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“Double carbapenem” and oral fosfomycin for the treatment of complicated urinary tract infections caused by bla NDM -harboring Enterobacteriaceae in kidney transplantation
... In the present study, the efficacy of the combination of ertapenem and doripenem was evaluated both as an in vitro chemostat model and an in vivo rat experiment, and the combination of two carbapenems increased the efficacy compared with both agents used alone [5] . An observational cohort study by Souli et al. [16] investigating ertapenem + meropenem as a rescue therapy in 27 [17] , 36 patients with CRKP bacteremia were enrolled, including 18 patients receiving doripenem + ertapenem and 18 receiving doripenem + colistin, and the treatment success rate was higher (p=0.049) and 30day mortality was lower (p=0.087) in the dual carbapenem group. Oliva et al. [18] enrolled 32 patients with CRKP infection, which included 18 patients receiving ertapenem + meropenem and 14 receiving ertapenem + meropenem + colistin, and found that the combination of colistin with dual carbapenem achieved faster bactericidal activity in the in vitro analysis; however, no significant differences were found between the two groups in terms of early response or 60-day mortality. ...
... Despite the lack of solid evidence, some clinicians have favored double carbapenem therapy for the treatment of infections caused by MBLs. Rosa et al. [27] published two case reports on patients who underwent kidney transplantation with complicated urinary tract infections caused by NDM-producing Enterobacterales. Both patients received oral fosfomycin (3 g q48-72 h 21 days) and renally adjusted meropenem (1 g q12 h) plus ertapenem (1 g per day) for 14 days, achieving complete clinical recovery and microbiological clearance [27] . ...
... Rosa et al. [27] published two case reports on patients who underwent kidney transplantation with complicated urinary tract infections caused by NDM-producing Enterobacterales. Both patients received oral fosfomycin (3 g q48-72 h 21 days) and renally adjusted meropenem (1 g q12 h) plus ertapenem (1 g per day) for 14 days, achieving complete clinical recovery and microbiological clearance [27] . ...
Introduction: To investigate the efficacy of double carbapenem therapy (ertapenem + meropenem combination) in an experimental sepsis model in rats with Klebsiella pneumoniae (K. pneumoniae), which is carbapenem-resistant and colistin susceptible, and compare it with colistin and meropenem monotherapy.
Materials and Methods: K. pneumoniae isolate that is known to carry the blaOXA-48 and blaNDM carbapenemase genes was used, and 1-2×108 colony forming unit/ml was inoculated intraperitoneally to 40 rats (20 males/20 females), and a sepsis model was created. The rats were divided into four equal groups: control, colistin, meropenem, and meropenem + ertapenem combination. The rats were followed for 24 h for signs of sepsis and mortality. Euthanasia was then performed, and blood cultures were taken.
Results: After 24 h, none of the rats in the control or treatment groups died. K. pneumoniae growth was observed in all rats in the control, five in the colistin, seven in the meropenem, and five in the meropenem + ertapenem combination groups. A statistically significant difference was found between the control group and the colistin and meropenem + ertapenem combination groups (p=0.033 and p=0.033, respectively). No statistically significant difference was found between the control group and the meropenem monotherapy group (p=0.215). The numbers of non-growth blood cultures were comparable between the colistin group and the meropenem + ertapenem combination group, and no statistically significant difference was found between the two groups (p=1). The mean time of growth signals (minutes) were compared between the treatment groups: colistin, 642.6 ± 116.4; meropenem, 582.6 ± 107.7; and meropenem + ertapenem combination, 701.2 ± 70.4 min.
Conclusion: Meropenem + ertapenem combination treatment was comparable to colistin monotherapy, and the mean time of growth signals of blood cultures were longer than those in the colistin and meropenem monotherapy groups.
... Immunosuppressed patients are particularly susceptible to infection by multidrug-resistant bacteria, including solid-organ transplant patients, perhaps because this population is frequently exposed to health facilities, invasive devices, and antimicrobial agents [10][11][12][13] . However, there are few published reports of NDM-producing bacterial infections in kidney transplant recipients [14][15][16] . ...
... This incidence is of concern because kidney transplantation limits the use of nephrotoxic antimicrobials such as aminoglycosides reducing the available therapeutic options. There are no guidelines for the correct choice of antimicrobial agent and treatment duration, but there are reported cases of resolution of infection after treatment with phosphomycin alone or in combination with carbapenems lasting 14 days in these patients [14][15][16] . Although new antimicrobials such as ceftazidime-avibactam are good options for the therapy of infections caused by KPC-producing strains, they have no action against NDM-1 strains. ...
