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1.  Endovascular Repair of Abdominal Aortic Aneurysm 
The Medical Advisory Secretariat conducted a systematic review of the evidence on the effectiveness and cost-effectiveness of endovascular repair of abdominal aortic aneurysm in comparison to open surgical repair. An abdominal aortic aneurysm [AAA] is the enlargement and weakening of the aorta (major blood artery) that may rupture and result in stroke and death. Endovascular abdominal aortic aneurysm repair [EVAR] is a procedure for repairing abdominal aortic aneurysms from within the blood vessel without open surgery. In this procedure, an aneurysm is excluded from blood circulation by an endograft (a device) delivered to the site of the aneurysm via a catheter inserted into an artery in the groin. The Medical Advisory Secretariat conducted a review of the evidence on the effectiveness and cost-effectiveness of this technology. The review included 44 eligible articles out of 489 citations identified through a systematic literature search. Most of the research evidence is based on non-randomized comparative studies and case series. In the short-term, EVAR appears to be safe and comparable to open surgical repair in terms of survival. It is associated with less severe hemodynamic changes, less blood transfusion and shorter stay in the intensive care and hospital. However, there is concern about a high incidence of endoleak, requiring secondary interventions, and in some cases, conversion to open surgical repair. Current evidence does not support the use of EVAR in all patients. EVAR might benefit individuals who are not fit for surgical repair of abdominal aortic aneurysm and whose risk of rupture of the aneurysm outweighs the risk of death from EVAR. The long-term effectiveness and cost-effectiveness of EVAR cannot be determined at this time. Further evaluation of this technology is required.
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of endovascular repair of abdominal aortic aneurysms (EVAR) in comparison to open surgical repair (OSR).
Clinical Need
An abdominal aortic aneurysm (AAA) is a localized, abnormal dilatation of the aorta greater than 3 cm or 50% of the aortic diameter at the diaphragm. (1) A true AAA involves all 3 layers of the vessel wall. If left untreated, the continuing extension and thinning of the vessel wall may eventually result in rupture of the AAA. The risk of death from ruptured AAA is 80% to 90%. (61) Heller et al. (44) analyzed information from a national hospital database in the United States. They found no significant change in the incidence rate of elective AAA repair or ruptured AAA presented to the nation’s hospitals. The investigators concluded that technologic and treatment advances over the past 19 years have not affected the outcomes of patients with AAAs, and the ability to identify and to treat patients with AAAs has not improved.
Classification of Abdominal Aortic Aneurysms
At least 90% of the AAAs are affected by atherosclerosis, and most of these aneurysms are below the level of the renal arteries.(1)
An abdominal aortic aneurysm may be symptomatic or asymptomatic. An AAA may be classified according to their sizes:(7)
Small aneurysms: less than 5 cm in diameter.
Medium aneurysms: 5-7cm.
Large aneurysms: more than 7 cm in diameter.
Small aneurysms account for approximately 50% of all clinically recognized aneurysms.(7)
Aortic aneurysms may be classified according to their gross appearance as follows (1):
Fusiform aneurysms affect the entire circumference of a vessel, resulting in a diffusely dilated lesion
Saccular aneurysms involve only a portion of the circumference, resulting in an outpouching (protrusion) in the vessel wall.
Prevalence of Abdominal Aortic Aneurysms
In community surveys, the prevalence of AAA is reported to be between 1% and 5.4%. (61) The prevalence is related to age and vascular risk factors. It is more common in men and in those with a positive family history.
In Canada, Abdominal aortic aneurysms are the 10th leading cause of death in men 65 years of age or older. (60) Naylor (60) reported that the rate of AAA repair in Ontario has increased from 38 per 100,000 population in 1981/1982 to 54 per 100,000 population in 1991/1992. For the period of 1989/90 to 1991/92, the rate of AAA repair in Ontarians age 45 years and over was 53 per 100,000. (60) In the United States, about 200,000 new cases are diagnosed each year, and 50,000 to 60,000 surgical AAA repairs are performed. (2) Ruptured AAAs are responsible for about 15,000 deaths in the United States annually. One in 10 men older than 80 years has some aneurysmal change in his aorta. (2)
Symptoms of Abdominal Aortic Aneurysms
AAAs usually do not produce symptoms. However, as they expand, they may become painful. Compression or erosion of adjacent tissue by aneurysms also may cause symptoms. The formation of mural thrombi, a type of blood clots, within the aneurysm may predispose people to peripheral embolization, where blood vessels become blocked. Occasionally, an aneurysm may leak into the vessel wall and the periadventitial area, causing pain and local tenderness. More often, acute rupture occurs without any prior warning, causing acute pain and hypotension. This complication is always life-threatening and requires an emergency operation.
Diagnosis of Abdominal Aortic Aneurysms
An AAA is usually detected on routine examination as a palpable, pulsatile, and non-tender mass. (1)
Abdominal radiography may show the calcified outline of the aneurysms; however, about 25% of aneurysms are not calcified and cannot be visualized by plain x-ray. (1) An abdominal ultrasound provides more accurate detection, can delineate the traverse and longitudinal dimensions of the aneurysm, and is useful for serial documentation of aneurysm size. Computed tomography and magnetic resonance have also been used for follow-up of aortic aneurysms. These technologies, particularly contrast-enhanced computer tomography, provide higher resolution than ultrasound.
Abdominal aortography remains the gold standard to evaluate patients with aneurysms for surgery. This technique helps document the extent of the aneurysms, especially their upper and lower limits. It also helps show the extent of associated athereosclerotic vascular disease. However, the procedure carries a small risk of complications, such as bleeding, allergic reactions, and atheroembolism. (1)
Prognosis of Abdominal Aortic Aneurysms
The risk of rupture of an untreated AAA is a continuous function of aneurysm size as represented by the maximal diameter of the AAA. The annual rupture rate is near zero for aneurysms less than 4 cm in diameter. The risk is about 1% per year for aneurysms 4 to 4.9 cm, 11% per year for aneurysms 5 to 5.9 cm, and 25% per year or more for aneurysms greater than 6 cm. (7)
The 1-year mortality rate of patients with AAAs who do not undergo surgical treatment is about 25% if the aneurysms are 4 to 6 cm in diameter. This increases to 50% for aneurysms exceeding 6 cm. Other major causes of mortality for people with AAAs include coronary heart disease and stroke.
Treatment of Abdominal Aortic Aneurysms
Treatment of an aneurysm is indicated under any one of the following conditions:
The AAA is greater than 6 cm in diameter.
The patient is symptomatic.
The AAA is rapidly expanding irrespective of the absolute diameter.
Open surgical repair of AAA is still the gold standard. It is a major operation involving the excision of dilated area and placement of a sutured woven graft. The surgery may be performed under emergent situation following the rupture of an AAA, or it may be performed electively.
Elective OSR is generally considered appropriate for healthy patients with aneurysms 5 to 6 cm in diameter. (7) Coronary artery disease is the major underlying illness contributing to morbidity and mortality in OSR. Other medical comorbidities, such as chronic renal failure, chronic lung disease, and liver cirrhosis with portal hypertension, may double or triple the usual risk of OSR.
Serial noninvasive follow-up of small aneurysms (less than 5 cm) is an alternative to immediate surgery.
Endovascular repair of AAA is the third treatment option and is the topic of this review.
PMCID: PMC3387737  PMID: 23074438
2.  Distribution of Strain Type and Antimicrobial Susceptibility of Escherichia coli Isolates Causing Meningitis in a Large Urban Setting in Brazil 
Journal of Clinical Microbiology  2014;52(5):1418-1422.
