Infectious

Infectious Diseases

د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Tafenoquine is an 8-aminoquinoline drug manufactured by GlaxoSmithKline that is currently being investigated as a potential treatment for malaria, as well as for malaria prevention.
The main advantage of tafenoquine is that it has a long half-life and therefore does not need to be taken as frequently as primaquine. Like primaquine, tafenoquine causes haemolysis in people with G-6-PD deficiency.
The dose of tafenoquine has not been firmly established, but for the treatment of vivax malaria, a dose of 800 mg over three days has been used.
Tafenoquine

• A large study finds that a single oral dose of azithromycin can be curative in patients with early syphilis.
• Even after all these years, a single dose of intramuscular penicillin G remains the preferred treatment for early-stage syphilis. The usual alternative, oral doxycycline, is problematic because several weeks of treatment are needed, and poor patient adherence can compromise efficacy.



Treating Syphilis Without Penicillin

In a multinational randomized nonblinded trial, 517 nonpregnant, HIV-negative adults with primary, secondary, or early latent syphilis received benzathine penicillin G (2.4 million units administered in 2 intramuscular injections) or azithromycin (2 g, administered as four 500-mg tablets). After 6 months, about 75% of patients in each group were judged as cured by the usual serologic standard of a drop in rapid plasma reagin (RPR) titer of 2 dilutions. Four patients had clear treatment failure with a significant rise in RPR titers; all had received azithromycin.

Comment: Single-dose azithromycin is an attractive treatment option for syphilis: It can be given under observation, is generally well tolerated, and can also be effective against chancroid, chlamydia, and gonorrhea. This study adds to the evidence that it works for syphilis, but concerns remain. Among them: efficacy in HIV infection, efficacy in pregnancy, and the observation that a mutation encoding for macrolide resistance is rapidly emerging in Treponema pallidum isolates.
Published in Journal Watch General Medicine June 17, 2010

• Polymerase Chain Reaction vs. Blood Culture in Sepsis

• Correlation with sepsis severity parameters was better for PCR than for blood culture; in patients with sepsis, concordance between the two methods was modest.
• In patients with sepsis, rapid initiation of adequate antibiotic therapy is a key component of therapy. Empirical therapy with broad-spectrum antibiotics is used until the causative pathogen is identified. Polymerase chain reaction (PCR)-based detection systems could markedly shorten the time to pathogen identification, thus hastening the start of targeted antibiotic therapy. But how well do such PCR-based systems perform?



To find out, researchers in Germany — sponsored by industry — compared results of a whole-blood bacterial and fungal DNA multiplex PCR system with conventional blood culture (BC) in 142 surgical patients with severe sepsis or septic shock and 63 surgical patients with no signs of infection (controls). Blood samples were obtained for 3 days following study inclusion (patients with sepsis) or admission (controls).

Among controls, 1.6% of BCs and 4.8% of PCRs were positive at baseline, but none of these positives were confirmed by a positive result using the alternative technique. Among patients with sepsis, these rates were 17.8% and 33.1%; the sensitivity and specificity of PCR to detect culture-positive bacteremia were 0.80 and 0.77, respectively. PCR detected 70.3% of microorganisms identified by BC, whereas BC detected 21.4% of those identified by PCR. Overall, PCR-suspected infections were microbiologically confirmed from blood (in 23%) or a focus of infection (in 38%); BC-positive cases were confirmed in 42% from the site of infection. Positive PCR results correlated significantly with elevated procalcitonin and interleukin (IL)-6 levels and with greater organ dysfunction scores; positive BCs were significantly associated only with higher IL-6 levels.

Comment: For patients with sepsis, PCR appears to provide more information on causative pathogens than conventional BCs, possibly by avoiding false-negative results if antibiotics have been initiated before specimens are obtained. Nevertheless, PCR results must be interpreted with caution. Furthermore, PCR has a significant shortcoming: It yields no information on susceptibility results yet.
Published in Journal Watch Infectious Diseases March 10, 2010

Researchers focused on randomized, placebo-controlled trials of corticosteroids for sore throat that were published between 1966 and 2008.
Most participants received antibiotics, and concomitant use of other medications was generally permitted but not controlled. The overall study quality was moderate.
There were no major adverse effects associated with study treatments.
There were a total of 413 patients in 5 trials of adults. The trials examined different corticosteroids, and 4 studies used intramuscular corticosteroids. 4 trials used a visual analog scale to measure throat pain.


