase-producing E. coli . Conclusion NDM-1 was the most common carbapenemase and combination of CMY-2 and concurrent OmpF and OmpC porin loss was the most prevalent resistance mechanism in CnsEC in Taiwan.

Fluoroquinolone resistance in extended-spectrum β-lactamases (ESBL)-producing isolates results in very few antimicrobial treatment options. In Taiwan's Surveillance of Antimicrobial Resistance (TSAR) III program, 124 (52.8%) cases of ESBL-producing Klebsiella pneumoniae (ESBL-KP) were resistant to ciprofloxacin. The prevalence of plasmid-mediated quinolone resistance (PMQR) determinants and chromosomal quinolone resistance-determining regions (QRDR) of gyrA and parC genes among ESBL-KP isolates was assessed via PCR sequencing. Chromosomal QRDR mutations were present in most of the 123 (96.8%) cases of ciprofloxacin-resistant ESBL-KP isolates. Sixty-six (53.2%) isolates had at least one PMQR gene. qnrB2, qnrB4, and qnrS1 were detected in 26, 19, and 13 isolates, respectively, whereas qnrA, qnrC, and qnrD were not detected. ESBL genes were transferable via conjugation with either aac(6')Ib-cr or qnrB in 63.6% of the isolates carrying PMQR genes. QnrB was associated with either CTX-M-15 or SHV-12, and aac(6')Ib-cr was linked to CTX-M-3 or CTX-M-14 in plasmids. qnrS did not co-transfer with ESBL genes. Clonal spread of PMQR genes harboring ESBL-KP isolates was observed in three hospitals. QnrA, which is common in Asia, was unexpectedly absent in ESBL-KP in Taiwan. Aside from transmission via clonal spread for ciprofloxacin-resistant ESBL-KP, concomitant transference of PMQR genes with either bla(CTX-M) or bla(SHV) via plasmid was common.

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

Mucormycosis is an invasive fungal infection associated with a high mortality rate, especially in immunocompromised hosts. Mucormycosis rarely occurs in cirrhotic patients. Here, we report a case of mucormycosis with underlying liver cirrhosis and diabetes mellitus. The patient suffered from maxillary sinusitis and osteomyelitis, and the infection was successfully treated with antifungal agents, surgical debridement, and hyperbaric oxygen therapy. The antifungal treatments used were liposomal amphotericin B, itraconazole, and posaconazole. Although our patient had liver cirrhosis (Child-Pugh classification B), no hepatic decompensation was developed during the treatment course of posaconazole. This is the first report of the safe and effective use of posaconazole for the treatment of mucormycosis in a cirrhotic patient.