The clinical management of meningitis caused by Escherichia coli is greatly complicated when the organism becomes resistant to broad-spectrum antibiotics. We sought to characterize the antimicrobial susceptibilities, sequence types (ST), and presence of known drug resistance genes of E. coli isolates that caused meningitis between 1996 and 2011 in Salvador, Brazil. We then compared these findings to those for E. coli isolates from community-acquired urinary tract infections (UTI) that occurred during the same time period and in the same city. We found that 19% of E. coli isolates from cases of meningitis and less than 1% of isolates from UTI were resistant to third-generation cephalosporins. The sequence types of E. coli isolates from cases of meningitis included ST131, ST69, ST405, and ST62, which were also found among isolates from UTI. Additionally, among the E. coli isolates that were resistant to third-generation cephalosporins, we found genes that encode the extended-spectrum beta-lactamases CTX-M-2, CTX-M-14, and CTX-M-15. These observations demonstrate that compared to E. coli strains isolated from cases of community-acquired UTI, those isolated from cases of meningitis are more resistant to third-generation cephalosporins, even though the same sequence types are shared between the two forms of extraintestinal infections.
PMCID: PMC3993653  PMID: 24523478
3.  Coil Embolization for Intracranial Aneurysms 
Executive Summary
To determine the effectiveness and cost-effectiveness of coil embolization compared with surgical clipping to treat intracranial aneurysms.
The Technology
Endovascular coil embolization is a percutaneous approach to treat an intracranial aneurysm from within the blood vessel without the need of a craniotomy. In this procedure, a microcatheter is inserted into the femoral artery near the groin and navigated to the site of the aneurysm. Small helical platinum coils are deployed through the microcatheter to fill the aneurysm, and prevent it from further expansion and rupture. Health Canada has approved numerous types of coils and coil delivery systems to treat intracranial aneurysms. The most favoured are controlled detachable coils. Coil embolization may be used with other adjunct endovascular devices such as stents and balloons.
Intracranial Aneurysms
Intracranial aneurysms are the dilation or ballooning of part of a blood vessel in the brain. Intracranial aneurysms range in size from small (<12 mm in diameter) to large (12–25 mm), and to giant (>25 mm). There are 3 main types of aneurysms. Fusiform aneurysms involve the entire circumference of the artery; saccular aneurysms have outpouchings; and dissecting aneurysms have tears in the arterial wall. Berry aneurysms are saccular aneurysms with well-defined necks.
Intracranial aneurysms may occur in any blood vessel of the brain; however, they are most commonly found at the branch points of large arteries that form the circle of Willis at the base of the brain. In 85% to 95% of patients, they are found in the anterior circulation. Aneurysms in the posterior circulation are less frequent, and are more difficult to treat surgically due to inaccessibility.
Most intracranial aneurysms are small and asymptomatic. Large aneurysms may have a mass effect, causing compression on the brain and cranial nerves and neurological deficits. When an intracranial aneurysm ruptures and bleeds, resulting in a subarachnoid hemorrhage (SAH), the mortality rate can be 40% to 50%, with severe morbidity of 10% to 20%. The reported overall risk of rupture is 1.9% per year and is higher for women, cigarette smokers, and cocaine users, and in aneurysms that are symptomatic, greater than 10 mm in diameter, or located in the posterior circulation. If left untreated, there is a considerable risk of repeat hemorrhage in a ruptured aneurysm that results in increased mortality.
In Ontario, intracranial aneurysms occur in about 1% to 4% of the population, and the annual incidence of SAH is about 10 cases per 100,000 people. In 2004-2005, about 660 intracranial aneurysm repairs were performed in Ontario.
Treatment of Intracranial Aneurysms
Treatment of an unruptured aneurysm attempts to prevent the aneurysm from rupturing. The treatment of a ruptured intracranial aneurysm aims to prevent further hemorrhage. There are 3 approaches to treating an intracranial aneurysm.
Small, asymptomatic aneurysms less than 10 mm in diameter may be monitored without any intervention other than treatment for underlying risk factors such as hypertension.
Open surgical clipping, involves craniotomy, brain retraction, and placement of a silver clip across the neck of the aneurysm while a patient is under general anesthesia. This procedure is associated with surgical risks and neurological deficits.
Endovascular coil embolization, introduced in the 1990s, is the health technology under review.
Literature Review
The Medical Advisory Secretariat searched the International Health Technology Assessment (INAHTA) Database and the Cochrane Database of Systematic Reviews to identify relevant systematic reviews. OVID Medline, Medline In-Process and Other Non-Indexed Citations, and Embase were searched for English-language journal articles that reported primary data on the effectiveness or cost-effectiveness of treatments for intracranial aneurysms, obtained in a clinical setting or analyses of primary data maintained in registers or institutional databases. Internet searches of Medscape and manufacturers’ databases were conducted to identify product information and recent reports on trials that were unpublished but that were presented at international conferences. Four systematic reviews, 3 reports on 2 randomized controlled trials comparing coil embolization with surgical clipping of ruptured aneurysms, 30 observational studies, and 3 economic analysis reports were included in this review.
Safety and Effectiveness
Coil embolization appears to be a safe procedure. Complications associated with coil embolization ranged from 8.6% to 18.6% with a median of about 10.6%. Observational studies showed that coil embolization is associated with lower complication rates than surgical clipping (permanent complication 3-7% versus 10.9%; overall 23% versus 46% respectively, p=0.009). Common complications of coil embolization are thrombo-embolic events (2.5%–14.5%), perforation of aneurysm (2.3%–4.7%), parent artery obstruction (2%–3%), collapsed coils (8%), coil malposition (14.6%), and coil migration (0.5%–3%).
Randomized controlled trials showed that for ruptured intracranial aneurysms with SAH, suitable for both coil embolization and surgical clipping (mostly saccular aneurysms <10 mm in diameter located in the anterior circulation) in people with good clinical condition:Coil embolization resulted in a statistically significant 23.9% relative risk reduction and 7% absolute risk reduction in the composite rate of death and dependency compared to surgical clipping (modified Rankin score 3–6) at 1-year.
The advantage of coil embolization over surgical clipping varies widely with aneurysm location, but endovascular treatment seems beneficial for all sites.
There were less deaths in the first 7 years following coil embolization compared to surgical clipping (10.8% vs 13.7%). This survival benefit seemed to be consistent over time, and was statistically significant (log-rank p= 0.03).
Coil embolization is associated with less frequent MRI-detected superficial brain deficits and ischemic lesions at 1-year.
The 1- year rebleeding rate was 2.4% after coil embolization and 1% for surgical clipping. Confirmed rebleeding from the repaired aneurysm after the first year and up to year eight was low and not significantly different between coil embolization and surgical clipping (7 patients for coil embolization vs 2 patients for surgical clipping, log-rank p=0.22).
Observational studies showed that patients with SAH and good clinical grade had better 6-month outcomes and lower risk of symptomatic cerebral vasospasm after coil embolization compared to surgical clipping.
For unruptured intracranial aneurysms, there were no randomized controlled trials that compared coil embolization to surgical clipping. Large observational studies showed that:
The risk of rupture in unruptured aneurysms less than 10 mm in diameter is about 0.05% per year for patients with no pervious history of SAH from another aneurysm. The risk of rupture increases with history of SAH and as the diameter of the aneurysm reaches 10 mm or more.
Coil embolization reduced the composite rate of in hospital deaths and discharge to long-term or short-term care facilities compared to surgical clipping (Odds Ratio 2.2, 95% CI 1.6–3.1, p<0.001). The improvement in discharge disposition was highest in people older than 65 years.
