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Renal vein thrombosis complicating severe acute pyelonephritis with renal abscesses and associated bacteraemia caused by extended-spectrum beta-lactamase producing Escherichia coli

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Abstract

Acute pyelonephritis might be complicated by the formation of renal and perirenal abscesses and very rarely by renal vein thrombosis, which is a life-threatening condition. The main causative agents of acute pyelonephritis are enterobacteriaceae with the incidence of extended-spectrum beta-lactamase (ESBL)-producing strains increasing worldwide. We present the case of a 71-year-old Greek man with history of diabetes mellitus and recent hospitalization, who suffered from severe pyelonephritis with renal abscesses formation and associated bacteraemia caused by ESBL-producing Escherichia coli, complicated by extensive thrombosis of the ipsilateral renal vein and its branches, protruding also in the inferior venal cava. Our patient was effectively treated with anticoagulants and targeted antibiotic therapy, respectively, consisted of low molecular weight heparin transitioned to oral acenocoumarol for 3 months and 2-week course of intravenous meropenem followed by oral fosfomycin for additional 3 weeks as quidded by clinical and computed tomographic follow-up. In conclusion, in complicated urinary infections, caused by ESBL-producing enterobacteriaceae, oral fosfomycin might represent an effective option for step-down therapy of carbapenems, allowing the shortness of the duration of patient’s hospitalization and carbapenem use.
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CEN Case Reports
Official Publication of the Japanese
Society of Nephrology
e-ISSN 2192-4449
CEN Case Rep
DOI 10.1007/s13730-017-0301-2
Renal vein thrombosis complicating severe
acute pyelonephritis with renal abscesses
and associated bacteraemia caused
by extended-spectrum beta-lactamase
producing Escherichia coli
Stelios F.Assimakopoulos, Pantelis
Kraniotis, Charalambos Gogos &
Markos Marangos
1 23
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Vol.:(0123456789)
1 3
CEN Case Reports
https://doi.org/10.1007/s13730-017-0301-2
CASE REPORT
Renal vein thrombosis complicating severe acute pyelonephritis
withrenal abscesses andassociated bacteraemia caused byextended-
spectrum beta-lactamase producing Escherichia coli
SteliosF.Assimakopoulos1· PantelisKraniotis2· CharalambosGogos1· MarkosMarangos1
Received: 5 November 2017 / Accepted: 27 December 2017
© Japanese Society of Nephrology 2018
Abstract
Acute pyelonephritis might be complicated by the formation of renal and perirenal abscesses and very rarely by renal vein
thrombosis, which is a life-threatening condition. The main causative agents of acute pyelonephritis are enterobacteriaceae
with the incidence of extended-spectrum beta-lactamase (ESBL)-producing strains increasing worldwide. We present the case
of a 71-year-old Greek man with history of diabetes mellitus and recent hospitalization, who suffered from severe pyelone-
phritis with renal abscesses formation and associated bacteraemia caused by ESBL-producing Escherichia coli, complicated
by extensive thrombosis of the ipsilateral renal vein and its branches, protruding also in the inferior venal cava. Our patient
was effectively treated with anticoagulants and targeted antibiotic therapy, respectively, consisted of low molecular weight
heparin transitioned to oral acenocoumarol for 3months and 2-week course of intravenous meropenem followed by oral
fosfomycin for additional 3weeks as quidded by clinical and computed tomographic follow-up. In conclusion, in complicated
urinary infections, caused by ESBL-producing enterobacteriaceae, oral fosfomycin might represent an effective option for
step-down therapy of carbapenems, allowing the shortness of the duration of patient’s hospitalization and carbapenem use.
Keywords Urinary tract infections· Renal abscess· Renal vein thrombosis· Extended-spectrum beta-lactamase· ESBL·
Fosfomycin
Introduction
Renal vein thrombosis is a very rare and life-threatening
complication of acute pyelonephritis [1]. To our knowledge,
only seven cases of RVT complicating acute pyelonephritis
have been described in the literature [1]. The main patho-
gen implicated as a causative agent in renal abscesses is by
far Escherichia coli (E. coli), while there is a continuously
increasing prevalence of community-acquired urinary infec-
tions caused by extended-spectrum beta-lactamase (ESBL)-
producing enterobacteriaceae [2, 3]. We describe herein, a
case of severe pyelonephritis with the formation of multiple
renal abscesses and bacteraemia, due to ESBL-producing E.
coli, complicated by extensive thrombosis of the ipsilateral
renal vein and its branches, protruding also in the inferior
venal cava.