Background:
The emergence of multidrug-resistant NDM-1-producing enterobacteriaceae strains has become a threat to inpatients, especially to immunosuppressed ones, such as kidney transplant recipients. NDM-1 is a carbapenemase that makes gram-negative bacteria resistant to many types of antibiotics. The incidence of carbapenemase-producing enterobacteria infection in solid organ transplant recipients is around 3 to 10%, with a mortality rate of up to 30%.
Methods:
We present a case series of 4 patients with NDM-1-producing enterobacteria isolated in urine cultures or rectal swabs. We also conducted a cross-sectional study 30 days after patient identification, collecting surveillance cultures (rectal swab) from all inpatients to assess the extent of spread of this resistance mechanism; a total of 101 patients were included.
Results:
Two patients were adequately treated with negative control cultures. The other two patients were not treated because they were asymptomatic and had subsequent negative urine cultures. No new colonization was identified in the cross-sectional screening, and no new cases of urinary NDM-1 infection were recorded after a 4-year follow-up.
Conclusion:
Surveillance for infections caused by multidrug-resistant strains in hospitals treating immunosuppressed patients should be continued and prompt action should be taken in cases of outbreaks of multidrug-resistant infections.
... Overall, 28 studies were selected for fulltext review, and 21 studies met our inclusion criteria. For these 21 studies, three trials [33][34][35] were cohort or casecontrol studies, and 18 reports [26,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] were case series or case reports. The flow diagram ( Fig. 1) showed the detailed screening and selection process for the trials included in our analysis. ...
Background:
To compare the efficacy and safety of double-carbapenem therapy (DCT) with other antibiotics for the treatment of multidrug resistant (MDR) Gram-negative bacterial infections.
Methods:
Cochrane Library, PubMed, Embase and Web of Science as well as Chinese databases were searched from database establishment to February 2019. All types of studies were included if they had evaluated efficacy and safety of DCT regimens in patients with MDR Gram-negative bacterial infections. Clinical response, microbiological response, adverse events and mortality were the main outcomes. The protocol was registered with PROSPERO No. CRD42019129979.
Results:
Three cohort or case-control studies consisting of 235 patients and 18 case series or case reports consisting of 90 patients were included. The clinical and microbiological responses were similar between DCT and other regimens in patients with carbapenem-resistant Enterobacteriaceae (CRE) infection. DCT achieved a lower mortality than comparators in patients with CRE infection (OR = 0.44, 95% CI = 0.24-0.82, P = 0.009). Ertapenem was the most reported antibiotic in DCT regimens in case series or case reports. Moreover, clinical and microbiological improvements were found in 59 (65.6%) and 63 (70%) in total 90 cases, respectively.
Conclusions:
DCT was as effective as other antibiotics in treating MDR Gram-negative bacterial infections, with similar efficacy response and lower mortality. DCT could be an alternative therapeutic option in the treatment of MDR Gram-negative bacterial infections. High-quality randomized controlled trials were required to confirm the beneficial effects of DCT.
... The bla KPC gene was detected in 84 (90%) of the isolates. Five (5%) of the isolates were positive for bla NDM (New Delhi Metallo-b-lactamase); 3 of them were from international patients or recent travelers to Turkey, 25 Cuba, and the Bahamas; the other two cases were local patients. Most of the first isolates per case were resistant to piperacillin-tazobactam (96%), aztreonam (96%), cefazolin (97%), ceftriaxone (91%), and meropenem (92%) but susceptible to amikacin (87%) ( Table 2). ...
Background
Carbapenem-resistant Enterobacteriaceae (CRE) is an urgent public health threat globally. Limited data are available regarding the epidemiology of CRE in South Florida.
We describe the epidemiology of CRE within a large public healthcare system in Miami, FL, the experience with an internal registry, active surveillance testing, and the impact of infection prevention practices.
Methods
Retrospective cohort study in four hospitals from a large healthcare system in Miami-Dade County, FL from 2012 to 2016. The internal registry included all CRE cases from active surveillance testing from rectal/tracheal screening occurring in the ICUs of two of the hospitals and clinical cultures across the healthcare system. All CRE cases were tagged in the electronic medical record and automatically entered into a platform for automatic infection control surveillance. The system alerted about new cases, readmissions, and transfers.
Results
A total of 371 CRE cases were identified. The overall prevalence was 0.077 cases per 100 patient-admissions; the admission prevalence was 0.019 per 100 patient-admissions, and the incidence density was 1.46 cases per 10,000 patient-days. Rates increased during the first three years of the study and declined later to a lower level than at the beginning of study period.
Conclusion
Active surveillance testing and the use of an internal registry facilitated prompt identification of cases contributing to control increasing rates of CRE by rapid implementation of infection prevention strategies.