In-hospital mortality rate following treatment of intracranial aneurysm ranged from 0.5% to 1.7% for coil embolization and from 2.1% to 3.5% for surgical clipping. The overall 1-year mortality rate was 3.1% for coil embolization and 2.3% for surgical clipping. One-year morbidity rate was 6.4% for coil embolization and 9.8% for surgical clipping. It is not clear whether these differences were statistically significant.
Coil embolization is associated with shorter hospital stay compared to surgical clipping.
For both ruptured and unruptured aneurysms, the outcome of coil embolization does not appear to be dependent on age, whereas surgical clipping has been shown to yield worse outcome for patients older than 64 years.
Angiographic Efficiency and Recurrences
The main drawback of coil embolization is its low angiographic efficiency. The percentage of complete aneurysm occlusion after coil embolization (27%–79%, median 55%) remains lower than that achieved with surgical clipping (82%–100%). However, about 90% of coiled aneurysms achieve near total occlusion or better. Incompletely coiled aneurysms have been shown to have higher aneurysm recurrence rates ranging from 7% to 39% for coil embolization compared to 2.9% for surgical clipping. Recurrence is defined as refilling of the neck, sac, or dome of a successfully treated aneurysm as shown on an angiogram. The long-term clinical significance of incomplete occlusion following coil embolization is unknown, but in one case series, 20% of patients had major recurrences, and 50% of these required further treatment.
Long-Term Outcomes
A large international randomized trial reported that the survival benefit from coil embolization was sustained for at least 7 years. The rebleeding rate between year 2 and year 8 following coil embolization was low and not significantly different from that of surgical clipping. However, high quality long-term angiographic evidence is lacking. Accordingly, there is uncertainty about long-term occlusion status, coil durability, and recurrence rates. While surgical clipping is associated with higher immediate procedural risks, its long-term effectiveness has been established.
Indications and Contraindications
Coil embolization offers treatment for people at increased risk for craniotomy, such as those over 65 years of age, with poor clinical status, or with comorbid conditions. The technology also makes it possible to treat surgical high-risk aneurysms.
Not all aneurysms are suitable for coil embolization. Suitability depends on the size, anatomy, and location of the aneurysm. Aneurysms more than 10 mm in diameter or with an aneurysm neck greater than or equal to 4 mm are less likely to achieve total occlusion. They are also more prone to aneurysm recurrences and to complications such as coil compaction or parent vessel occlusion. Aneurysms with a dome to neck ratio of less than 1 have been shown to have lower obliteration rates and poorer outcome following coil embolization. Furthermore, aneurysms in the middle cerebral artery bifurcation are less suitable for coil embolization. For some aneurysms, treatment may require the use of both coil embolization and surgical clipping or adjunctive technologies, such as stents and balloons, to obtain optimal results.
Information from 3 countries indicates that coil embolization is a rapidly diffusing technology. For example, it accounted for about 40% of aneurysm treatments in the United Kingdom.
In Ontario, coil embolization is an insured health service, with the same fee code and fee schedule as open surgical repair requiring craniotomy. Other costs associated with coil embolization are covered under hospitals’ global budgets. Utilization data showed that in 2004-2005, coil embolization accounted for about 38% (251 cases) of all intracranial aneurysm repairs in the province. With the 2005 publication of the positive long-term survival data from the International Subarachnoid Aneursym Trial, the pressure for diffusion will likely increase.
Economic Analysis
Recent economic studies show that treatment of unruptured intracranial aneurysms smaller than 10 mm in diameter in people with no previous history of SAH, either by coil embolization or surgical clipping, would not be effective or cost-effective. However, in patients with aneurysms that are greater than or equal to 10 mm or symptomatic, or in patients with a history of SAH, treatment appears to be cost-effective.
In Ontario, the average device cost of coil embolization per case was estimated to be about $7,500 higher than surgical clipping. Assuming that the total number of intracranial aneurysm repairs in Ontario increases to 750 in the fiscal year of 2007, and assuming that up to 60% (450 cases) of these will be repaired by coil embolization, the difference in device costs for the 450 cases (including a 15% recurrence rate) would be approximately $3.8 million. This figure does not include capital costs (e.g. $3 million for an angiosuite), additional human resources required, or costs of follow-up. The increase in expenditures associated with coil embolization may be offset partially, by shorter operating room times and hospitalization stays for endovascular repair of unruptured aneurysms; however, the impact of these cost savings is probably not likely to be greater than 25% of the total outlay since the majority of cases involve ruptured aneurysms. Furthermore, the recent growth in aneurysm repair has predominantly been in the area of coil embolization presumably for patients for whom surgical clipping would not be advised; therefore, no offset of surgical clipping costs could be applied in such cases. For ruptured aneurysms, downstream cost savings from endovascular repair are likely to be minimal even though the savings for individual cases may be substantial due to lower perioperative complications for endovascular aneurysm repair.
The two Guidance documents issued by the National Institute of Clinical Excellence (UK) in 2005 support the use of coil embolization for both unruptured and ruptured (SAH) intracranial aneurysms, provided that procedures are in place for informed consent, audit, and clinical governance, and that the procedure is performed in specialist units with expertise in the endovascular treatment of intracranial aneurysms.
For people in good clinical condition following subarachnoid hemorrhage from an acute ruptured intracranial aneurysm suitable for either surgical clipping or endovascular repair, coil embolization results in improved independent survival in the first year and improved survival for up to seven years compared to surgical clipping. The rebleeding rate is low and not significantly different between the two procedures after the first year. However, there is uncertainty regarding the long-term occlusion status, durability of the stent graft, and long-term complications.
For people with unruptured aneurysms, level 4 evidence suggests that coil embolization may be associated with comparable or less mortality and morbidity, shorter hospital stay, and less need for discharge to short-term rehabilitation facilities. The greatest benefit was observed in people over 65 years of age. In these patients, the decision regarding treatment needs to be based on the assessment of the risk of rupture against the risk of the procedure, as well as the morphology of the aneurysm.
In people who require treatment for intracranial aneurysm, but for whom surgical clipping is too risky or not feasible, coil embolization provides survival benefits over surgical clipping, even though the outcomes may not be as favourable as in people in good clinical condition and with small aneurysms. The procedure may be considered under the following circumstances provided that the aneurysm is suitable for coil embolization:
Patients in poor/unstable clinical or neurological state
Patients at high risk for surgical repair (e.g. people>age 65 or with comorbidity), or
Aneurysm(s) with poor accessibility or visibility for surgical treatment due to their location (e.g. ophthalmic or basilar tip aneurysms)
Compared to small aneurysms with a narrow neck in the anterior circulation, large aneurysms (> 10 mm in diameter), aneurysms with a wide neck (>4mm in diameter), and aneurysms in the posterior circulation have lower occlusion rates and higher rate of hemorrhage when treated with coil embolization.
The extent of aneurysm obliteration after coil embolization remains lower than that achieved with surgical clipping. Aneurysm recurrences after successful coiling may require repeat treatment with endovascular or surgical procedures. Experts caution that long-term angiographic outcomes of coil embolization are unknown at this time. Informed consent for and long-term follow-up after coil embolization are recommended.
The decision to treat an intracranial aneurysm with surgical clipping or coil embolization needs to be made jointly by the neurosurgeon and neuro-intervention specialist, based on the clinical status of the patient, the size and morphology of the aneurysm, and the preference of the patient.
The performance of endovascular coil embolization should take place in centres with expertise in both neurosurgery and endovascular neuro-interventions, with adequate treatment volumes to maintain good outcomes. Distribution of the technology should also take into account that patients with SAH should be treated as soon as possible with minimal disruption.