Case report
A 71-year-old man with a past medical history of diabetes
mellitus type II and recent hospitalization (2months ago),
for surgical repair of right scrotal hernia, presented fever
(39.5°C) with rigors and dysuria 2weeks before admis-
sion to our clinic. Urinalysis showed pyuria, bacteriuria
and nitrites presence, and ciprofloxacin 500mg bid was
empirically administered by his urologist. Urine culture
grew E. coli resistant to b-lactams including aztreonam,
b-lactam/b-lactamase inhibitors (piperacillin–tazobactam
MIC > 16/4 μg/ml), fluoroquinolones, trimethoprim/sul-
famethoxazole and sensitive to aminoglycosides amikacin
and netilmicin, carbapenems and colimycin. Ciprofloxacin
was discontinued and amikacin was prescribed 1g once a
* Stelios F. Assimakopoulos
sassim@upatras.gr
1 Division ofInfectious Diseases, Department ofInternal
Medicine, University General Hospital ofPatras,
26504Patras, Greece
2 Department ofRadiology, University General Hospital
ofPatras, 26504Patras, Greece
Author's personal copy
CEN Case Reports
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day intramuscularly with gradual clinical improvement and
resolution of fever the fourth day of treatment. However, due
to increase in creatinine values from 1.0mg/dL pre-treat-
ment to 2.1mg/dL the seventh day of treatment, amikacin
was discontinued. 4days later patient’s symptoms relapsed
with fever 39.5°C with rigors, anorexia, nausea and flank
pain and the next day he was referred to our hospital for fur-
ther evaluation and treatment. Physical examination revealed
a shivering man with 39.5°C of temperature, blood pressure
130/70mm Hg, pulse rate 110 beats per minute, respiratory
rate 14 breaths per minute with an oxygen saturation of 98%
on room air. He weighed 74kg with a BMI of 25.6kg/m2
and a height of 170cm. Right costovertebral angle tender-
ness (Giordano sign) was observed on palpation. The physi-
cal examination was otherwise unremarkable. Blood tests
showed leucocytosis (19.300/mm3 with 87% polymorpho-
nuclear predominance), normal hemoglobin levels 13.6g/dL
and platelets count of 337.000/μL. CRP levels were elevated
at 28.5IU/L (normal value < 0.5IU/L). Biochemical tests
revealed hyperglycaemia of 380mg/dL (without diabetic
ketoacidosis), normal levels of aminotransferases, direct
and indirect bilirubin and lactate dehydrogenase, while also
renal function had returned to normal with creatinine levels
of 1.1mg/dL and urea 36mg/dL. Prothrombin and partial
thromboplastin times were normal, d-dimers were increased
at 2.49μg/ml and fibrinogen was also increased at 613mg/
dL. Urinalysis showed greater than 100 white blood cells
and 100 bacteria per high-power field, microscopic haema-
turia with 30–40 red blood cells per high-power field and
presence of nitrates. Urine and blood cultures grew E. coli
with the same antibiogram as reported in the patient’s pre-
hospital evaluation. Initial imaging evaluation of the right
kidney and ureter with ultrasonography did not show evi-
dence of urinary flow obstruction but multiple hypoechoic
cystic lesions with inner diaphragms were detected in the
right renal parenchyma. Further imaging evaluation with
abdominal computed tomography (CT scan) with intrave-
nous iodine contrast medium showed extensive thrombosis
of the right renal vein and its branches protruding to the
inferior vena cava (Fig.1a) and right kidney pyelonephritis
with multiple renal abscesses the largest exhibiting a diam-
eter of 2.1cm (Fig.1b). Thrombophilia screening including
protein S, protein C, antithrombin deficiency, factor V Lei-
den, prothrombin 20210A and MTHFR (C677T) mutations,
homocysteine plasma level, paroxysmal nocturnal hemoglo-
binuria flow cytometry flair, antiphospholipid antibodies,
lupus anticoagulant, anti-cardiolipin and b2 glycoprotein-1
autoantibodies turned out negative.