Corticosteroids were significantly effective in reducing sore throat in adults. They reduced pain from 4 to 11.8 hours faster vs placebo and were associated with complete pain relief in 24.4 to 28.2 hours.
3 trials examined 393 children, with an average age of participants of 8 to 11 years. All trials tested oral dexamethasone at a single dose of 0.6 mg/kg.
All included research in children found a significant benefit of corticosteroids for sore throat, with an earlier reduction in pain that ranged from 5.1 hours to 1 day.
1 trial found that dexamethasone for 3 days was not superior to a single dose of dexamethasone.

Corticosteroids failed to improve absence rates from school or work in 3 studies.

Subgroup analysis based on results of bacterial tests from the throat provided inconsistent results. Some research suggested that corticosteroids were more effective among patients with positive tests, whereas other analyses found the opposite.

In a previous meta-analysis, antibiotics for sore throat were associated with reduced rates of rheumatic fever, sinusitis, and otitis media, but there were not enough cases to demonstrate efficacy in preventing glomerulonephritis. Antibiotics also reduced throat pain and fever by approximately one half.
In the current systematic review, corticosteroids were effective in relieving pain in acute pharyngitis, although treatment expedited pain relief by only 4 to 24 hours vs placebo.
Medscape CME 01/19/2010

Staphylococcus Epidermidis: Stick It up Your Nose?

Certain strains of Staphylococcus epidermidis inhibit nasal S. aureus colonization, and their introduction into the nares may prevent recurrent infections.
Nasal colonization with Staphylococcus aureus (SA) is prevalent in 20% to 40% of the general population; SA infections of the skin (and other sites) typically originate from this locus. Prospective studies in healthy people demonstrate that nasal carriage is persistent in some and intermittent in others, and many are never colonized, but why is unclear. Results of a study in 88 college students (32% SA carriers) suggest how SA colonization might be averted or eliminated.

The investigators evaluated whether S. epidermidis (SE), the most common commensal bacterium found in the nasal cavity, inhibits SA. Some strains of SE express a serine protease that destroys SA biofilms. In the study cohort, nasal carriage of SA was 19% in those who also carried ESP-secreting SE and 44% in those who did not. Furthermore, daily inoculation of Esp-secreting SE into the noses of SA carriers eliminated SA in seven of eight subjects. Inoculation of the pure serine protease reduced but did not completely eliminate the SA population in three students. Co-culture of SA with the serine protease for 1 year did not promote the emergence of resistance.

Comment: The current approach to reducing the S. aureus population in nasal carriers with recurrent SA skin infections is application of topical mupirocin in the nares 5 days every month. Unfortunately, some SA are resistant to mupirocin. These results suggest that deliberate colonization with serine protease–producing strains of S. epidermidis is a promising approach. Alternatively, use in the nose of the serine protease itself might reduce or eliminate SA carriage.
Published in Journal Watch Dermatology June 11, 2010


Skin and Soft Tissue Infections in Immunocompetent Patients Reviewed
especially community-acquired methicillin-resistant Staphylococcus aureus (MRSA),
Purulent types of SSTI include abscess, folliculitis, furuncle, and carbuncle. An abscess is a collection of pus within the dermis, associated with erythema and fluctuance, of polymicrobial cause, often involving skin flora (staphylococci and streptococci) and organisms from adjacent mucous membranes. An abscess is characterized as a complicated SSTI if the perianal or perineal areas are affected.

Folliculitis is defined as purulence limited to the epidermis, usually in body areas prone to friction and heavy perspiration. A furuncle is purulence surrounding the hair follicles and extending to subcutaneous tissue, and a carbuncle is the coalescence of several furuncles. In immunocompetent patients, these types of SSTIs are caused by S aureus.

Nonpurulent SSTIs include cellulitis, erysipelas, and impetigo. Cellulitis has a well-demarcated border of erythema, warmth, edema, and pain, caused by streptococci without abscess formation or staphylococci with abscess. Complications may include lymphangitis, necrotizing infections, or gangrene.
Erysipelas is associated with intense erythema and a well-demarcated, painful plaque caused by beta-hemolytic streptococci. Impetigo is characterized by crusted exudates with pustules or vesicles, often seen in preschool-aged children or under conditions of poor hygiene, high humidity, or warm temperature.