... In vitro data showed synergistic activity of DCC against OXA-48 producing MDR and XDR K. pneumoniae (134). Finally, two kidney transplant recipients were reportedly cured with DCC plus oral fosfomycin from urinary tract infections caused by NDM-harboring Enterobacteriaceae (135). Further randomized controlled trials are needed to assess DCC as salvage treatment in infections by XDR pathogens exhibiting various mechanisms of resistance to carbapenems. ...
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 P. aeruginosa (CRPA). Less options are available against carbapenem-resistant Acinetobacter baumannii (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 in vitro active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and P. aeruginosa, deserves a greater attention. Optimal conditions for monotherapy and the “when and how” of combination treatments integrating the novel agents will be discussed.
... On the one hand, case reports serve to probe the validity of the mechanistic rationale underlying novel therapeutic approaches; on the other hand, case reports also help clinicians identify valid options for their patients. It is clear, however, that case reports do not replace rigorous attempts at collating scientific and clinical evidence [49][50][51][52]. ...
Polymyxins have been a mainstay for the treatment of extensively drug resistant (XDR) Gram-negative bacteria for the past two decades. Many questions regarding the clinical use of polymyxins have been answered, but whether the administration of polymyxins in combination with other antibiotics leads to better outcomes remains unknown. This review discusses the limitations of observational studies that suggest a benefit of combinations of colistin and carbapenems to treat infections caused by carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, and summarizes the results of randomized controlled trials in which treatment with colistin in combination with meropenem or rifampin does not lead to better clinical outcomes than colisitn monotherapy in infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). Although the introduction of new antibiotics makes it possible to treat certain strains of CRE and carbapenem-resistant P. aeruginosa (CRPA) with polymyxin-sparing regimens, the use of polymyxins is, for now, still necessary in CRAB and in CRE and CRPA harboring metallo-beta-lactamases. Therefore, strategies must be developed to optimize polymyxin-based treatments, informed by in vitro hollow fiber models, careful clinical observations, and high-quality evidence from appropriately designed trials.
... The findings in this in vivo study are inconsistent with those of the in vitro study (283). Dual carbapenems (meropenem and ertapenem) plus fosfomycin were used to successfully treat urinary tract infections caused by NDM-positive Enterobacteriaceae in two patients (285). In general, there are very few studies of dual carbapenems against NDM-positive strains, and the current evidence is contradictory. ...
New Delhi metallo-β-lactamase (NDM) is a metallo-β-lactamase able to hydrolyze almost all β-lactams. Twenty-four NDM variants have been identified in >60 species of 11 bacterial families, and several variants have enhanced carbapenemase activity. Klebsiella pneumoniae and Escherichia coli are the predominant carriers of blaNDM, with certain sequence types (STs) (for K. pneumoniae, ST11, ST14, ST15, or ST147; for E. coli, ST167, ST410, or ST617) being the most prevalent. NDM-positive strains have been identified worldwide, with the highest prevalence in the Indian subcontinent, the Middle East, and the Balkans. Most blaNDM-carrying plasmids belong to limited replicon types (IncX3, IncFII, or IncC). Commonly used phenotypic tests cannot specifically identify NDM. Lateral flow immunoassays specifically detect NDM, and molecular approaches remain the reference methods for detecting blaNDM Polymyxins combined with other agents remain the mainstream options of antimicrobial treatment. Compounds able to inhibit NDM have been found, but none have been approved for clinical use. Outbreaks caused by NDM-positive strains have been reported worldwide, attributable to sources such as contaminated devices. Evidence-based guidelines on prevention and control of carbapenem-resistant Gram-negative bacteria are available, although none are specific for NDM-positive strains. NDM will remain a severe challenge in health care settings, and more studies on appropriate countermeasures are required.
... In a multicenter study that analyzed strains of K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae, fosfomycin resistance was identified in 60.8%, whereas other studies have reported fosfomycin resistance rates of 6.25-14.7% among CRE strains [16,22,23]. ...
Kidney transplant recipients are at risk for infections due to carbapenem-resistant Enterobacteriaceae (CRE). Polymyxin-resistant CRE (PR-CRE) infections are especially difficult to treat. The aim of this study was to characterize PR-CRE infections among kidney transplant recipients and identify risk factors for treatment failure. This retrospective cohort study involved all kidney transplant recipients with PR-CRE infection between 2013 and 2017 at our center. Minimal inhibitory concentrations for polymyxin B were determined by broth microdilution. Carbapenem-resistant genes (blaKPC, blaNDM, and blaOXA-48), aminoglycoside-resistance genes, and polymyxin-resistant gene mcr-1 were identified by polymerase chain reaction. All but one of the 47PR-CRE infections identified were due to Klebsiella pneumoniae. The most common type of infection (in 54.3%) was urinary tract infection (UTI). Monotherapy was used in 10 cases. Combined treatment regimens included double-carbapenem therapy in 19 cases, oral fosfomycin in 19, and amikacin in 13. Treatment failure occurred in 21 cases (45.7%). Clinical success was achieved 78.9% of patients who used aminoglycosides versus 37.0% of those who not used this drug (p = 0.007). Multivariate analysis showed diabetes mellitus to be a risk factor for treatment failure; amikacin use and UTI were found to be protective. Nine strains were RmtB producers. Although aminoglycosides constitute an important therapeutic option for PR-CRE infection, the emergence of aminoglycoside resistance could have a major impact on the management of CRE infection.