The patient was treated with intravenous meropenem
2g (in 3-h intravenous infusion) every 8h and antico-
agulation with low molecular weight heparin, which was
transitioned to oral acenocoumarol. The patient became
asymptomatic and afebrile the fourth day of his hospitali-
zation with gradual reduction of inflammatory markers. A
repeated CT imaging performed 10days after the initial
CT, showed reduction of renal abscesses dimensions, which
were measured up to 1.5cm in their maximum diameter
as compared to 2.1cm at the initial imaging. Intravenous
Fig. 1 a, c, e Volume-rendered coronal reformatted CT images. Renal
parenchymal phase post IV contrast. Imaging at patient’s initial pres-
entation (a), at 5-week interval of antibiotic and anticoagulant treat-
ment (c), and at 12-week interval of anticoagulant therapy (e). b, d,
f Minimum intensity projection (MinIP) reformatted images. Renal
parenchymal phase post IV contrast at presentation (b), at 5weeks
(d), and at 12weeks (f). a There is thrombus within the right renal
vein (arrow) and its branches (arrowhead). The thrombus is protrud-
ing in the inferior vena cava (asterisk). b Two of the largest abscesses
are depicted in the right kidney (arrows). c There is no thrombus in
the right renal vein and its branches. However, a small residual com-
ponent still exists in the inferior vena cava (asterisk). d There are only
small residual changes (arrows), in the corresponding positions of the
abscesses depicted in b, consistent with the formation of scar tissue,
5 weeks after treatment. There is no appreciable interval change in
the lower pole renal cyst, on the right. e The residual inferior vena
cava thrombus seen in previous image is now imperceptible (cycle). f
A typical scar is left in the renal parenchyma (arrow)
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CEN Case Reports
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meropenem was administered for a total of 14days. The
patient was discharged on oral fosfomycin 3g once daily for
3days followed by every-other-day 3g dosing and aceno-
coumarol with an INR target of 2.5 (2.0–3.0). On this treat-
ment, the patient remained asymptomatic and afebrile and
a repeated retroperitoneal CT performed 3weeks after his
hospital discharge demonstrated that the extensive right
renal vein thrombosis had completely resolved and only a
small residual thrombus had remained in the inferior vena
cava (Fig.1c). The renal abscesses had also resolved with
only small residual changes, consistent with the formation
of scar tissue (Fig.1d). Oral fosfomycin was discontinued
and acenocoumarol was administered for additional 7weeks
(total duration of anticoagulation 3months as provoked deep
venous thrombosis). A follow-up CT performed at 3months
after the initial CT imaging, showed that the residual infe-
rior vena cava thrombus seen in the previous CT had been
totally resolved (Fig.1e), while a typical scar was left in the
renal parenchyma (Fig.1f). To date, 2years later, no relapse
of the patient’s pyelonephritis/renal abscess and renal vein
thrombosis has occurred.
Discussion
Renal vein thrombosis occurs mainly due to systemic hyper-
coagulable states, the most common being nephrotic syn-
drome with urinary losses of anticoagulant proteins [4].
Other prothrombotic aetiologies of renal vein thrombosis
include hyperhomocysteinemia, antiphospholipid syndrome,
paroxysmal nocturnal hemoglobinuria, renal cell carcinoma
or other active malignancy, renal transplantation, trauma,
postpartum, oral contraceptive use and sepsis syndrome
[510]. Only seven previous cases of RVT complicating
acute pyelonephritis or renal and perirenal abscesses have
been described [1].
The potential mechanism of renal vein thrombosis in the
presented bacteremic patient might be an endotoxin-induced
procoagulant state. Endotoxin, a lipopolysaccharide found
in the cell wall of Gram-negative bacteria, might promote a
prothrombotic state through changes in the endothelial sur-
face, by increasing the expression of the gene encoding tis-
sue factor (procoagulant molecule) and by rising endothelial
cell production of the fibrinolytic inhibitor plasminogen acti-
vator inhibitor-1 [11]. A mechanism of disseminated intra-
vascular coagulation in the context of our patient’s serious
infection is not supported by laboratory findings because
there was no thrombocytopenia or increased markers of
haemolysis (indirect bilirubin and lactate dehydrogenase),
coagulation parameters were not prolonged and fibrinogen
was not decreased.