PMCID: PMC3379525  PMID: 23074479
4.  E. coli Meningitis Presenting in a Patient with Disseminated Strongyloides stercoralis 
Introduction. Spontaneous Escherichia coli meningitis is an infrequent condition in adults and is associated with some predisposing factors, including severe Strongyloides stercoralis (SS) infections. Case Presentation. A 43-year-old Hispanic man, with history of travelling to the jungle regions of Peru and Brazil two decades ago, and who received prednisone due to Bell's palsy for three weeks before admission, presented to the Emergency Department with diarrhea, fever, and hematochezia. A week after admission he developed drowsiness, meningeal signs, abdominal distension, and constipation. A cerebrospinal fluid culture showed extended spectrum β-lactamase producing E. coli. A colonoscopy was performed and showed pancolitis. Three days after the procedure the patient became unstable and developed peritoneal signs. He underwent a laparotomy, which ended up in a total colectomy and partial proctectomy due to toxic megacolon. Three days later the patient died in the intensive care unit due to septic shock. Autopsy was performed and microscopic examination revealed the presence of multiple Strongyloides larvae throughout the body. Conclusion. Strongyloides stercoralis infection should be excluded in adults with spontaneous E. coli meningitis, especially, if gastrointestinal symptoms and history of travelling to an endemic area are present. Even with a proper diagnosis and management, disseminated strongyloidiasis has a poor prognosis.
PMCID: PMC3845250  PMID: 24324900
5.  Aorto-enteric fistula development secondary to mycotic abdominal aortic aneurysm following intravesical bacillus Calmette–Guerin (BCG) treatment for transitional cell carcinoma of the bladder 
Intravesical BCG-instillation for bladder cancer is considered safe but is not without risk. While most side-effects are localised and self-limiting, the development of secondary vascular pathology is a rare but significant complication.
A 77-year-old male presented with a mycotic abdominal aortic aneurysm and associated aorto-enteric fistula 18 months after receiving intravesical BCG-instillations for early stage transitional cell carcinoma.
Response rates to intravesical BCG for early stage transitional cell carcinoma are high. The procedure produces a localised inflammatory response in the bladder but the exact mechanism of action is unclear. The treatment is generally well tolerated but BCG-sepsis and secondary vascular complications have been documented.
Mycotic abdominal aortic aneurysm with associated aorto-enteric fistula secondary to BCG is very rare. Few examples have been documented internationally and the extent of corresponding research and associated management proposals is limited.
Surgical options include in situ repair with prosthetic graft, debridement with extra-anatomical bypass and, occasionally, endovascular stent grafting. Recommended medical therapy for systemic BCG infection is Isoniazid, Rifampicin and Ethambutol.
Current screening methods must be updated with clarification regarding duration of anti-tuberculous therapy and impact of concomitant anti-tuberculous medication on the therapeutic action of intravesical BCG. Long-term outcomes for patients post graft repair for mycotic aneurysm are unknown and more research is required regarding the susceptibility of vascular grafts to mycobacterial infection.
Recognition of the risks associated with BCG-instillations, even in immunocompetent subjects, is paramount and must be considered even several months or years after receiving the therapy.
PMCID: PMC3537938  PMID: 23127864
BCG; Aortic aneurysm; Aorto-enteric fistula; Bladder carcinoma
6.  Mycotic Abdominal Aneurysm Caused by Campylobacter Fetus: A Case Report for Surgical Management 
Annals of Vascular Diseases  2011;4(1):56-59.
We report a rare case of mycotic abdominal aortic aneurysm associated with Campylobacter fetus. A 72-year-old male admitted to the hospital because of pain in the right lower quadrant with pyrexia. The enhanced abdominal computed tomography (CT) examination showed abdominal aortic aneurysm (AAA) measuring 50 mm in maximum diameter and a high-density area of soft tissue density from the right lateral wall to the anterior wall of the aorta. However, since the patient showed no significant signs of defervescence after antibiotics administration, so we performed emergency surgery on the patient based on the diagnosis of impending rupture of mycotic AAA. The aneurysm was resected in situ reconstruction using a bifurcated albumin-coated knitted Dacron graft was performed. The cultures of blood and aneurysmal wall grew Campylobacter fetus, allowing early diagnosis and appropriate surgical management in this case, and the patient is making satisfactory progress. This is the fifth report of mycotic AAA characterizing culture positive for Campylobacter fetus in blood and tissue culture of the aortic aneurysm wall.
PMCID: PMC3595778  PMID: 23555431
mycotic abdominal aneurysm; Campylobacter fetus; vascular surgery
7.  Detection of extended-spectrum beta-lactamases in members of the family Enterobacteriaceae: comparison of the double-disk and three-dimensional tests. 
The three-dimensional and clavulanate double-disk potentiation tests were compared as procedures for the detection of extended-spectrum beta-lactamase production in 32 strains of Escherichia coli and Klebsiella pneumoniae, 31 of which produced TEM-1, TEM-2, TEM-3, TEM-4, TEM-5, TEM-7, TEM-8, TEM-9, TEM-10, TEM-12, TEM-101, SHV-1, SHV-2, SHV-3, SHV-4, SHV-5, CAZ-2, MIR-1, or an unidentified extended-spectrum beta-lactamase with a pI of 5.95, with some strains producing multiple beta-lactamases. The three-dimensional test, which was performed in conjunction with a routine disk diffusion test, detected extended-spectrum beta-lactamase production in 26 of 28 (93%) of the strains that produced extended-spectrum beta-lactamases. The clavulanate double-disk potentiation test detected extended-spectrum beta-lactamases in only 22 of the 28 strains (79%) when it was performed as currently recommended. The three-dimensional test, when performed in conjunction with the disk diffusion test, offered the advantages of providing simultaneous information about both antibiotic susceptibility and extended-spectrum beta-lactamase production, coupled with a greater sensitivity and earlier detection of extended-spectrum beta-lactamases.
PMCID: PMC192203  PMID: 1416878
8.  Frequency of Severe Malaria and Invasive Bacterial Infections among Children Admitted to a Rural Hospital in Burkina Faso 
PLoS ONE  2014;9(2):e89103.
Although severe malaria is an important cause of mortality among children in Burkina Faso, data on community-acquired invasive bacterial infections (IBI, bacteremia and meningitis) are lacking, as well as data on the involved pathogens and their antibiotic resistance rates.
The present study was conducted in a rural hospital and health center in Burkina Faso, in a seasonal malaria transmission area. Hospitalized children (<15 years) presenting with T≥38.0°C and/or signs of severe illness were enrolled upon admission. Malaria diagnosis and blood culture were performed for all participants, lumbar puncture when clinically indicated. We assessed the frequency of severe malaria (microscopically confirmed, according to World Health Organization definitions) and IBI, and the species distribution and antibiotic resistance of the bacterial pathogens causing IBI.
From July 2012 to July 2013, a total of 711 patients were included. Severe malaria was diagnosed in 292 (41.1%) children, including 8 (2.7%) with IBI co-infection. IBI was demonstrated in 67 (9.7%) children (bacteremia, n = 63; meningitis, n = 6), 8 (11.8%) were co-infected with malaria. Non-Typhoid Salmonella spp. (NTS) was the predominant isolate from blood culture (32.8%), followed by Salmonella Typhi (18.8%), Streptococcus pneumoniae (18.8%) and Escherichia coli (12.5%). High antibiotic resistance rates to first line antibiotics were observed, particularly among Gram-negative pathogens. In addition, decreased ciprofloxacin susceptibility and extended-spectrum beta lactamase (ESBL) production was reported for one NTS isolate each. ESBL production was observed in 3/8 E. coli isolates. In-hospital mortality was 8.2% and case-fatality rates for IBI (23.4%) were significantly higher compared to severe malaria (6.8%, p<0.001).
