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Abstract

Background

Mismanagement of asymptomatic patients with positive urine cultures (referred to as asymptomatic bacteriuria [ASB] in the literature) promotes antimicrobial resistance and results in unnecessary antimicrobial-related adverse events and increased health care costs.

Methods

We conducted a systematic review and meta-analysis of studies that reported on the rate of inappropriate ASB treatment published from 2004 to August 2016. The appropriateness of antimicrobial administration was based on guidelines published by the Infectious Diseases Society of America.

Results

A total of 2142 nonduplicate articles were identified, and among them 30 fulfilled our inclusion criteria. The pooled prevalence of antimicrobial treatment among 4129 cases who did not require treatment was 45% (95% CI, 39–50). Isolation of gram-negative pathogens (odds ratio [OR], 3.58; 95% CI, 2.12–6.06), pyuria (OR, 2.83; 95% CI, 1.9–4.22), nitrite positivity (OR, 3.83; 95% CI, 2.24–6.54), and female sex (OR, 2.11; 95% CI, 1.46–3.06) increased the odds of receiving treatment. The rates of treatment were higher in studies with ≥100 000 cfu/mL cutoff values compared with <10 000 cfu/mL for bacterial growth ( P , .011). The implementation of educational and organizational interventions designed to eliminate the overtreatment of ASB resulted in a median absolute risk reduction of 33% (range ARR , 16–36%, median RRR , 53%; range RRR , 25–80%).

Conclusion

The mismanagement of ASB remains extremely frequent. Female sex and the overinterpretation of certain laboratory data (positive nitrites, pyuria, isolation of gram-negative bacteria and cultures with higher microbial count) are associated with overtreatment. Even simple stewardship interventions can be particularly effective, and antimicrobial stewardship programs should focus on the challenge of differentiating true urinary tract infection from ASB.

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A positive urine culture for bacteria or fungi, in the absence of symptoms (reported in the literature simply as asymptomatic bacteriuria [ASB] for reasons of convenience [ 1 ]) is a common clinical finding, especially among the inpatient population, the elderly, and patients with indwelling urinary catheters [ 2 ]. Antimicrobial therapy has no role in the majority of cases of ASB, and withholding treatment has no effect in mortality or renal function [ 2 , 3 ]. Moreover, overtreatment of ASB may result in a number of undesirable outcomes, such as disturbance of the intestinal flora that increases the risk for Clostridium difficile infection, antibiotic resistance, and increased health care–associated costs [ 4 , 5 ]. Furthermore, treatment of ASB may eliminate low-virulence strains that suppress the development of uropathogens, thus counterintuitively promoting the development of symptomatic urinary tract infections (UTIs) [ 6 , 7 ].

Coculture assay

Inhibition of viral attachment Virus was preincubated with heparin or d -mannose, at 37°C for 60 min, and was added to Ect1 cell monolayer. The culture was washed 5 times the next day and lysed immediately, and p24 was determined. For treatment with heparitinase, the cells were pretreated with 0.1 U of heparitinase III (Sigma-Aldrich) for 60 min at 37°C, followed by exposure to virus for 16 h. The cells were then thoroughly washed and lysed for determination of p24. Cells without treatment served as controls

Inhibition of viral attachment

HIV-1 infection of epithelial cells The generation and characterization of the Ect1 cell line have been reported elsewhere [ 17 ]. Our preliminary results indicated that the epithelial cells were resistant to cell-free HIV-1 infection. To determine whether the epithelial cells require higher viral input to become infected, Ect1 cells were exposed to an increasing viral input, and the culture supernatants were monitored for production of p24 over a period of up to 13 days after exposure to virus. Figure 1A and 1B show the supernatant viral p24 in Ect1 cells exposed to either RF (a CXCR4-using, synctium-inducing [SI] virus) or BaL (a CCR5-using, non–synctium-inducing [NSI] virus) at increasing viral inputs. With a viral input of 10 or 20 ng/mL p24, which nevertheless resulted in a productive infection of H9 cells or PBMCs (data not shown), there was no appreciable level of p24 detected during the entire period of culture (up to 13 days after exposure to virus). However, with higher viral inputs, we consistently observed increasing levels of p24 in the Ect1 culture, levels that peaked around 9 days after exposure to virus. For example, with RF virus input at 250 ng/mL, the level of p24 increased during the culture period and reached ∼2.3 ng/mL at the peak, 9 days after exposure to virus. We also tested another CCR5 isolate, ADA, and a dual-tropic isolate, 89.6, and found that the profiles of p24 in the culture supernatants, during the time, did not appear to have any relationship with the viral phenotypes (data not shown). Consistent with all the virus isolates tested the levels of p24 were generally significantly lower than those for the input virus, even at the peak