... Moreover, the efficacy of the DC regimen has been demonstrated in immunocompromised patients, including kidney transplanted patients [23,28] and a patient after allogenic hematopoietic stem cell transplantation [29]. ...
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.
... Thus, while KPC would be "engaged" by ertapenem, a co-administered different carbapenem could exert its bactericidal activity. Although recent quality observational data are encouraging (56)(57)(58), additional, adequately powered studies are urgently warranted. Moreover, such evidence may ideally foster the development of ertapenem analogues characterized by higher affinity for KPC compared to the founder compound, in order to optimally exploit such "engagement" activity on carbapenemases. ...
Urinary tract infections are among the most common infectious diseases in humans. Today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world. It is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. Carbapenemase-producing Enterobacteriaceae, multidrug- resistant Enterococci and fluoroquinolone resistance determinants in both Gram-negative and Gram-positive uropathogens are among the greatest emergencies. In this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older – but still active – recommended drugs are summarized.
Antimicrobial resistance is a global public health threat due to its associated increase in mortality, and the most appropriate treatment algorithms for resistant and persistent Gram-positive and Gram-negative infections have yet to be elucidated. Whilst combination therapy has been touted as a viable method to overcome prominent resistant mechanisms represented amongst these microbes, the optimal agents to utilize remains controversial. Beta-lactams have a safe profile and are bactericidal against most Gram-positive and Gram-negative microorganisms. Thus, the use of dual beta-lactam therapy to overcome multidrug-resistant pathogens is of supreme interest. This article reviews the mechanisms of beta-lactam resistance in Gram-positive and Gram-negative bacteria, discusses the rationale for dual beta-lactam use against multidrug-resistant infections (and other scenarios in which this strategy may be most utilized in clinical practice), explores the available in vitro, in vivo and clinical data, and provides considerations for the use of dual beta-lactam therapy against Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii pathogens.
Urinary tract infections (UTIs) are common bacterial infections that are at most inconvenient for some patients while they seriously impede health for others. The first part of this thesis addresses the antibiotic treatment of cystitis in general practice. Its high incidence makes it a relevant topic and an attractive object for epidemiological research. We found that the effectiveness and safety of the antibiotic nitrofurantoin is determined by the dose that is given. This applies to the treatment of cystitis as well as to the daily prophylaxis for recurrent UTI. The guideline makes no distinction between the doses that we investigated. Furthermore, we found that the antibiotic fosfomycin appears to be more effective than nitrofurantoin for treatment of cystitis in patients with impaired renal function, while nitrofurantoin is currently the first choice. Bacterial resistance to antibiotics complicates the treatment of UTI in the hospital. In the second part we investigate this problem. The main finding is that fosfomycin is efficacious for the targeted treatment of UTI in hospitalized women, caused by the bacterium Escherichia coli. Due to low resistance percentages to fosfomycin among Escherichia coli, a new treatment option is created for patients, as an alternative to parenteral antibiotics. In other chapters, we investigated the use of fosfomycin for UTIs in renal transplant patients, the reliability of susceptibility tests against fosfomycin, the acquisition of resistance of Escherichia coli to fosfomycin, the duration of carriage of multidrug resistant gut bacteria and the effectiveness of antibiotics for UTIs caused by multidrug resistant bacteria.
Background: Carbapenemase-producing Klebsiella pneumoniae (CpKP) has been implicated as an increasing threat to public health. CpKP is a ubiquitous, opportunistic pathogen that causes both hospital and community acquired infections. This organism hydrolyzes carbapenems and other β-lactams and thus, leading to multiple resistance to these antibiotics. Despite the difficult to treat nature of infections caused by CpKP, little has been discussed on the mortality, clinical response and microbiological success rates associated with various antibiotic regimen against CpKP. This meta-analysis was designed to fill the paucity of information on the clinical impact of various antibiotic therapeutic regimens among patients infected with CpKP.