Although severe malaria was the main cause of illness, IBI were not uncommon and had higher case-fatality rates. The high frequency, antibiotic resistance rates and mortality rates of community acquired IBI require improvement in hygiene, better diagnostic methods and revision of current treatment guidelines.
PMCID: PMC3925230  PMID: 24551225
9.  Ceftazidime–avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections 
Core Evidence  2014;9:13-25.
Avibactam (NXL104, AVE1330A) is a semi-synthetic, non-β-lactam, β-lactamase inhibitor that is active against Ambler class A, class C, and some class D serine β-lactamases. In this review, we summarize the in vitro data, pharmacology, mechanisms of action and resistance, and clinical trial data relating to the use of this agent combined with ceftazidime for the treatment of Gram-negative bacterial infections. The addition of avibactam to ceftazidime improves its in vitro activity against Enterobacteriaceae and Pseudomonas aeruginosa. Avibactam does not improve the activity of ceftazidime against Acinetobacter spp., Burkholderia spp., or most anaerobic Gram-negative rods. Pharmacodynamic data indicate that ceftazidime—avibactam is bactericidal at concentrations achievable in human serum. Animal studies demonstrate that ceftazidime–avibactam is effective in ceftazidime-resistant Gram-negative septicemia, meningitis, pyelonephritis, and pneumonia. Limited clinical trials published to date have reported that ceftazidime–avibactam is as effective as therapy with a carbapenem in complicated urinary tract infection and complicated intra-abdominal infection (combined with metronidazole) including infection caused by cephalosporin-resistant Gram-negative isolates. Safety and tolerability of ceftazidime–avibactam in clinical trials has been excellent, with few serious drug-related adverse events reported. Given the abundant clinical experience with ceftazidime and the significant improvement that avibactam provides in its activity against contemporary β-lactamase-producing Gram-negative pathogens, it is likely this new combination agent will play a role in the empiric treatment of complicated urinary tract infections (monotherapy) and complicated intra-abdominal infections (in combination with metronidazole) caused or suspected to be caused by antimicrobial-resistant pathogens (eg, extended spectrum beta-lactamase-, AmpC-, or Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa). Potential future uses also include hospital-acquired pneumonia (in combination with antistaphylococcal and antipneumococcal agents) or treatment of skin and soft tissue infections caused by antimicrobial-resistant Gram-negative pathogens (eg, diabetic foot infections), but further clinical trials are required.
PMCID: PMC3908787  PMID: 24493994
β-lactamase; microbiology; pharmacokinetics; NXL-104; clinical trials; review
10.  Resolution of a fungal mycotic aneurysm after a contaminated steroid injection: a case report 
BMC Research Notes  2014;7:327.
In the past ten years there have been three separate outbreaks of fungal contaminated steroid injections from compounding pharmacies. The 2012 outbreak of central nervous system fungal infections associated with contaminated methylprednisolone produced by a United States compounding pharmacy has led to 750 infections (151 with meningitis and paraspinal infections and 325 cases with paraspinal infections without meningitis) and 64 deaths as of October 23, 2013. Exserohilum rostratum has been the predominant pathogen identified by culture, polymerase chain reaction or antibody tests. According to previous reports, cerebral involvement with phaeohyphomycosis has a high risk of morbidity and mortality.
Case presentation
We report a 41 year-old Caucasian woman who received a lumbar methylprednisolone injection from a contaminated lot in August 2012. She was diagnosed with fungal meningitis by cerebrospinal fluid pleocytosis and positive (1, 3) beta-D-glucan after cultures and polymerase chain reaction were negative. Two weeks after onset of therapy, she developed a 4.1 mm superior cerebellar artery mycotic aneurysm associated with new stroke symptoms, which resolved with thirty-two weeks of antifungal treatment.
This is the rare case report of successful medical management of a cerebral mycotic aneurysm with stroke symptoms related to a presumed phaeohyphomycosis in an immunocompetent individual. Further studies are needed to determine the utility of cerebrospinal fluid (1, 3) beta-D-glucan in diagnosing and monitoring patients with meningitis thought to be related to fungal infection.
PMCID: PMC4057927  PMID: 24885172
Fungal polysaccharides; (1,3) beta-D-glucan; Mycoses; Infected aneurysm; Voriconazole
11.  Aortoesophageal Fistula after Endovascular Aortic Aneurysm Repair of a Mycotic Thoracic Aneurysm 
Mycotic aneurysms constitute a small proportion of aortic aneurysms. Endovascular repair of mycotic aneurysms has been applied with good short-term and midterm results. However, the uncommon aortoenteric fistula formation remains a potentially fatal complication when repairing such infective aneurysms. We present the case of an 80-year-old woman with thoracic and abdominal aortic mycotic aneurysms, which were successfully treated with endografting. However, the patient presented 3 months later with upper gastrointestinal bleeding secondary to erosion of the thoracic graft into the oesophagus. The patient was treated conservatively due to the high risk of surgical repair. There is currently little exposure to the management of mycotic aortic aneurysms. If suspected, imaging of the entire vasculature will aid initial diagnosis and highlight the extent of the disease process, allowing for efficient management. Aortic endografting for mycotic thoracic aneurysms is a high-risk procedure yet is still an appropriate intervention. Aortoenteric fistulae pose a rare but severe complication of aortic endografting in this setting.
PMCID: PMC3167181  PMID: 21904681
12.  Nosocomial acquisition of methicillin-resistant Staphyloccocus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae in hospitalised patients: a prospective multicenter study 
The risk of acquisition of antibiotic resistant-bacteria during or shortly after antibiotic therapy is still unclear and it is often confounded by scarce data on antibiotic usage.
Primary objective of the study is to compare rates of acquisition of methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae in hospitalised patients, after starting antibiotic therapy.
The study, running in three European hospitals, is a multicenter, prospective, longitudinal, observational cohort study funded from the European Community's Seventh Framework Programme [FP7/2007-2013] within the project 'Impact of Specific Antibiotic Therapies on the prevalence of hUman host ResistaNt bacteria' (acronym SATURN). Nasal and rectal screening for methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae will be obtained at hospital admission, discharge, at antibiotic start (t0, within one hour) and at the following intervals: day 3 (t1), 7 (t2), 15 (t3), and 30 (t4). Two nested case-control studies will be performed. The objective of the first study will be to define individual level of risk related to specific antibiotics. Patients acquiring methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae (cases) will be compared with patients not acquiring antibiotic-resistant strains after starting antibiotic therapy (controls; ratio 1:4). To define the impact of antibiotics on new acquisition of target antibiotic-resistant bacteria, a second nested case-control study will be done (ratio 1:4). Control group will be selected among patients not receiving antibiotics, admitted in the same ward on the day of the corresponding case, with negative cultures at admission. Epidemiological, clinical and microbiological data will be prospective collected.
The rationale of this study is to better understand the impact of antibiotic use on acquisition, selection and transmission of antimicrobial resistant-bacteria in European hospitals.
Trial registration NCT01208519.