The therapeutic approach to our patient was directed
towards two parallel directions; anticoagulant treatment for
renal vein thrombosis and effective antimicrobial therapy
of the ESBL-producing E. coli-induced renal infection and
bacteraemia. Since no underlying thrombophilic condition
was found, we considered that renal vein thrombosis was
provoked in our patient by his serious acute pyelonephritis
and renal abscesses. Low molecular weight heparin with
subsequent oral anticoagulation for 3months, as commonly
used in other provoked thromboembolic states, proved to be
an effective treatment, as also demonstrated in other reported
similar cases of renal vein thrombosis complicating renal
infection [1, 12].
The causative agent of our patient’s renal infection and
bacteraemia was demonstrated to be an ESBL-producing
E. coli strain. ESBL are enzymes that confer resistance to
most beta-lactam antibiotics, including penicillins, cephalo-
sporins and the monobactam aztreonam, while emergence
of plasmid-mediated quinolone resistance in ESBL-produc-
ing isolates has become a global problem for treating these
infections [2]. Despite sensitivity of our patient’s pathogen
to aminoglycosides, induction of renal toxicity excluded
this therapeutic option. In this context, carbapenem use
was reasonable and almost inevitable. Alternative to car-
bapenems options include the beta-lactam/beta-lactamase
inhibitor combinations of piperacillin–tazobactam, ceftolo-
zane–tazobactam and ceftazidime–avibactam [13]. The last
two options were not available in Greece when this case
occurred, while piperacillin–tazobactam was not used owing
to increased MIC (> 16/4μg/mL) [13, 14].
Renal abscesses < 5cm in diameter, are initially treated
with antimicrobial therapy alone (without drainage) [15].
In case of clinical response, the intravenous antimicrobial
treatment is instituted for 2weeks followed by oral step-
down therapy, which is extended for at least two additional
weeks, depending on the results of radiographic follow-up
[16]. However, in the case of ESBL-associated upper urinary
tract infections, the selection of oral step-down therapies is
problematic, because these pathogens are commonly resist-
ant to available oral options such as amoxycillin/clavula-
nate, oral cephalosporins, trimethoprim–sulfamethoxazole
and fluoroquinolones.
Fosfomycin is an old agent that remains active against
ESBL-producing E. coli strains, but it is currently only
approved for a 3g single-dose treatment of uncomplicated
lower urinary tract infections. Two sequential studies, the
PROOF and FOCUS, are being implemented and planned,
respectively, to test the optimal dosing and the efficacy of
fosfomycin over levofloxacin as oral step-down therapy in
complicated urinary tract infections including pyelonephri-
tis [3]. Pending these results, in our patient, we selected to
give three consecutive daily oral doses of 3g fosfomycin
as a loading scheme, followed by every-other-day 3g dos-
ing for additional 3weeks. This treatment schedule was
proven an effective carbapenem step-down oral therapy,
Author's personal copy
CEN Case Reports
1 3
as demonstrated by the complete resolution of clinical and
radiological signs of renal infection and by the absence of
relapse during follow-up.
In conclusion, we presented a rare case of extensive renal
vein thrombosis complicating severe pyelonephritis with
multiple abscesses formation and associated bacteraemia,
caused by an ESBL-producing strain of E. coli. Our patient
was effectively treated with anticoagulants, low molecular
heparin transitioned to acenocoumarol, for 3months and
targeted antibiotic therapy consisted of 2-week course of
intravenous meropenem followed by oral fosfomycin for
additional 3weeks as quidded by clinical and computed
tomographic follow-up. In complicated urinary infections,
caused by ESBL-producing enterobacteriaceae, oral fosfo-
mycin might represent an effective option for oral step-down
therapy of carbapenems, but results from randomized clini-
cal studies are needed.
Compliance with ethical standards
Conflict of interest The authors have declared that no conflict of inter-
est exists.
Human rights This article does not contain any studies with human
participants performed by any of the authors.
Informed consent Informed consent was obtained from all individual
participants included in the study.
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Author's personal copy
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... 19,24 In fact, it was reported that K. pneumoniae and E. coli are the two main pathogens among Enterobacteriaceae species involved in severe infections. [25][26][27][28] In our study, it was noted that the majority of these resistant strains were isolated from patients hospitalized in the neonatology and intensive care units. Thus, several factors can explain the high levels of 3GC-resistant bacteria in these two services, such as antibiotic use, long hospital stay, fragility of patients, and severity of illness. ...