Materials and Methods: Literature in most English databases such as Medline through PubMed, Google Scholar, Web of Science, Cochrane Library and EMBASE, were searched for most studies published between the years 2015–2020. Data were analyzed using the R studio 2.15.2 statistical software program (metaphor and meta Package, Version 2) by random-effects (DerSimonian and Laird) model.
Results: Twenty-one (21) studies including 2841 patients who had been infected with CpKP were analysed. The overall mortality rate was 32.2% (95% CI = 26.23–38.87; I 2 = 89%; p -value ≤ 0.01, Number of patients = 2716). Pooled clinical and microbiological success rates were 67.6% (95% CI = 58.35–75.64, I 2 = 22%, p -value = 0.25, Number of patients = 171) and 74.9% (95% CI = 59.02–86.09, I 2 = 53%, p -value = 0.05, Number of patients = 121), respectively. CpKP infected patients treated with combination therapy are less likely to die as compared to those treated with monotherapy (OR = 0.55, 95% CI = 0.35–0.87, p -value = 0.01, Number of patients = 1,475). No significant difference existed between the mortality rate among 60years and above patients vs below 60years (OR = 0.84, 95% CI = 0.28–2.57, p -value = 0.76, 6 studies, Number of patients = 1,688), and among patients treated with triple therapy vs. double therapy (OR = 0.50, 95% CI = 0.21–1.22, p -value = 0.13, 2 studies, Number of patients = 102). When compared with aminoglycoside-sparing therapies, aminoglycoside-containing therapies had positive significant outcomes on both mortality and microbiological success rates.
Conclusion: New effective therapies are urgently needed to help fight infections caused by this organism. The effective use of various therapeutic options and the strict implementation of infection control measures are of utmost importance in order to prevent infections caused by CpKP. Strict national or international implementation of infection control measures and treatment guidelines will help improve healthcare, and equip governments and communities to respond to and prevent the spread of infectious diseases caused by CpKP.
The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.
Introduction: Carbapenem-resistant Enterobacterales (CRE) represent a global public health problem. Precision medicine (PM) is a multicomponent medical approach that should be used to individualize the management of patients infected with CRE.
Areas covered: Here, we differentiate carbapenem-producing CRE (CP-CRE) from non-CP-CRE and the importance of this distinction in clinical practice. The current phenotypic CRE-case definition and its implications are also discussed. Additionally, we summarize data regarding phenotypic and molecular diagnostic tools and available antibiotics. In order to review the most relevant data, a comprehensive literature search of peer-reviewed articles in PubMed and abstracts presented at high-impact conferences was performed.
Expert opinion: PM in CRE infections entails a multi-step process that includes applying the current phenotypic definition, utilization of the right phenotypic or molecular testing methods, and thorough evaluation of risk factors, source of infection, and comorbidities. A powerful armamentarium is available to treat CRE infections, including recently approved agents. Randomized controlled trials targeting specific pathogens instead of site of infections may be appropriate to fill in the current gaps. In light of the diverse enzymology behind CP-CRE, PM should be employed to provide the best therapy based on the underlying resistance mechanism.
Urinary tract infections are one of the most common health problems and entail a high consumption of health system resources. Due to the increase in global antibiotic resistances in recent years, it is increasingly common to find uropathogens with multiple resistance mechanisms, including quinolone-resistant bacteria, broad-spectrum β-lactamase producers and carbapenemase producers. In this scenario, the role of fosfomycin has gained considerable importance, given its spectrum of activity against multidrug resistant microorganisms (Gram-positive and Gram-negative), becoming an attractive alternative therapy. Regarding the use of fosfomycin in complicated urinary tract infections, there is increasing clinical experience with patients with infections caused by multidrug resistant bacteria, those with recurrent urinary tract infection and special populations such as those with kidney transplants. Randomized comparative studies and series are underway, which will provide greater evidence. Nevertheless, more studies are needed to confirm the enormous potential of fosfomycin in complicated urinary tract infection in the era of multiresistance.
Purpose of review:
Carbapenem-resistant enterobacteriaceae (CRE) are a critical healthcare threat. Infections caused by CRE disproportionately affect transplant patients. Retrospective case studies suggest that up to 10% of transplant recipients develop a CRE infection. The current literature is reviewed with a particular focus on transplant-specific implications.
Recent findings:
There are specific risks inherent to transplant recipients that result in an elevated risk for CRE carriage and subsequent infection. Additionally, the manifestations of these infections are dependent on the specific transplant type. The optimal treatment of CRE infections in transplant recipients has not been defined.
Summary:
A reduction in the regional community CRE burden can lead to a secondary reduction in their occurrence within vulnerable transplant populations. Therefore, core principles of antibiotic stewardship and infection control within all levels of the healthcare system remains the most effective strategy for addressing the current health crisis. Simultaneously, an integrated approach to risk stratification and an approach to treatment is postulated for management of CRE infection within the solid-organ transplant population.