PMCID: PMC3340319  PMID: 22458427
MRSA; ESBL; Antibiotic resistance; SATURN; Antibiotic use
13.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
PMCID: PMC1563501  PMID: 16953658
14.  Infective endocarditis with cerebrovascular complications: timing of surgical intervention 
Management of infective endocarditis (IE) with cerebrovascular complications is difficult due to absence of concrete evidence. These patients usually have multiple neurological deficits and the optimal timing for cardiac operation remains controversial. The aims of this study were to present cases and discuss the treatment options for IE with cerebrovascular complications. From 1998 to 2010, 51 patients underwent operations for IE at our institution. From a review of medical records, 10 patients (19.6%) with preoperative neurological complications were identified. Data on these 10 patients were analysed. Cerebrovascular complications included cerebral infarction (n = 4, 40.0%), mycotic aneurysm (n = 1, 10.0%), mycotic aneurysm plus cerebral infarction (n = 3, 30.0%), meningitis (n = 1, 10.0%) and mycotic aneurysm with cerebral haemorrhage plus meningitis (n = 1, 10.0%). Of 5 patients having mycotic aneurysms, 3 underwent clipping before cardiac operations. The mean interval from craniotomy to cardiac operations was 26.7 ± 21.8 days. A cardiac operation was performed initially on seven patients. The mean interval from the onset of neurological deficit to cardiac operation was 7.4 ± 9.8 days. The mortality rate was 10.0%. Postoperative deterioration was not observed. Management of IE with cerebrovascular complications should be based on case-by-case multidisciplinary assessment of potential risks and benefits of intracranial and cardiac operations.
PMCID: PMC3420269  PMID: 22108940
Infective endocarditis; Cerebrovascular complications; Surgical intervention
15.  Prevalence and Mechanisms of Broad-Spectrum β-Lactam Resistance in Enterobacteriaceae: a Children's Hospital Experience▿  
Antimicrobial Agents and Chemotherapy  2008;52(11):3909-3914.
The objective of this study was to investigate the trends and patterns of resistance in β-lactamase-producing members of the family Enterobacteriaceae in a children's hospital over a 9-year period (1999 to 2007). Clinically significant isolates of the Enterobacteriaceae were screened for patterns of broad-spectrum resistance to β-lactams. The strains likely to be resistant were subsequently confirmed by an inhibitor-based disc test. The plasmid-mediated resistance determinants in these isolates were identified by PCR and by in vitro transformation, which successfully reproduced the AmpC phenotype unrestricted by the species of the host organisms. Among 8,048 Enterobacteriaceae isolates belonging to the four chromosomal ampC-negative or -nonfunctional genera, 86 (1.07%) isolates (56 Escherichia coli isolates, 22 Klebsiella species isolates, 1 Proteus mirabilis isolate, and 7 Salmonella species isolates) exhibited broad-spectrum β-lactam resistance patterns. These organisms collectively produced three classes of β-lactamases, including class A extended-spectrum β-lactamases (n = 47), class C or AmpC β-lactamases (n = 36, including 4 isolates that produced both class A and class C enzymes), and class A or B carbapenem-hydrolyzing β-lactamases (n = 3). The proportion increased from 0.46% during the first 3 years to 1.84% during the last 3 years (relative risk [RR], 4.04; 95% confidence interval [CI], 2.28 to 7.42; P < 0.001). The increase was mainly due to the emergence of a plasmid-mediated blaCMY-2 β-lactamase, the incidence of which increased from 0.11% during the first 3 years to 0.96% during the last 3 years (RR, 9.11; 95% CI, 2.76 to 30.1; P = 0.001). Class A-type resistance increased slightly during the study period, from 0.35% during the first 3 years to 0.85% during the last 3 years (RR, 2.42; 95% CI, 1.15 to 5.07; P = 0.02). A Proteus mirabilis strain was documented to possess a novel blaDHA determinant. Of special concern, three carbapenemase-producing isolates were identified between 2003 and 2006. The infections caused by resistant isolates of the Enterobacteriaceae mainly affected hospitalized patients with underlying conditions; however, 19 (22%) episodes were of community onset in otherwise well children. The rate of resistance to broad-spectrum β-lactams among isolates of the Enterobacteriaceae is increasing in children in both hospital- and community-acquired settings, and the resistance is driven largely by plasmid-mediated AmpC β-lactamases. These data have important implications for empirical antimicrobial strategies targeting serious pediatric infections. Further study of this problem is warranted.
PMCID: PMC2573145  PMID: 18765688
16.  Enterobacter cloacae infection of an expanded polytetrafluoroethylene femoral-popliteal bypass graft: a case report 
Enterobacter cloacae infections are common among burn victims, immunocompromised patients, and patients with malignancy. Most commonly these infections are manifested as nosocomial urinary tract or pulmonary infections. Nosocomial outbreaks have also been associated with colonization of certain surgical equipment and operative cleaning solutions. Infections of an aortobifemoral prosthesis, an aortic graft, and arteriovenous fistulae are noted in the literature. To our knowledge, this is the first isolated account of an E. cloacae infection of a femoral-popliteal expanded polytetrafluoroethylene bypass graft.
Case presentation
A 68-year-old Caucasian man presented with fever and rest pain in the right lower extremity five months after the placement of a vascular expanded polytetrafluoroethylene graft for femoral-popliteal bypass. Computed tomography angiography demonstrated peri-graft fluid that was aspirated percutaneously with image guidance and cultured to reveal E. cloacae. The graft was revised and then removed. The patient completed a six-week course of ceftazidime and is currently without signs of infection. There were no other reports of E. cloacae graft infections in any patients receiving treatment in the same surgical suite within a month of this report.
Isolated cases of E. cloacae infection of surgical bypass grafts are rare (unique in this setting). Clinicians should have a high index of suspicion for device contamination in such cases and should consider testing for possible microbial reservoirs. Graft removal is required due to the formation of biofilm and the recent emergence of Enterobacteriaceae producing extended-spectrum beta-lactamase in community acquired infections.
PMCID: PMC2873459  PMID: 20459698
17.  Etiology and antibiotic resistance patterns of community-acquired urinary tract infections in J N M C Hospital Aligarh, India 
Urinary tract infections (UTIs) remain the common infections diagnosed in outpatients as well as hospitalized patients. Current knowledge on antimicrobial susceptibility pattern is essential for appropriate therapy. Extended-Spectrum beta-Lactamase (ESBL) producing bacteria may not be detected by routine disk diffusion susceptibility test, leading to inappropriate use of antibiotics and treatment failure. The aim of this study was to determine the distribution and antibiotic susceptibility patterns of bacterial strains isolated from patients with community acquired urinary tract infections (UTIs) at Aligarh hospital in India as well as identification of ESBL producers in the population of different uropathogens.
Urinary isolates from symptomatic UTI cases attending to the JN Medical College and hospital at Aligarh were identified by conventional methods. Antimicrobial susceptibility testing was performed by Kirby Bauer's disc diffusion method. Isolates resistant to third generation cephalosporin were tested for ESBL production by double disk synergy test method.
Of the 920 tested sample 100 samples showed growth of pathogens among which the most prevalent were E. coli (61%) followed by Klebsiella spp (22%). The majority (66.66%) of the isolates were from female while the remaining were from male. Among the gram-negative enteric bacilli high prevalence of resistance was observed against ampicillin and co-trimoxazole. Most of the isolates were resistant to 4 or more number of antibiotics. Forty two percent of isolates were detected to produce ESBL among which 34.42 % were E. coli isolates.
This study revealed that E. coli was the predominant bacterial pathogen of community acquired UTIs in Aligarh, India. It also demonstrated an increasing resistance to Co-trimoxazole and production of extended spectrum β-lactamase among UTI pathogens in the community. This study is useful for clinician in order to improve the empiric treatment.
