Ceftazidime/avibactam-resistant meropenem-susceptible KPC-producing Klebsiella pneumoniae: Analysis of cases and evaluation of in vitro activity of fosfomycin-containing combinations.

OBJECTIVES: Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations. METHODS: Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested. RESULTS: Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance. CONCLUSIONS: Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

Clinical course of Coronavirus Disease-19 in patients with haematological malignancies is characterized by a longer time to respiratory deterioration compared to non-haematological ones: results from a case-control study.

BACKGROUND: We evaluated clinical features and risk factors for mortality in patients with haematological malignancies and COVID-19. METHODS: Retrospective, case-control (1:3) study in hospitalized patients with COVID-19. Cases were patients with haematological malignancies and COVID-19, controls had COVID-19 without haematological malignancies. Patients were matched for sex, age and time of hospitalization. RESULTS: Overall, 66 cases and 198 controls were included in the study. Cases had higher prior corticosteroid use, infection rates, thrombocytopenia and neutropenia and more likely received corticosteroids and antibiotics than controls. Cases had higher respiratory deterioration than controls (78.7% vs 65.5%, p = 0.04). Notably, 29% of cases developed respiratory worsening > 10 days after hospital admission, compared to only 5% in controls. Intensive Care Unit admission and mortality were higher in cases than in controls (27% vs 8%, p = 0.002, and 35% vs 10%, p < 0.001). At multivariable analysis, having haematological malignancy [OR4.76, p < 0.001], chronic corticosteroid therapy [OR3.65, p = 0.004], prior infections [OR57.7, p = 0.006], thrombocytopenia [OR3.03, p < 0.001] and neutropenia [OR31.1, p = 0.001], low albumin levels [OR3.1, p = 0.001] and ≥ 10 days from hospital admission to respiratory worsening [OR3.3, p = 0.002] were independently associated with mortality. In cases, neutropenia [OR3.1, p < 0.001], prior infections [OR7.7, p < 0.001], ≥ 10 days to respiratory worsening [OR4.1, p < 0.001], multiple myeloma [OR1.5, p = 0.044], the variation of the CT lung score during hospitalization [OR2.6, p = 0.006] and active treatment [OR 4.4, p < 0.001] all were associated with a worse outcome. CONCLUSION: An underlying haematological malignancy was associated with a worse clinical outcome in COVID-19 patients. A prolonged clinical monitoring is needed, since respiratory worsening may occur later during hospitalization.

Determinants of prolonged viral RNA shedding in hospitalized patients with SARS-CoV-2 infection.

OBJECTIVE: To evaluate determinants of prolonged viral RNA shedding in hospitalized patients with SARS-CoV-2 infection. MATERIALS AND METHODS: Hospitalized patients with SARS-CoV-2 positive nasopharyngeal RT-PCR were included in a single-center, retrospective study. Patients were divided in 2 groups according to the timing of viral clearance [≤14 days, "early clearance (EC)" and >14 days, "late clearance (LC)"]. RESULTS: 179 patients were included in the study (101 EC, 78 LC), with median age 62 years. Median time of viral shedding was 14 days (EC/LC 10 and 19 days, respectively, P < 0.0001). Univariate analyses showed that age, male gender, receiving corticosteroids, receiving tocilizumab, ICU admission, low albumin and NLR ratio were associated with late viral clearance. In the multivariable analysis, older age (P = 0.016), albumin level (P = 0.048), corticosteroids (P = 0.021), and tocilizumab (P = 0.015) were significantly associated with late viral clearance. CONCLUSIONS: Age, albumin, tocilizumab and corticosteroid treatment were independently associated with a prolonged SARS-CoV-2 RNA shedding.

Co-infection of SARS-CoV-2 with Chlamydia or Mycoplasma pneumoniae: a case series and review of the literature.

