Neutrophils and macrophages are the foot soldiers asserting first major line of defense against most bacterial and fungal infections.

In diabetic patients with higher than normal blood glucose levels (prolonged hyperglycemia) often seen in individuals with inadequately controlled diabetes, this critical element of host defense becomes less effective in prevention and containment of infections. It is important to note that such impairment in host immune defenses makes it more likely for infections to spread locally and systemically (throughout the body) leading to a potential for life-threatening illness, especially if not recognized promptly and managed with appropriate care.

This compromise in neutrophil and macrophage function occurs at various levels of white blood cells’ ability to combat invading bacteria and fungi.

Prominent features in antimicrobial function of neutrophils and macrophages that may be impaired due to prolonged exposure to high blood glucose levels in diabetic patients are mainly due to “altered glucose metabolism” and “oxidative stress“, which is an imbalance between the production of free radicals and body’s ability to detoxify the harmful effects of these free radicals by antioxidants.

Following are the salient known defects in neutrophil and macrophage’s handling of invading pathogens in patients with poorly controlled diabetes:

 

[]  Adhesion of neutrophils to the endothelium (sticking to the inner lining of blood vessels) and migration (leaving the blood vessel and entering the tissue to access the infected area), which is triggered by release of pro-inflammatory signals (cytokine and chemokine, including leukotrienes) by cells that commonly reside in the tissue (Natural killer cells, macrophages, dendritic cells). This initial important step in combating infection becomes less effective in diabetic patients with persistently high blood glucose levels.

 

[] Engulfing (entrapment) of pathogens by neutrophils and macrophages requires “expenditure of cellular energy”. Metabolic changes (such as glycolytic and glutaminolytic pathways) in patients with diabetes impairs such critical function by lowering expendable cellular energy levels and thereby leading to a compromised capacity to effectively ingest invading bacteria and fungi.

 

[] Once the bacteria are ingested (taken inside the cell) the killing mechanisms (intracellular killing) are of utmost significance. Effective “intracellular killing” ensures that ingested pathogens DO NOT find a secure residence inside the cell, which may than make these disease-fighting-cells unwittingly act as “Trojan horse” providing safe (intracellular) sanctuary to pathogens. Production of the key elements for effective intracellular killing of bacteria and fungi include bursts (high level production) of “reactive oxygen radicals”, a response that appears to be stunted in patients with poorly controlled diabetes.

 

[] The natural killer cells provide an important stimulus for neutrophils and more importantly, macrophages for a robust antibacterial response against the ingested pathogens. In patients with poorly controlled diabetes, ineffective activation of natural killer cells in response to invading bacteria and fungi results in suboptimum “chemical signaling” via inadequate release of gamma interferon. The resulting low gamma interferon levels in tissue with bacterial and fungal invasion, weakens white blood cells’ ability to effectively neutralize these potential threats.

 

[] Furthermore, convergence of aforementioned factors and other conditions in such patients may promote “programed cell death” or “apoptosis” among the white blood cells, resulting in premature self-destruction of this sentinel component of a persons’ immune defense.  An important, recently recognized mechanism includes a state of chronic, unimpeded low-grade inflammation in patients with diabetes mellitus resulting from the formation of “advanced glycation endproducts” which by way of RAGE (receptor for advanced glycation endproducts) activation yields to the highly undesirable condition of “sustained low-grade inflammation”. The microenvironment or milieu yielded due to “sustained low-grade inflammation” has been implicated in fostering shortened lifespan (premature self-destruction) of the white blood cells.

 

 

Please take note,

Diabetes is associated with a number of complications and among which, infections are of serious concern. 

Better control of diabetes by a) a significant change in life-style; b) appropriate diet modifications and adjustments; c) and an effective, multifaceted approach towards anti-diabetic therapy can significantly ameliorate these potential complications.

 

 

Safdar A, Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects. Clin Infect Dis. 2011 Oct;53(8):798-806. Review. PubMed PMID: 21890754.

Hodgson K, Morris J, Bridson T, Govan B, Rush C, Ketheesan N. Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections. Immunology. 2015 Feb;144(2):171-85.  Review. PubMed PMID: 25262977.

Alba-Loureiro TC, Munhoz CD, Martins JO, Cerchiaro GA, Scavone C, Curi R, Sannomiya P. Neutrophil function and metabolism in individuals with diabetes mellitus. Braz J Med Biol Res. 2007 Aug;40(8):1037-44. Review. PubMed PMID:
17665039.

Djaldetti M, Salman H, Bergman M, Djaldetti R, Bessler H. Phagocytosis–the mighty weapon of the silent warriors. Microsc Res Tech. 2002 Jun 15;57(6):421-31. Review. PubMed PMID: 12112425.

Urinary tract infections (UTI) are common among women and hospitalized patients with an indwelling urinary catheter like Foley catheter.

A considerable number of patients, mostly in the community are subject to misdiagnosis and may be given unnecessary antibiotic therapy that they DO NOT need.

 

Schulz L, et al, provided the following comprehensive perspective regarding such misconceptions in the diagnosis and management of urinary tract infections:

 

Urine is Cloudy and Smells Bad.

Urine color and clarity or odor by itself are unreliable indicator of UTI and should not be used to start antibiotic therapy.

 

 Urine has Bacteria Present.

The presence of bacteria in the urine on microscopic examination or by culture in patients with no signs or symptoms associated with UTI is not sufficient for the diagnosis of UTI.

Urine may contain bacteria due to contamination; or patients may have “asymptomatic bacteriuria” (described later), which is not uncommon in women of all ages.

 

Possible Contamination of Urine Culture.

In samples with >5 squamous epithelial cells under the microscopic examination suggests the possibility for contamination of urine sample. An attempt should be made to collect a “midstream clean catch” or “straight catheter” urine sample.