PMCID: PMC1852324  PMID: 17378940
18.  Characterization of Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli Strains Involved in Maternal-Fetal Colonization: Prevalence of E. coli ST131 
Journal of Clinical Microbiology  2013;51(6):1727-1732.
Maternal-fetal Escherichia coli infections, such as neonatal bacteremia and meningitis, are important causes of morbidity and mortality. From 2006 to 2010, we studied newborns and their mothers who were colonized with E. coli in a French hospital in order to document (i) the epidemiology and genetic characteristics of extended-spectrum-beta-lactamase (ESBL)-producing E. coli strains, (ii) the prevalence of associated virulence genes, (iii) the prevalence of clone sequence type 131 (ST131), and (iv) the genetic relationship among ESBL-producing strains. Among the 2,755 E. coli cultures recovered from vaginal or neonatal samples, 68 were ESBL producers (2.46%). We found a wide diversity of ESBL genes, with the majority being blaCTX-M-14, blaCTX-M-1, and blaCTX-M-15, distributed among the 4 main phylogenetic groups. Genes encoding virulence factors were found in 90.7% of the isolates, with ≥2 virulence genes present in 76% of cases. The prevalence of ST131 among ESBL-producing E. coli isolates was 9.4% (6/64). Five of these 6 ST131 isolates possessed blaCTX-M-15 enzymes (and also were resistant to quinolones), and one possessed blaCTX-M-2 enzymes. Two possessed virulence genes, suggesting the presence of pathogenicity island IIJ96 (PAI IIJ96)-like domains. Pulsed-field gel electrophoresis (PFGE) revealed a high level of genomic diversity overall, except for 3 closely related isolates belonging to clonal group ST131. Repetitive PCR showed that the six ST131 isolates were closely related to ST131 control strains (>95% similarity). This study shows a high prevalence of ESBL-producing E. coli strains and clonal group ST131 in the French maternal-fetal population. These results suggest a widespread distribution of ESBL enzymes in the community and highlight the early transmission between mothers and neonates. These findings are worrisome, especially for this particularly vulnerable population.
PMCID: PMC3716058  PMID: 23515552
19.  Phenotypic and Molecular Characterization of Extended-Spectrum β-Lactamase Produced by Escherichia coli, and Klebsiella pneumoniae Isolates in an Educational Hospital 
Extended-spectrum beta-lactamases (ESBLs) are a group of enzymes that hydrolyze antibiotics, including those containing new cephalosporins, and they are found in a significant percentage of Escherichia coli and Klebsiella pneumoniae strains. With the widespread use of antibiotics, difficulties with infection therapy caused by drug resistant organisms, especially those that have acquired resistance to beta-lactams, such as broad-spectrum cephalosporins, have amplified the above-mentioned organisms.
This study was conducted to characterize ESBLs among E. coli and K. pneumonia isolates by molecular and phenotypic methods.
Materials and Methods:
Different strains of E. coli and K. pneumonia were collected from patients with urinary tract infections. The ESBL phenotype was determined by a double disk diffusion test (DDDT). In addition, polymerase chain reaction (PCR) analysis specific for β-lactamase genes of the TEM and SHV family was carried out. The PCR products were run on agarose and examined for DNA bands.
A total of 245 E. coli and 55 K. pneumonia strains were isolated from different samples. In total, 128 of the 300 isolates were confirmed as potential ESBLs producers as follows: 107 (43.67%) E. coli and 21 (38.18%) K. pneumonia. ESBLs genes were found in 24 isolates (18.75%): 21 E. coli and 3 K. pneumonia isolates. The TEM gene was present in 13 (12.14%) E. coli strains, but it was not detected in K. pneumonia. In addition, the SHV gene was present in 8 (7.47%) E. coli and 3 (14.28%) K. pneumonia isolates. Five (4.67%) of the E. coli isolates harbored both TEM and SHV genes. All isolates (100%) were susceptible to imipenem. The lowest rates of resistance to other antibiotics were observed for; piperacillin-tazobactam (6.25%), amikacin (12.5%) and gentamicin (14.84%). The rates of resistance to other antibiotics were as follow: nitrofurantoin (16.4%), nalidixic acid (23.43), co-trimoxazole (25%), cefepime (32%), ciprofloxacin (55.46%), ampicillin (69.53%), ceftazidime (100%), and cefotaxime (100%).
The results of this study indicate the widespread prevalence of ESBLs and multiple antibiotic resistance in E. coli and K. pneumoniae. Therefore, beta-lactam antibiotics and beta-lactamase inhibitors or carbapenems should be prescribed based on an antibacterial susceptibility test.
PMCID: PMC4295312  PMID: 25632322
Phenotypic; Molecular; extended-spectrum β-lactamase (ESBL); Escherichia coli; Klebsiella pneumonia
20.  Spontaneous infective spondylitis and mycotic aneurysm: incidence, risk factors, outcome and management experience 
European Spine Journal  2007;17(3):439-444.
Infective spondylitis occurring concomitantly with mycotic aneurysm is rare. A retrospective record review was conducted in all cases of mycotic aneurysm from January 1995 to December 2004, occurring in a primary care and tertiary referral center. Spontaneous infective spondylitis and mycotic aneurysm were found in six cases (10.3% of 58 mycotic aneurysm patients). Neurological deficit (50% vs. 0; P < 0.001) is the significant clinical manifestation in patients with spontaneous infective spondylitis and mycotic aneurysm. The presence of psoas abscess on computed tomography (83.3% vs. 0; P < 0.001) and endplate destruction on radiography (50% vs. 0; P < 0.001) are predominated in patients with spontaneous infective spondylitis and mycotic aneurysm. Of these six patients, four with Salmonella infection received surgical intervention and all survived. Another two patients (one with Streptococcus pyogenes, another with Staphylococcus aureus) received conservative therapy and subsequently died from rupture of aneurysm or septic shock. Paravertebral soft tissue swelling, presence of psoas abscess and/or unclear soft tissue plane between the aorta and vertebral body in relation to mycotic aneurysm may indicate a concomitant infection in the spine. In contrast, if prevertebral mass is found in the survey of spine infection, coexisting mycotic aneurysm should be considered.
PMCID: PMC2270374  PMID: 18046585
Infective spondylitis; Mycotic aneurysm; Psoas abscess
21.  The Epidemic of Extended-Spectrum-β-Lactamase-Producing Escherichia coli ST131 Is Driven by a Single Highly Pathogenic Subclone, H30-Rx 
mBio  2013;4(6):e00377-13.
The Escherichia coli sequence type 131 (ST131) clone is notorious for extraintestinal infections, fluoroquinolone resistance, and extended-spectrum beta-lactamase (ESBL) production, attributable to a CTX-M-15-encoding mobile element. Here, we applied pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing to reconstruct the evolutionary history of the ST131 clone. PFGE-based cluster analyses suggested that both fluoroquinolone resistance and ESBL production had been acquired by multiple ST131 sublineages through independent genetic events. In contrast, the more robust whole-genome-sequence-based phylogenomic analysis revealed that fluoroquinolone resistance was confined almost entirely to a single, rapidly expanding ST131 subclone, designated H30-R. Strikingly, 91% of the CTX-M-15-producing isolates also belonged to a single, well-defined clade nested within H30-R, which was named H30-Rx due to its more extensive resistance. Despite its tight clonal relationship with H30Rx, the CTX-M-15 mobile element was inserted variably in plasmid and chromosomal locations within the H30-Rx genome. Screening of a large collection of recent clinical E. coli isolates both confirmed the global clonal expansion of H30-Rx and revealed its disproportionate association with sepsis (relative risk, 7.5; P < 0.001). Together, these results suggest that the high prevalence of CTX-M-15 production among ST131 isolates is due primarily to the expansion of a single, highly virulent subclone, H30-Rx.