HIV-1 infection of epithelial cells
Figure 1
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Viral production in Ect1 cells or primary keratinocytes. Ect1 cells and or primary keratinocytes were exposed to increasing amounts of RF and or BaL virus overnight at 37°C. The viral production was monitored by measuring supernatant p24 at the indicated time points. Each data point represents mean of duplicate wells, and each virus was repeated at least 3 times. Viral input: RF and ○, 10 ng/mL; ▪, 50 ng/mL; ▴, 250 ng/mL; BaL ○, 20 ng/mL; ▪, 100 ng/mL; ▴, 500 ng/mL

Figure 1
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Viral production in Ect1 cells or primary keratinocytes. Ect1 cells and or primary keratinocytes were exposed to increasing amounts of RF and or BaL virus overnight at 37°C. The viral production was monitored by measuring supernatant p24 at the indicated time points. Each data point represents mean of duplicate wells, and each virus was repeated at least 3 times. Viral input: RF and ○, 10 ng/mL; ▪, 50 ng/mL; ▴, 250 ng/mL; BaL ○, 20 ng/mL; ▪, 100 ng/mL; ▴, 500 ng/mL

To investigate whether this is a phenomenon specifically associated with transformed epithelial cells, monolayers of human primary foreskin keratinocytes were exposed to 10 and 250 ng/mL p24 of RF virus. Again, the profile of production of p24 was similar to that of Ect1 cells, except that much higher levels of p24 were detected in the culture supernatant ( figure 1C ). For example, at 9 days after exposure to virus, 12 ng/mL p24 was detected in Ect1 cell culture exposed to 250 ng/mL p24 of virus. Because of the limited life span of the primary cells, we did not obtain p24 values from cultures >9 days after exposure to virus

Hm, I have to agree with you here. I was intrigued by the info until I read that, which I happen to know is not true. Is it that I am learning new things from this article, or learning fake things?

Please, not trying to be a hard time and correct me if I am wrong, but I believe that the reason animal products have B12, is because they eat grass and soil contaminated with the micro organisms.. So vegans can also get from the same sources, but not already digested once over…

Reply

Jenn,

Sorry, humans can’t process the original sources.

Reply

Stephen,

The USRDA for B12 would not keep a flea alive. If vegan and yeast work for you, that’s great, but I also find stories all over the place of vegans that had to return to meat for health reasons. For me, I have to take 15,000 mcg just to keep most of my symptoms at bay. The FDA recommends 2.5 mcg.

There are a few B12 supplements, though, that say that they are good for vegans (because of not using animal sources, not just because vegans should supplement B12), so vegans should look around.

Reply

ravk says

I am in early 30’s having B12 deficiency, lots of relief after started taking needles or methylcobalamin supplements. It took 7 years for me to figure out the root cause for daily suffering. From few years I am pushing hardly to fullfil daily activities.The symptoms are crystal clear, pains all over body, fatigue, needles pains, sometimes headaches, mucus filled throat, gut problems. when you woke up get ready to go work you feel very tired will push yourself. slowly the day will be better again feel fatigue from evenings. I feel light headed ,no more body pains feeling lot better now. Symptoms mimic lots of other dangerous diseases which you feel like you have all of them when you google them ask doctor to do all those tests. All results will get normal as usual at this young age. but still suffering will be there. It seems like a growing problem.

Reply

barbara says

Hi you sound like me I to have suffered from b12 deficiency all my life and had injections in the past but I would like to know what the count should be as I have just been to my doctor and she wouldn’t do the blood test as the last time I had a test was last year sometime so I am going to ask her for a print out so I will know if it’s low or not and if it’s only a little bit down it still makes a big difference on how you feel they don’t seem to understand this so please can you help me thank you

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