Background:
The treatment of urinary tract infections (UTI's) in kidney transplant recipients (KTRs) with oral antibiotics is complicated by increasing resistance to trimethoprim-sulfamethoxazole, amoxicillin/clavulanic acid and ciprofloxacin. Fosfomycin-trometamol (FT) could be an alternative, but evidence on clinical effectiveness is scarce. We evaluated the use, effectiveness and safety of FT for UTI in KTRs.
Methods:
Data were retrospectively collected in 2 Dutch transplant hospitals from adult KTRs that were treated with FT as initial treatment for lower-UTI or asymptomatic bacteriuria or as stepdown treatment for upper-UTI after initial intravenous antibiotics. Exclusion criteria were in vitro resistance to FT or concomitant antibiotic treatment. Endpoints were clinical cure within 14 days and severe clinical failure, microbiological cure, relapse, recurrence, and acquired resistance within 90 days postend of treatment.
Results:
53 episodes in 40 KTRs were included (ASB n=15; lower-UTI n=33; upper-UTI n=5). FT was used for a median short duration in a heterogeneous gift interval. FT resulted in microbiological cure in 25, 28 and 100% of ASB, lower-UTI and upper-UTI with initial positive culture and follow-up culture performed, respectively. Clinical cure rates were 67% for lower-UTI and 80% for upper-UTI. Relapses or recurrences occurred in 31% and 24% of symptomatic UTI episodes, without severe clinical failure. Acquired resistance to fosfomycin was observed in 6 episodes.
Conclusions:
FT has a reasonable effectiveness as last-resort oral treatment for lower-UTI and stepdown treatment for upper-UTI in KTRs. Randomized controlled trials with optimal dosage regimens are warranted. Use of FT is not recommended for ASB.
Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness of the combination of ceftazidime/avibactam (CAZ/AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk-diffusion and agar based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ/AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP , blaNDM , blaOXA-48 , blaCTX-M , blaAmpC , and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ/AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ/AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥ 21 mm. All isolates demonstrated a reduction in CAZ/AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥ 4 log 10 CFU decrease for all groups that had CAZ/AVI plus ATM (8 μg/ml) added, compared to the CAZ/AVI alone group. In the murine neutropenic thigh infection model, an almost 4 log 10 reduction in CFUs was noted at 24 h for CAZ/AVI (32 mg/kg q8h) plus ATM (32 mg/kg q8h) vs. CAZ/AVI (32 mg/kg q8h) alone. The data presented herein, requires us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae .
Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part due to limited treatment options. Here we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts. This article is protected by copyright. All rights reserved.
Objectives:
This study aimed to analyse the in vitro activity of dual combinations of carbapenems against Klebsiella pneumoniae producing the main carbapenemase types.
Methods:
MIC values of the carbapenems, imipenem, meropenem, ertapenem and doripenem were determined alone and in dual combinations for 20 clinical K. pneumoniae isolates producing representative carbapenemases, i.e. OXA-48 (n = 6), NDM-1 (n = 4), NDM-1 + OXA-48 (n = 2) and KPC-2 (n = 8). MICs were also determined for Escherichia coli recombinant strains with or without permeability defects producing NDM-1, OXA-48 or KPC-2. In vitro synergy combination testing was performed using the microdilution and chequerboard techniques. Fractional inhibitory concentration indexes were calculated to determine whether the combinations were synergistic, indifferent or antagonistic.
Results:
All carbapenemase producers were resistant to the tested carbapenems, with most isolates showing MICs of carbapenems >32 mg/L. None of the combinations was antagonistic. For KPC producers, synergistic combinations were observed with imipenem/ertapenem (5/8 isolates), imipenem/doripenem (4/8), imipenem/doripenem (4/8), meropenem/doripenem (3/8) and ertapenem/doripenem (3/8), while no synergy was observed with meropenem/ertapenem. For OXA-48 producers, synergies were observed with imipenem/ertapenem and with imipenem/meropenem for both isolates tested. Notably, combining imipenem with a non-carbapenem β-lactam (cefalotin) did not give any synergistic result. No synergy was observed for all NDM-1 and NDM-1+OXA-48 producers. Time-kill assays confirmed most of the data obtained by chequerboard testing.
Conclusions:
The data strongly support the hypothesis that dual carbapenem combinations might be effective against serine-β-lactamase producers (KPC, OXA-48). The imipenem-containing combinations appeared to be the most efficient.