We applied an advanced genomic approach to study the recent evolutionary history of one of the most important Escherichia coli strains in circulation today. This strain, called sequence type 131 (ST131), causes multidrug-resistant bladder, kidney, and bloodstream infections around the world. The rising prevalence of antibiotic resistance in E. coli is making these infections more difficult to treat and is leading to increased mortality. Past studies suggested that many different ST131 strains gained resistance to extended-spectrum cephalosporins independently. In contrast, our research indicates that most extended-spectrum-cephalosporin-resistant ST131 strains belong to a single highly pathogenic subclone, called H30-Rx. The clonal nature of H30-Rx may provide opportunities for vaccine or transmission prevention-based control strategies, which could gain importance as H30-Rx and other extraintestinal pathogenic E. coli subclones become resistant to our best antibiotics.
PMCID: PMC3870262  PMID: 24345742
22.  Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase. 
We evaluated the pharmacokinetics and therapeutic efficacies of piperacillin and tazobactam, a beta-lactamase inhibitor, given either alone or in different combinations (80:10, 200:10, and 80:25 mg/kg/h), in experimental meningitis due to a strain of Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase. Treatment was administered intravenously as a 7-h constant infusion preceded by a bolus of 20% of the total dose. The mean (+/- standard deviation) rates of penetration into the cerebrospinal fluid (CSF) of infected animals were 6.7 +/- 3.9% for piperacillin given alone and 36.3 +/- 21.9% for tazobactam given alone. Combination treatment significantly magnified the concentration of either drug in CSF. Concentrations of bacteria in CSF increased throughout therapy in animals given either drug alone, even at high dosages. In animals given the combination at dosages of 80:10 and 200/10 mg/kg/h, only a suboptimal reduction of CSF bacterial titers was obtained in vivo, i.e. -0.49 +/- 0.34 and -0.73 +/- 0.49 log CFU/ml/h, respectively. An increase in the tazobactam dosage within the combination (80:25 mg/kg/h) was required in order to obtain a significantly faster elimination of viable organisms from the CSF (-0.97 +/- 0.35 log CFU/ml/h). The study shows that tazobactam is able to provide effective protection against piperacillin hydrolysis by the TEM-3 enzyme within the CSF. Appropriate dosage regimens of various beta-lactam-tazobactam combinations may deserve comparative studies in experimental meningitis caused by organisms producing extended-spectrum beta-lactamases.
PMCID: PMC284425  PMID: 8192442
23.  Surgical treatment of primary aortojejunal fistula☆ 
Primary aortoenteric fistula is a rare clinical situation with a high mortality rate. One should suspect that condition when an abdominal aortic aneurysm is known to be present. We describe the case of a 60 year old man who presented with upper gastrointestinal bleeding as the first and sole manifestation of an abdominal aortic aneurysm, due to the rupture of the aneurysm in the jejunum.
The patient was admitted with hematemesis and melena. He reported no abdominal pain. Upper gastrointestinal endoscopy disclosed no bleeding or lesions of the stomach and duodenum. Bleeding stopped the following day, only to recur 4 days later. The patient was then subjected to abdominal CT scan, which revealed the presence of a subrenal aortic aneurysm, with fistulization to the small intestine. At laparotomy the aortic aneurysm was adherent to the first centimeters of jejunum. The diseased aorta was excised and replaced with a Dacron Y graft in situ.
Primary aortojejunal fistulas are only rarely encountered. They usually are the result of a nonspecific aneurysm of the abdominal aorta. They usually manifest with premonitory bleeding, followed by catastrophic hemorrhage few days later. Even with surgery the mortality rate is high.
Diagnosis of primary aortoenteric fistula requires a high index of suspicion in cases of upper gastrointestinal bleeding, especially when endoscopy is negative and there is no knowledge of the existence of an abdominal aortic aneurysm. CT scan and prompt surgery are crucial to the survival of these patients.
PMCID: PMC3731696  PMID: 23557938
Aortojejunal fistula; Primary; Abdominal aneurysm; Left thoracotomy; Abdominal aneurysm repair
24.  Large Intracranial Aneurysm after Transsphenoidal Surgery for Pituitary Macroadenoma 
Uncontrolled cerebrospinal fluid (CSF) leakage after transsphenoidal surgery (TSS) for pituitary adenoma can lead to meningitis. Intracranial mycotic pseudoaneurysm is a rare complication in central nervous system infection. Large single pseudoaneurysm is more uncommon. Most mycotic aneurysms occur due to endocarditis. The present patient had no heart problem and was infected by CSF leakage after transsphenoidal surgery. We present a case of large ruptured mycotic pseudoaneurysm as a complication of cerebral infection after TSS for pituitary macroadenoma.
PMCID: PMC4024817  PMID: 24851153
Intracranial aneurysm; Transsphenoidal surgery; Pituitary macroadenoma
25.  Extended-Spectrum Beta-Lactamases Producing Escherichia coli and Klebsiella pneumoniae: A Multi-Centric Study Across Karnataka 
There are sporadic reports on detection of extended-spectrum beta-lactamases (ESBL) producers from Karnataka; hence, this is a first multicentric study across Karnataka state to determine the prevalence of ESBL production among clinical isolates of Escherichia coli and Klebsiella pneumoniae.
Aims and objectives:
To determine the prevalence of ESBL producing clinical isolates of E. coli and K. pneumoniae from five geographically distributed centers across Karnataka, to study the susceptibility of ESBL producing isolates to other beta-lactam and beta-lactam-beta-lactamase inhibitors and to demonstrate transferability of plasmids coding for ESBL phenotype.
Materials and Methods:
Two hundred isolates of E. coli and K. pneumoniae each were collected from each of the five centers (Bellary, Dharwad, Davangere, Kolar and Mangalore). They were screened for resistance to screening agents (ceftazidime, cefotaxime, ceftriaxone, aztreonam) and positive isolates were confirmed for ESBL production by test described by Clinical and Laboratory Standards Institute. Co-production of ESBL and AmpC beta-lactamase was identified by using amino-phenylboronic acid disk method. Susceptibility of ESBL producers to beta-lactam antibiotics and beta-lactamase inhibitors was performed. Transferability of plasmids was performed by conjugation experiment.
Overall prevalence of ESBL production among E. coli and K. pneumoniae across five centers of the state was 57.5%. ESBL production was found to be 61.4% among E. coli and 46.2% among K. pneumoniae. ESBL production was significantly more among E. coli than K. pneumoniae. Significant variations in distribution of ESBL across the state was observed among E. coli isolates, but not among K. pneumoniae isolates. All ESBL producers demonstrated minimum inhibitory concentration levels ≥2 μg/ml towards cefotaxime, ceftazidime and ceftriaxone.
Overall prevalence of ESBL production among clinical isolates of E. coli and K. pneumoniae across Karnataka state was high. The prevalence of ESBL production was significantly higher with E. coli than K. pneumoniae isolates. Higher rates of resistance to ceftriaxone and cefotaxime than to ceftazidime suggests the possibility of presence of CTX-M type ESBLs. Of all the beta-lactam/beta-lactamase inhibitor combinations tested, cefepime-tazobactam demonstrated highest in-vitro activity against ESBL producers. There was no statistical difference in the transferability of plasmids among E. coli and K. pneumoniae.
PMCID: PMC3969652  PMID: 24696553
Beta-lactamase; beta-lactamase inhibitor; extended-spectrum beta-lactamases

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