 

 Presence of white blood cells (WBC) in urine known as “Pyuria”.

Presence of WBC in urine alone, should not be used make a diagnosis of UTI or start empiric antimicrobial therapy.

A low level increase in urine WBC is seen in patients with dehydration or kidney dysfunction such as renal failure. Similarly, WBC may also be present in urine in conditions associated with presence of blood in the urinary tract.

Acute renal failure, sexually transmitted infections, and noninfectious inflammation of the urinary bladder “cystitis” may also cause WBC to be present in patients’ urine sample.

 

 Urine has Positive Leukocyte Esterase.

Presence of leukocyte esterase alone is not sufficient for establishing diagnosis of UTI and/or commence antibiotic therapy.

As mentioned with pyuria alone, a high positive leukocyte esterase is NOT sufficient by itself for the diagnosis of UTI.

A negative leukocyte esterase in patients with UTI symptoms should prompt a search for other infections such as urethritis, vaginitis, or sexually transmitted infection.

 

Nitrates Present in the Urine.

Urine nitrates should not be used alone to diagnosis or start antimicrobial therapy in any patient population. Presence of nitrates may also reflect presence of “asymptomatic bacteriuria”.

 

 Bacteriuria if not Treated May Progress to a Serious Infection.

Presence of bacteriuria DOES NOT establish diagnosis of UTI. Antimicrobial therapy should not be initiated in asymptomatic patients, with the exception of patients with severe immune dysfunction, kidney transplantation and those with severe neutropenia (very low blood white cell count).

Bacteriuria and pyuria may be seen in elderly nursing home population; and in a good number of these patients these finds occur even in the absence of an infection. Therefore, by itself these findings should not trigger antibiotic therapy.

Asymptomatic bacteriuria has not been associated with “down the road” risk for kidney infection (pyelonephritis), blood borne infection (bacteria or sepsis) or loss of kidney function (renal failure) or high blood pressure (hypertension).

Some exceptions to the above statement are a) pregnancy and b) following urologic procedure with bleeding, such as placement of urinary tract stents and other foreign devices.

 

 Presence of Yeast (Candida) in Urine (Candiduria) Indicates Yeast UTI.

Patients with a urinary catheter may frequently have candiduria, and in most instances this represents colonization or asymptomatic infection.

Treatment of Candida in the urine should be undertaken once diagnosis of infection has been well-established and there is no alternative source of infection.

Patient who exhibit candiduria have a low risk for a widespread (systemic) fungal infection infection such as presence of yeast in the blood circulation called fungemia or candidemia.

Isolation of Candida in a urine sample from a patient without urinary catheter, should raise concerns for vaginal or external contamination.

Patients with severe disorders of immune function, presence of candiduria requires a thorough investigation for the possibility of a local or a systemic infection.

 

 

Please take note,

A positive urine culture without signs and symptoms of UTI known as “asymptomatic bacteriuria” is common in all age groups of women and is frequently over treated with antibiotics.

 

Diagnosis of UTI requires:

1. Presence of clinical signs & symptoms consistent with a urinary tract infection

Plus

1. Laboratory information that highlights presence of a pathogen (bacteria; nitrates) and evidence of inflammation of the urinary tract (pyuria, leukocyte esterase, hematuria).

 

The overuse of antibiotics has been recognized as the leading cause for global spread of antibiotic resistance among common human pathogens. 

Unnecessary antibiotic therapy also underscores the grave concern for the risk of developing serious drug-related adverse events (side effects), which can be life-threatening.

 

 

Schulz L, Hoffman RJ, Pothof J, Fox B. Top Ten Myths Regarding the Diagnosis and Treatment of Urinary Tract Infections. J Emerg Med. 2016 Jul;51(1):25-30.

Nasal colonization or extended residence of Staph in the inner lining of nose has been a well-recognized risk factor for Staph infection in the deeper tissue including wound infections after undergoing surgery.

It is not certain why certain people may develop persistent nasal colonization whereas, most others remain free of such bacterial presence and persistence.

Nurjadi et al recently presented their compelling research, in which they compared individuals with Staph colonization versus those with no evidence of nasal colonization by Staphylococcus aureus. They found a significant difference among immune response in “T cell” or T lymphocyte function.

Persons with a prominent IL17A (a chemical directed response that promotes white blood cell/neutrophil inflammation in the tissue) had a nearly 100% increase in the risk for such colonization; whereas individuals with a prominent interferon-gamma based response had a 35% risk reduction for Staph colonization, which was most likely mediated by higher production of human-beta-defensin-3.

Beta defensin-3 is a “positively charged” antibacterial peptide (the small building blocks of a protein) that are secreted on the epithelial surfaces including the inner lining of nose and provide robust resistance to bacterial colonization (persistent presence). This protection is yielded against the “negatively charged” bacteria. The antibacterial peptide assists in forming pores or holes on outer covering (skin) of the bacteria resulting in eventual bacterial death.

 

Please take note,

Staph colonization of nose should be avoided by adhering to the standards of good hygiene.

Washing hands with soap and water remains the cornerstone for healthy lifestyle.

 

Albeit, the risk for persistent Staph in the nose for some individuals may have a more complex underlying reason;  further research will improve our understanding for these complexities that differentiate the risk of acquiring infection for one person than the other.

 

Nurjadi D, Kain M, Marcinek P, Gaile M, Heeg K, Zanger P. Ratio of T-Helper Type 1 (Th1) to Th17 Cytokines in Whole Blood Is Associated With Human β-Defensin 3 Expression in Skin and Persistent Staphylococcus aureus Nasal Carriage. J Infect Dis. 2016 Dec 1;214(11):1744-1751.