New antibiotic options are urgently needed for the treatment of carbapenem-resistant Enterobacteriaceae infections. We report a 64-year-old female with prolonged hospitalization following an intestinal transplant who developed
refractory bacteremia due to a serine carbapenemase-producing pandrug-resistant isolate of Klebsiella pneumoniae. After failing multiple antimicrobial regimens, the patient was successfully treated.
The objective of this study was to describe the microbiological characteristics of an extensively drug-resistant (XDR) isolate of Morganella morganii obtained from a patient with sepsis of urinary origin and to describe the patient's clinical characteristics. We further aimed to perform a literature review of the situation in Latin America regarding Gram-negative bacillus (GNB) carriers of New Delhi metallo-β-lactamase (NDM-1) and qnr genes and current reports on the treatment of infections caused by XDR enterobacteria, with particular attention to colistin-resistant isolates.
The patient's clinical data were obtained from his medical history. Microbiological identification and susceptibility testing were done using the VITEK 2 Compact System. Resistance genes were detected by PCR and sequencing. The bibliographic review was done using the following databases: PubMed (US National Library of Medicine, National Institutes of Health), Scopus, Elsevier, EBSCOhost, OvidSP, Springer, and ASM journals.
Blood and urine cultures grew an M. morganii isolate (Mm4232) harboring NDM-1 and qnrD1. The patient was treated successfully with fosfomycin and double doses of meropenem. There are no previous reports of the use of fosfomycin and meropenem to treat infections by XDR enterobacteria harboring NDM-1 carbapenemase.
This is the first report of qnrD1 in South America. We consider that this report could be helpful to physicians implementing treatments for infections caused by XDR GNB, including colistin-carbapenem-resistant GNB.
Copyright © 2014. Published by Elsevier Ltd.
Carbapenem-resistant Enterobacteriaceae (CRE) are emerging global pathogens. The spread of CRE to transplant recipients and
patients with hematologic malignancies has ominous implications. These patients rely on timely, active antibacterial therapy
to combat gram-negative infections; however, recommended empirical regimens are not active against CRE. Approximately 3%–10%
of solid organ transplant (SOT) recipients in CRE-endemic areas develop CRE infection, and the infection site correlates with
the transplanted organ. Mortality rates associated with CRE infections approach 40% in SOT recipients and 65% in patients
with hematologic malignancies. Given that the current antimicrobial armamentarium to combat CRE is extremely limited, a multifaceted
approach that includes antimicrobial stewardship and active surveillance is needed to prevent CRE infections in immunocompromised
hosts. Improving outcomes of established infections will require the use of risk factor–based prediction tools and molecular
assays to more rapidly administer CRE-active therapy and the development of new antimicrobial agents with activity against
CRE.
Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective
antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h
time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin,
meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a ≥2 log10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a
≥3 log10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated
for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam,
fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin
was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin,
meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of
this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date
have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.
The advancing antimicrobial drug resistance in common bacterial pathogens, along with the relative shortage of new antibacterial agents, call for the re-evaluation of available therapeutic options. Fosfomycin is an established treatment option for uncomplicated urinary tract infections. Here we review and evaluate the main pharmacokinetic and pharmacodynamic parameters of intravenously administered fosfomycin with regard to its use for systemic infections. Fosfomycin is a relatively small, hydrophilic agent with almost negligible serum protein binding. It is excreted unchanged in urine, achieving high concentrations for a prolonged period. Fosfomycin has good distribution into tissues, achieving clinically relevant concentrations in sites such as serum, soft tissue, lungs, bone, cerebrospinal fluid and heart valves. Fosfomycin has shown antimicrobial activity against biofilms, particularly in combination with fluoroquinolones. It also exerts immunomodulatory effects, mainly on lymphocyte and neutrophil function. Potentially useful properties of fosfomycin regarding its use in combination regimens include reduction in the expression of certain penicillin-binding proteins and attenuation of nephrotoxicity caused by several antimicrobial agents. In conclusion, the pharmacokinetic and pharmacodynamic properties of fosfomycin do not preclude its use for various types of systemic infections and suggest further research on relevant clinical applications of this agent.
Background:
Klebsiella pneumoniae New Delhi metallo-beta-lactamase-1 (NDM-1) strains have recently become a new threat in kidney transplant recipients due to the strains' resistance to almost all antibiotics, including carbapenems.
Methods:
We present a case series of 3 patients with urinary tract infections (UTIs) caused by multiresistant K pneumoniae NDM-1 strains who were treated with the same protocol. Genotyping sequencing with pulsed-field gel electrophoresis was performed in all cases.