INTRODUCTION: The novel coronavirus SARS-CoV-2 has spread all over the world causing a global pandemic and representing a great medical challenge. Nowadays, there is limited knowledge on the rate of co-infections with other respiratory pathogens, with viral co-infection being the most representative agents. Co-infection with Mycoplasma pneumoniae has been described both in adults and pediatrics whereas only two cases of Chlamydia pneumoniae have been reported in a large US study so far. METHODS: In the present report, we describe a series of seven patients where co-infection with C. pneumoniae (n = 5) or M. pneumoniae (n = 2) and SARS-CoV-2 was detected in a large teaching hospital in Rome. RESULTS AND CONCLUSION: An extensive review of the updated literature regarding the co-infection between SARS-CoV-2 and these atypical pathogens is also performed.

Role of Double-Carbapenem Regimen in the Treatment of Infections due to Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae: A Single-Center, Observational Study.

PURPOSE: (i) To compare infections caused by carbapenem-susceptible (CS) and carbapenemase producing carbapenem-resistant Enterobacteriaceae (CP-CRE); (ii) to evaluate the clinical effectiveness of the double-carbapenem (DC) regimen in comparison with the best available treatment (BAT) in infections caused by CP-CRE; and (iii) to determine the exact minimal inhibitory concentrations (MICs) of meropenem/ertapenem (MEM/ETP) and the degree of in vitro ETP+MEM synergism in subjects receiving the DC. METHODOLOGY: Over a 3-year period (2014-2017), patients with infections due to Enterobacteriaceae were included in a single-center, retrospective, observational study. According to the susceptibility to carbapenems, subjects were divided into CSE and CP-CRE groups. CP-CRE group was further divided into subjects receiving the DC regimen and those treated with other regimens (BAT group). Clinical characteristics and the presence of 5th-day response and 60-day outcome were evaluated for DC and BAT groups. The determination of MEM and ETP actual MICs and the MEM+ETP synergistic activity were performed on strains obtained from subjects receiving the DC regimen. RESULTS: A total of 128 patients were included in the study: 55/128 (43%) with infections due to CP-CRE and 73/128 (57%) with infections due to CSE. Among CP-CRE (n=55), 21 subjects (39%) were treated with the DC regimen whereas 34 (61%) received BAT. No differences in terms of severity of infection, presence/absence of concomitant bacteremia, type of infection, and resolution of infection were found; in contrast, DC group tended to have a higher rate of sepsis or septic shock at the onset of infection and a higher rate of 5th-day response. MICs 50/90 were 256/512 and 256/256 µg/mL for MEM and ETP, respectively. Overall, complete in vitro synergism was found in 6/20 strains (30%). CONCLUSION: The DC regimen is a valid and effective therapeutic option in patients with infections due to KPC producing CRE, including those with bacteremic infection and more severe clinical conditions. The clinical effectiveness is maintained even in the presence of extremely high MEM MICs.

In vitro evaluation of different antimicrobial combinations against carbapenemase-producing Klebsiella pneumoniae: the activity of the double-carbapenem regimen is related to meropenem MIC value.

Objectives and methods: We evaluated the in vitro activity of different antimicrobial combinations with and without colistin against 39 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains (colistin + meropenem/doripenem, colistin + tigecycline, colistin + rifampicin, gentamicin + meropenem, gentamicin + tigecycline and the double-carbapenem regimen meropenem + ertapenem) using the chequerboard method. The triple combination colistin + meropenem + tigecycline was also tested. In addition, killing studies were performed for meropenem + ertapenem. Results: Gentamicin-based combinations showed a high level of synergy. Meropenem + ertapenem was synergic in 12/39 (30.7%) of the strains, whereas based on killing studies 1 × MIC meropenem + 1 × MIC ertapenem and 2 × MIC meropenem + 1 × MIC ertapenem combinations were bactericidal and synergic at 24 h [mean area under the bactericidal curve (AUBC) 54.9 ±âŸ26.1 and 44.2 ±âŸ15.3 compared with 1 × MIC meropenem (134.5 ±âŸ40.1) and 2 × MIC meropenem (126.4 ±âŸ5.4), respectively, P < 0.0001]. When the results were stratified according to meropenem MIC, we found that the degree of synergy significantly increased for isolates with lower meropenem (and not ertapenem) MICs, up to an MIC of 128 mg/L. Among colistin-containing combinations, synergy was observed in 18/39 (46.1%), 33/34 (97%), 24/39 (61.5%) and 17/39 (43.5%) of the strains for colistin + meropenem, colistin + rifampicin, colistin + tigecycline and colistin + doripenem, respectively, including colistin-resistant strains. Colistin + meropenem + tigecycline at subinhibitory concentrations resulted in the absence of growth of 37/39 strains (94.8%). Conclusions: Our in vitro data suggest that colistin might be a valid therapeutic option against CR-Kp, even in the presence of colistin resistance, whereas the double-carbapenem regimen represents a viable option when colistin is not recommended, especially if the meropenem MIC is ≤ 128 mg/L. Since traditional antimicrobial susceptibility reports are not sufficiently informative for clinicians, synergy testing as well as actual meropenem MIC evaluation should always be performed in the case of CR-Kp infections.