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Metallo-β-lactamase (MBL) producing bacteria constitute nowadays a serious global concern worldwide. The purpose of our present study was to characterize molecular features of MBL producing bacteria and to identify the existing clones in our area. Thirteen MBL-producing-Klebsiella pneumoniae were detected in clinical samples from patients hospitalized in the Military hospital of Tunisia during 2017. The molecular research by polymerase chain reaction and sequencing of gene encoding MBL enzymes showed that only two types were identified in our study: blaNDM-1 and blaVIM-1 genes detected, respectively, in eight and six isolates. An association between these two MBL genes (blaNDM-1+blaVIM-1) has been observed in one of our isolates. Other β-lactamase types (CTXM-15/4 isolates; SHV/2 isolates; OXA-48/3 isolates) were detected in association with New Delhi metallo-beta-lactamase (NDM) and/or Verona Integron-Mediated Metallo-β-lactamase (VIM) enzymes. Furthermore, these isolates were resistant to other antimicrobial agents, including gentamicin [aac(3)-II/11 isolates], tetracycline (tetB or tetA/2 isolates), chloramphenicol (cmlA and/or floR/3 isolates), streptomycin (aadA/5 isolates), and sulfonamides (sul1 or sul2 or sul3/4isolates). The Multilocus Sequence Typing revealed 10 different Sequence types (ST) of which 7 novel ST: ST147 (3 isolates), ST101 (1 isolate), ST630 (1 isolate), ST3485 (1 isolate), ST3486 (1 isolate), ST3487 (1 isolate), ST3488 (1 isolate), ST3489 (1 isolate), ST3490 (1 isolate), ST3491 (2 isolates). Our study provides new data about MBL producing K. pneumoniae in Tunisia. Thus, we report for the first time the coexpression of blaNDM-1 and blaVIM-1 in our country and also we describe seven novel ST of MBL producing K. pneumoniae in the world.
... 19,24 In fact, it was reported that K. pneumoniae and E. coli are the two main pathogens among Enterobacteriaceae species involved in severe infections. [25][26][27][28] In our study, it was noted that the majority of these resistant strains were isolated from patients hospitalized in the neonatology and intensive care units. Thus, several factors can explain the high levels of 3GC-resistant bacteria in these two services, such as antibiotic use, long hospital stay, fragility of patients, and severity of illness. ...
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The aim of our study was to characterize third-generation cephalosporin (3GC)-resistant Enterobacteriaceae isolated over two different periods from patients hospitalized in the Military Hospital of Tunis with special focus to class A β-lactamases. This study included 180 Enterobacteriaceae resistant to 3GC isolated from samples of patients hospitalized in various services of the hospital. Enterobacteriaceae species detected by the Vitek 2 Compact® (BioMérieux®) automated system showed the dominance of Klebsiella pneumoniae followed by Escherichia coli during both periods. These strains were mainly isolated from urine samples and rectal swabs of patients hospitalized mostly in neonatology service and intensive care unit. The molecular research of genes encoding CTX-M, TEM, and SHV β-lactamase types showed a high rate of strains producing CTX-M β-lactamases, all of them harbored the blaCTX-M-15 gene. However, a huge diversity of SHV and TEM β-lactamases types was discovered in our study. In fact, nine various subvariants of blaSHV gene (blaSHV-1, blaSHV-11, blaSHV-12, blaSHV-27, blaSHV-28, blaSHV-31, blaSHV-38, blaSHV-79, and blaSHV-81) and eight subvariants of blaTEM gene (blaTEM-70, blaTEM-71,blaTEM-76,blaTEM-77, blaTEM-79, blaTEM-105, blaTEM-148, and blaTEM-186) were identified among our Enterobacteriaceae species during both periods. All subvariants of blaTEM gene and some subvariants of blaSHV gene (blaSHV-31, blaSHV-38, blaSHV-79, and blaSHV-81) have not been previously detected in our country.