Results:
All patients were male and had undergone kidney transplantation 4, 7, and 8 months, respectively, before the admission. Combined antibiotic therapy consisting of imipenem/cilastatin in maximal doses, gentamicin and/or colistin for 21 to 27 days, followed by oral fosfomycin, was used in all cases. There were no further UTI episodes in 2 patients at the 12-month visit. Three months after initial treatment, the third patient presented with leukocyturia with no clinical symptoms and a urine culture positive for K pneumonia NDM-1 strain. Interestingly, the strain was susceptible to trimethoprim/sulfamethoxazole despite resistance in previous urine culture samples. The patient was successfully treated with trimethoprim/sulfamethoxazole 2 × 960 mg/d for 3 weeks followed by 480 mg/d and 3 doses of fosfomycin. Genotyping sequencing revealed identical DNA restriction fragments in bacterial strains from 2 patients. In the third case, although a difference in 2 restriction fragments was observed, the strain was considered related to the others.
Conclusions:
In cases of UTI caused by K pneumoniae NDM-1 strains, prolong combined treatment followed by oral fosfomycin prophylaxis can be successful. Strain genotyping should be performed to optimize further treatment protocols in such cases.
Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase since 2000 in rates of extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an indwelling device), and these facilities are considered important originating sources of such strains for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden, including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and intensive care units. Control of resistant gram-negative infections requires a comprehensive approach, including strategies for risk factor identification, detection and identification of resistant organisms, and implementation of infection-control and prevention strategies. In treating resistant gram-negative infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the choice of empiric therapy. Although only a few agents are available with activity against resistant gram-negative organisms, two recently released β-lactam/β-lactamase inhibitor combinations - ceftolozane/tazobactam and ceftazidime/avibactam - have promising activity against these organisms. In this article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is provided.
Simkins, J, Aragon, L, Fan, J, Frederick, C, Camargo, J. F. Intravenous Fosfomycin Treatment for Carbapenem-Resistant Klebsiella pneumoniae in the United States. Ann Pharmacother. 2015;49:1177-1178 (Original doi: 10.1177/1060028015598326). On page 1177, Dr. Jose F. Camargo is listed as the 3(rd) author. However, he should be the last author in the sequence.
Carbapenemase-producing Enterobacteriaceae (CPE) were almost nonexistent up to the 1990s, but are today encountered routinely in hospitals and other healthcare facilities in many countries including the United States. KPC-producing Klebsiella pneumoniae was the first to emerge and spread globally and is endemic in the United States, Israel, Greece, and Italy. Recently, NDM-producing Enterobacteriaceae and OXA-48-producing K. pneumoniae appear to be disseminating from South Asia and Northern Africa, respectively. They are almost always resistant to all β-lactams including carbapenems and many other classes. Mortality from invasive CPE infections reaches up to 40%. To obtain the maximal benefit from the limited options available, dosing of antimicrobial agents should be optimized based on pharmacokinetic data, especially for colistin and carbapenems. In addition, multiple observational studies have associated combination antimicrobial therapy with lower mortality compared with monotherapy for these infections. The outcomes appear to be especially favorable when patients are treated with a carbapenem and a second agent such as colistin, tigecycline, and gentamicin, but the best approach is yet to be defined.
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Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units cross-linked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review aims at providing an overview of resistance mechanisms developed towards antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies towards the development of novel inhibitors that could overcome resistance are also discussed.
Fosfomycin trometamol (fosfomycin tromethamine) [Monuril(®), Monurol(®), Monural(®)] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum β-lactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3 g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.
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Fosfomycin, originally named phosphonomycin, was discovered in Spain in 1969. There are three forms of fosfomycin: fosfomycin tromethamine (a soluble salt) and fosfomycin calcium for oral use, and fosfomycin disodium for intravenous use. Fosfomycin is a bactericidal antibiotic that interferes with cell wall synthesis in both Gram-positive and Gram-negative bacteria by inhibiting the initial step involving phosphoenolpyruvate synthetase. It has a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. It is highly active against Gram-positive pathogens such as Staphylococcus aureus and Enterococcus, and against Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Its unique mechanism of action may provide a synergistic effect to other classes of antibiotics including beta-lactams, aminoglycosides, and fluoroquinolones. Oral fosfomycin is mainly used in the treatment of urinary tract infections, particularly those caused by Escherichia coli and Enterococcus faecalis. Intravenous fosfomycin has been administered in combination with other antibiotics for the treatment of nosocomial infections due to multidrug-resistant (MDR) Gram-positive and Gram-negative bacteria. Fosfomycin has good distribution into tissues, achieving clinically relevant concentrations in serum, kidneys, bladder wall, prostate, lungs, inflamed tissues, bone, cerebrospinal fluid, abscess fluid, and heart valves. Fosfomycin is well tolerated, with a low incidence of adverse events. Further randomized controlled trials are needed in order to evaluate the efficacy of intravenous fosfomycin for the management of nosocomial infections due to MDR pathogens.