Clostridium difficile-Associated Diarrhea – Reemergence of a Serious Disease and Exploring New Predictors for Treatment Failure

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Clostridium difficile-Associated Diarrhea (CDAD) or Clostridium difficile Infection (CDI) in the past 15 or so years has emerged as a serious challenge due to the following reasons:

 

[] Infections are more commonly seen, especially in older population. Nursing home and other assisted living residents with medical comorbidities are highly vulnerable to this potentially devastating illness.

[] Emergence and global spread of bacterial strains that frequently lead to serious diarrheal illness (hypervirulent strains) have become a commonplace occurrence.

[] The response to treatment is now less than satisfactory to medications that are regarded as standard-of-care, such as oral metronidazole and oral vancomycin.

[] Development of drug resistance among disease causing C. difficile bacteria DO NOT play a role in the noticeable less-than-satisfactory response to conventional drug therapy.

[] Infections recur (come back) after a course of successful therapy at an alarming rate and with each episode of C. diff returned infection, successful therapy becomes even more difficult to achieve.

[] Presently, arbitrary measures and indicators are used to predict response to anti-C. diff therapy, and to assess the risk for infection recurrence. Availability of reliable predictor(s) to evaluate such important parameters is highly desirable.

 

Khanna S, et al, recently published their finding regarding the aforementioned predictors of treatment response in patients with CDI and those individuals at risk for disease recurrence.

The authors postulated that individuals’ “microbial signature” which represents the bacterial flora in the intestinal tract may have an influencing on predicting response to CDI therapy.

Employing high-throughput nucleic acid sequencing analysis they were able to show that patient who had a response to CDI therapy, the risk-index was significantly favorable in the setting of a prominent presence of certain group of bacteria in the intestinal tract such as Ruminococcaceae, Rikenellaceae, Clostridiaceae, Bacteroides, Faecalibacterium and Rothia.

It was also interesting to note that patients who developed recurrent C. diff diarrhea had a different “microbial signature profile” (bacteria that normally reside in the gut). Probability of C. diff diarrhea recurrence (risk index) was significantly higher in patients with an increase intestinal presence of Veillonella, Enterobacteriaceae, Streptococci, Parabacteroides and Lachnospiraceae.

 

Please take note,

C. diff diarrhea has reemerged as a serious healthcare concern for patients in hospitals and older patients in the community and hospital alike.

Treatment response to CDI illness have declined over the past two decades. Newer treatment modalities are increasingly being sought to treat these difficult-to-treat infections.

More research is needed to validate “microbial signature profile” that may reliably predict and identify patients in whom, the risk for treatment failure is higher than general population. In concert, such profile analysis may also assist in recognizing individuals in advance, who may exhibit a higher probability of infection recurrence following initial successful anti-C. diff therapy. 

 

 

Khanna S, Montassier E, Schmidt B, Patel R, Knights D, Pardi DS, Kashyap PC. Gut microbiome predictors of treatment response and recurrence in primary Clostridium difficile infection. Aliment Pharmacol Ther. 2016 Oct;44(7):715-27.

Siegfried J, Dubrovskaya Y, Flagiello T, Scipione M, Chen D, Phillips M, Papadopoulos J, Safdar A. Initial therapy for mild to moderate Clostridium difficile infection (CDI): exploring the role of oral metronidazole vs. vancomycin in 168 hospitalized patients. Infectious Diseases in Clinical Practice 2016;24:210-216.

Penziner S, Dubrovskaya Y, Press R, Safdar A. Fidaxomicin therapy in critically ill patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2015 Mar;59(3):1776-81.

Clutter DS, Dubrovskaya Y, Merl MY, Teperman L, Press R, Safdar A. Fidaxomicin versus conventional antimicrobial therapy in 59 recipients of solid organ and hematopoietic stem cell transplantation with Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother. 2013 Sep;57(9):4501-5.

 

 

Common misconceptions about urinary tract infection

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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.

Pneumonia in older patients continues to be a serious illness

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Pneumonia that starts at home is called “community acquired pneumonia” or “CAP”.   This is a serious and potentially life-threatening infection that often requires admission to a hospital.

It is a well-known fact that risk and complications of pneumonia increase with advancing age.

The potential for a favorable impact on the incidence (frequency) and outcome of CAP in the current era with advances in medical care as stated below remains unclear:

  1. easy accessibility to medical care in most communities
  2. advances in infection management including new antibiotics, intensive care medicine, among others
  3. and importantly, infection prevention by more effective, new generation of vaccines

 

Centers for Disease Control and Prevention evaluated community-acquired pneumonia in 2,320 adults residing in Chicago and Nashville between 2010 and 2012. They reported patients with CAP had a median age of 57 years. A large number of patients with pneumonia had underlying chronic lung disease (42%), chronic heart disease (35%) and/or diabetes (26%).

Among those who required hospitalization for CAP, one fifth of patients (21%) needed urgent treatment in the intensive care unit. Deaths were observed in 2% of patients.

The yearly frequency of pneumonia in these two cities during the study years was 25 cases per 10,000 adults. However, the rate got substantially higher with increasing age; 63 cases per 10,000 adults among individuals age 65 to 79 years, and rose to an alarming 164 cases per 10,000 adults for individuals 80 years of age or older.  Need for hospitalization was highest among the oldest patients with community acquired pneumonia.

 

Please take note,

Strep pneumonia (Streptococcus pneumoniae) or pneumococcus is the most common cause of bacterial pneumonia and like influenza, this is a vaccine preventable illness.

Pneumonia acquired at home remains a serious and a daunting challenge, especially in old patients.

Underutilization of the new effective vaccines require urgent attention.

 

Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, et al; CDC EPIC Study Team. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27.

Why Staph may persist in the nose of certain individuals

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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.

Potential for severe Staph infection during and/or after recovering from Influenza

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Staphylococcus aureus, commonly known as “Staph” including, now widespread variety known as MRSA (drug-resistant Staph) can lead to serious pneumonia with invasion and spread via blood flow to almost all body parts. Secondary bacterial pneumonia after a serious respiratory viral infection is a well-known fact.

 

In a recent study, Reddinger et al have demonstrated a possible mechanism for this increased risk of developing Staph infection while infected with influenza virus in mice.

Influenza created an environment (milieu) for Staph to easily penetrate from the lining of respiratory tract (colonization) resulting in the invasion of lung tissue.

During influenza infection, hosts’ response to the viral infection resulted in fever (high core temperature), local release of norepinephrine, APT (the energy currency at the cellular level) and higher glucose concentration along and below the lining of respiratory tract. These factors significantly facilitated Staph’s ability to gain access of the deeper tissues including lungs, resulting in severe pneumonia.

 

Please take note,

Influenza is a vaccine preventable illness.

Getting a flu shot not only protects against developing serious influenza infection, it may also lend protection against subsequent or concommitent bacterial pneumonia, especially Staph pneumonia that is, in most cases a devastating illness.

 

Reddinger RM, Luke-Marshall NR, Hakansson AP, Campagnari AA. Host Physiologic Changes Induced by Influenza A Virus Lead to Staphylococcus aureus Biofilm Dispersion and Transition from Asymptomatic Colonization to Invasive Disease. MBio. 2016 Aug 9;7(4). pii: e01235-16. doi: 10.1128/mBio.01235-16. PubMed PMID: 27507829; PubMed Central PMCID: PMC4981728.