Weight loss and quality of life improvement in obese subjects treated with sibutramine: a double-blind randomized multicenter study.

BACKGROUND AND AIM: Obesity affects cardiovascular risk and also quality of life (QoL). The aim of this study was to test weight loss and impact on QoL after sibutramine treatment in obese subjects. METHODS: Double-blind randomized trial on 309 outpatients (51 males, 258 females; age 41.8 +/- 10.9 years, BMI 35.0 +/- 3.1 kg/m(2)) randomized to sibutramine (n = 154) or to placebo (n = 155) treatment. A combination of sibutramine 10 mg or matching placebo and a balanced hypocaloric diet was given for 6 months with monthly evaluations. The main outcome measures were weight loss, the impact of weight on QoL, BMI, and waist circumference. RESULTS: The mean weight reduction was 8.2 kg in the sibutramine group and 3.9 in the placebo group at 6 months (p < 0.01). 40% of the sibutramine subjects and 14% of the control subjects lost > or =10% of their body weight (p < 0.01). The improvement in the impact of weight on QoL was statistically significant only in the sibutramine group at 6 months (mean -12.5 vs. -4.5 points; p < 0.01). In the sibutramine group the reduction in BMI (-3.1 vs. -1.4 kg/m(2)) and waist circumference (7.7 vs. 3.5 cm) was significantly greater (p < 0.001). The incidence of adverse events was low and similar to the placebo. CONCLUSIONS: This study confirmed that sibutramine significantly enhances the effect of diet on weight loss, BMI and waist circumference reduction, and showed a significant improvement of QoL.

Efficacy of two micro-gravitational protocols to treat chronic low back pain associated with discal lesions: a randomized controlled trial.

AIM: Chronic low back pain is the most expensive benign illness in the industrialized world and is defined as a bio-psycho-social syndrome where the biological aspect has a very reduced importance when compared to the psychological and social aspects. The rehabilitative treatment of mechanical chronic lower back pain aims to modify the pain first and then postural local and general disorders. Rehabilitation in water is characterized by the possibility of reducing the gravity environment and the resistance to all motion and also of improving the proprioceptors and baroceptors sensation. Another modality exists in order to generate within a reduced gravity impact by means of the use of support systems during gait. The aim of this study is to compare the efficacy of these rehabilitative treatments in chronic low back pain. METHODS: Forty patients suffering from chronic low-back pain aged 50 years or less, (average age 43.46 years - max 50, min 28) were randomly divided into 2 groups (A and B) homogeneous for sex and age. They had an imaging exam that was positive for lumbar hernia or protrusion and were able to perform the defined rehabilitation with a 3 times frequency for 7 weeks. The people were studied for 1 year. Outcome measurements included the VAS and BACKILL scales. RESULTS: At the end of rehabilitation, all groups showed a statistically significant decrease of VAS values (p<0.01) and increase in Backill values (p<0.01). VAS and BK levels 1 year after treatment did not change in group B and remained significantly different from basal values, whereas in group A they were significantly different from the values at the end of treatment. The NSAIDs-intake was significantly reduced both at the end of treatment and after 1 year (p<0.01) in both groups. CONCLUSIONS: Body relief locomotion proved to give better results then aquatic rehabilitation in chronic low back pain patients, even if placebo controlled studies are needed to definitively prove the efficacy of the method.