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Introduction Acute pyelonephritis is among the most common bacterial infections. Options for initial treatment of pyelonephritis include an extended-spectrum cephalosporin or a fluoroquinolone. In this study, we aimed to compare the clinical outcomes of patients receiving ceftriaxone to those who received levofloxacin for the treatment of acute pyelone-phritis. Methods In this randomized, open-label trial, hospitalized adults with acute pyelonephritis were treated with ceftriaxone (1g IV every 12 hours) or levofloxacin (750 mg IV daily) for at least 7 days. Clinical and microbiological characteristics were compared among patients treated with ceftriaxone and levofloxacin. Results A total of 59 patients were randomized, 30 to the ceftriaxone group and 29 to the levofloxacin group. The clinical response for 68.0% of patients in the ceftriaxone group and 56.0% of patients in the levofloxacin group were cured. The mi-crobiological response (pathogen eradication rates) was 68.7% in the ceftriaxone group and 21.4% in the levofloxacin group.(P value=0.00028) Escherichia coliwas the most common pathogen (n = 31), followed by Klebsiella pneumoniae(n = 21). High resistance rates were detected for cotrimoxazole (55%), ciprofloxacin (48%), and ceftriaxone (34.4%) in isolat-ed E.coli. Likewise, all K. pneumoniaeisolates were resistant to ciprofloxacin. Conclusions Our study indicates that ceftriaxone was more effective than levofloxacin in the treatment of acute pyelone-phritis, on the basis of microbiological response, but there were no statistically significant differences between the treatment groups in the rates of clinical cure.The resistance of uropathogens to the most used antibiotics was relatively high. Choosing the treatment regimen based on susceptibility testing results and shortening the duration of the therapy are now recommend-ed to be the most important approaches to decrease the spread of antibiotic resistance worldwide.
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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic disorder characterized by a triad of clinical features - hemolytic anemia, pancytopenia, and thrombosis. Not many reports of renal involvement in PNH are available in literature. We present a case series of PNH with renal involvement. We present the data of PNH patients who attended to Departments of General Medicine and Nephrology at a government-run tertiary care institute in South India. The diagnosis of PNH in these patients during initial phase, between 1998 and 2004 was based on sucrose lysis and Ham's test. After 2004, the diagnosis was based on flow cytometry to detect CD59 (membrane inhibitor of reactive lysis), a glycoprotein, and CD55 (decay accelerating factor) in regulation of complement action. The patient data were collected from 1998 to 2014. There were 14 patients of PNH in this period. The mean age was 37 years and the range was 16-68 years. There were eight females. Acute kidney injury (AKI) was noted in six patients. Dialysis was performed in four of them. The mean serum creatinine and urea at the initiation of dialysis were 5.4 ± 0.6 and 64.1 ± 6.1 mg/dl, respectively. The median number of hemodialysis sessions done was four. Renal biopsy was done in four patients. In three patients, the urinalysis and serum chemistry were suggestive of Fanconi syndrome. In our patients, three renal manifestations of PNH were identified. They were AKI, renal vessel thrombosis, and Fanconi syndrome. Chronic renal failure was not identified.
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Introduction: Venous thrombosis is a serious surgical complication that frequently results in loss of kidney graft. Case presentation: We report the case of a female patient recipient of a decease kidney transplant that in the tenth postoperative presented with hematuria, graft pain and oliguria. Ultrasound examination was suggestive of venous thrombosis with abnormal doppler waveform pattern and reversal of diastolic flow. She underwent emergency surgical intervention after 2h of diagnosis. The vein thrombus was removed by perfusing the renal graft artery with 1000ml of Euro-Collins solution. The patient evolves with recovery of renal function after 1 week of the procedure DISCUSSION: Similar reports of graft rescue in the vein thrombosis are scarce and that the time of diagnosis to intervention is a determining factor. Conclusion: Rapid diagnosis of exactly 2h combined with the early re-operation may be successful in preserving renal graft in cases of venous thrombosis.
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A 68-year-old female presented with a week history of fever and generalized weakness. Clinical examination, blood work and urinalysis were compatible with sepsis due to acute pyelonephritis. Urine cultures were positive for Escherichia coli and blood cultures were negative. After 5 days of antibiotic therapy with cefuroxime, inflammatory parameters (CRP level and white blood cell count) remained highly elevated. Abdominal CT scan showed right kidney pyelonephritis with renal and perirenal abscess and right renal vein thrombosis. The patient improved after percutaneous drainage of the perirenal abscess and anticoagulation treatment.
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Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections.
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Purpose of review: Multidrug-resistant (MDR) Enterobacteriaceae are often related to the production of extended-spectrum b-lactamases (ESBLs) and carbapenemase-producing Enterobacteriaceae (CRE), and represent an increasing global threat. Recommendations for the therapeutic management of MDR-related infections, however, are mainly derived from retrospective and nonrandomized prospective studies. The aim of this review is to discuss the challenges in the treatment of patients with infections because of MDR Enterobacteriaceae and provide an expert opinion while awaiting for more definitive data. Recent findings: To avoid the selection of carbapenemase-producing Enterobacteriaceae, carbapenem-sparing strategies should be considered. B-lactams/b-lactamase inhibitors, mainly piperacillin-tazobactam, minimum inhibitory concentration (MIC) 16/4mg/ml or less represents the best alternative to carbapenems for the treatment of ESBL-producing strains. Overall, combination therapy may be preferred over monotherapy for CRE. The combination of a carbapenem-containing regimen with colistin or high-dose tigecycline or aminoglycoside can be administered at high-dose prolonged infusion with therapeutic drug monitoring for the treatment of CRE with MIC for meropenem 8-16 mg/l or less. For MIC higher than 8-16 mg/l, the use of meropenem should be avoided and various combination therapies based on the in-vitro susceptibility of antimicrobials (e.g., colistin, high-dose tigecycline, fosfomycin, and aminoglycosides) should be selected. Summary: Carbapenem-sparing strategies should be used, when feasible, for ESBL infections. The majority of available nonrandomized studies highlight that combination for CRE seem to offer some therapeutic advantage over monotherapy. Strict infection control measures toward MDR Gram-negative pathogens remain necessary while awaiting for new treatment options.
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Background: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics. Methods: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence. Results: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C). Conclusions: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.
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Background: The effectiveness of piperacillin-tazobactam (PTZ) for the treatment of extended-spectrum β-lactamase (ESBL) bacteremia is controversial. We compared 14-day mortality of PTZ vs carbapenems as empiric therapy in a cohort of patients with ESBL bacteremia who all received definitive therapy with a carbapenem. Methods: Patients hospitalized between January 2007 and April 2014 with monomicrobial ESBL bacteremia were included. A decrease of >3 doubling dilutions in the minimum inhibitory concentration for third-generation cephalosporins tested in combination with 4 µg/mL of clavulanic acid was used to confirm ESBL status. The primary exposure was empiric therapy, defined as antibiotic therapy administered to a patient before ESBL status was known. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. The primary outcome was time to death from the first day of bacteremia. Propensity scores using inverse probability of exposure weighting (IPW) were used to estimate the probability that a patient would receive PTZ vs carbapenems empirically. We calculated overall hazard ratios for mortality censored at 14 days using Cox proportional hazards models on an IPW-adjusted cohort. Results: A total of 331 unique patients with ESBL bacteremia were identified. One hundred three (48%) patients received PTZ empirically and 110 (52%) received carbapenems empirically. The adjusted risk of death was 1.92 times higher for patients receiving empiric PTZ compared with empiric carbapenem therapy (95% confidence interval, 1.07-3.45). Conclusions: PTZ appears inferior to carbapenems for the treatment of ESBL bacteremia. For patients at high risk of invasive ESBL infections, early carbapenem therapy should be considered. Our findings should not be extended to β-lactam/β-lactamase inhibitor combinations in development, as limited clinical data are available for these agents.
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Renal involvement in antiphospholipid syndrome (APS), either primary or systemic lupus erythematosus (SLE)-related APS, includes renal artery stenosis or thrombosis, renal infarction, renal vein thrombosis and a small-vessel vaso-occlusive nephropathy defined as "antiphospholipid antibody (aPL)-associated nephropathy." aPL-associated nephropathy is characterized by acute lesions, thrombotic microangiopathy, and chronic lesions such as fibrous intimal hyperplasia, organizing thrombi with or without recanalization, fibrous occlusions of arteries or arterioles and focal cortical atrophy. Systemic hypertension, hematuria, proteinuria (ranging from mild to nephrotic level) and renal insufficiency represent the major clinical manifestations associated with aPL-associated nephropathy. Similar renal histologic and clinical characteristics have been described among all different groups of patients with positive aPL (primary APS, SLE-related APS, catastrophic APS and SLE/non-APS with positive aPL). In patients with aPL-associated nephropathy lesions in the absence of other causes associated with similar histological characteristics, aPL testing needs to be considered.