Treatment Options

The main treatment of uncomplicated abscesses measuring less than 5 cm in diameter is surgical drainage alone. Outcomes are similar when wounds are irrigated with tap water or sterile water.
Fever, tachycardia, hypotension, or other signs of systemic infection are red flags warning of the need for inpatient treatment. For patients with life-threatening or rapidly advancing infections, urgent surgical referral is required.

Local resistance and susceptibility patterns should determine choice of antimicrobial agents when these are indicated. For uncomplicated SSTIs without focal coalescence or trauma, beta-lactam antibiotics are the first-line treatments in settings where suspicion is low for MRSA.

When empiric coverage for MRSA is indicated for uncomplicated SSTIs, oral agents are preferred (eg, tetracyclines, trimethoprim/sulfamethoxazole, and clindamycin). In hospitalized patients, vancomycin is the first-line agent for MRSA. Linezolid, daptomycin, tigecycline, and other newer agents should be given only to patients who are refractory to or cannot tolerate vancomycin.

To date, evidence is insufficient to support use of nasal mupirocin or antibacterial body washes to eradicate the carrier state in patients with MRSA or their contacts. The mainstay of MRSA prevention is proper and frequent handwashing as well as other standard infection-control precautions.

Key Recommendations

Specific key clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:
In patients with uncomplicated SSTIs, wound and blood cultures are not needed because results rarely change management decisions (level of evidence: C, based on retrospective analyses).
For uncomplicated SSTIs with abscesses measuring less than 5 cm in diameter, incision and drainage alone is often curative (level of evidence: A, based on retrospective chart review and randomized, double-blind trials).


For surgical drainage of SSTIs, clinical outcomes are no different for wound irrigation with tap water vs sterile water (level of evidence: A, based on prospective trials from urban pediatric emergency departments).
Clinicians should consider local prevalence and resistance patterns of MRSA and other pathogens when starting empiric antimicrobial therapy for uncomplicated SSTIs (level of evidence: C, based on expert opinion).
Eradicating the MRSA carrier state does not appear to be associated with a lower incidence of clinical MRSA infection (level of evidence: A, based on a randomized, double-blind trial and Cochrane review).

"Standard infection control precautions should be implemented and encouraged for all patients in ambulatory and inpatient settings, including proper and frequent handwashing, use of gloves when managing wounds, and contact precautions (e.g., use of gowns and gloves, grouping patients with similar infections) for patients with known or suspected MRSA infections," Dr. Breen concludes. "To prevent SSTIs, current consensus guidelines support proper foot care among patients with diabetes, tinea pedis, or pedal edema from venous insufficiency or lymphedema."
Am Fam Physician. 2010

Single-Dose Therapy for Visceral Leishmaniasis

A single infusion of liposomal amphotericin B was not inferior to a 15-dose regimen of amphotericin B deoxycholate.
Despite impressive cure rates for several antileishmanial agents, lengthy treatment courses limit the appeal of these therapies. In recent clinical trials, high cure rates have been seen with a 5-day course of liposomal amphotericin B. This finding, coupled with a price reduction for this antimicrobial in developing countries, prompted evaluation of even shorter courses of therapy.

In an open-label trial, 410 patients with visceral leishmaniasis, or kala-azar, were randomized to receive a single infusion of liposomal amphotericin B (10 mg/kg) or 15 alternate-day infusions of amphotericin B deoxycholate (1 mg/kg; conventional therapy). The trial was conducted in northeastern India, which is home to approximately 50% of such patients worldwide. Participants — aged 2 to 65 years — were evaluated at 30 days postenrollment for apparent cure (i.e., absence of fever, clinical improvement, reduction in spleen size, and a splenic-aspirate score of 0) and then at 6 months for cure (being healthy, with no signs or symptoms of relapse).

All 304 patients in the liposomal-therapy group and 106 (98%) of 108 in the conventional-therapy group had apparent cure at 30 days postenrollment. At 6 months, cure rates were similar between groups: 95.7% (95% confidence interval, 93.4%–97.9%) and 96.3% (95% CI, 92.6%–99.9%), respectively. No serious adverse events were reported in either group. The estimated treatment costs were higher for amphotericin B deoxycholate than for liposomal amphotericin B (US$436 vs. $162).

Comment: The availability of a new preferential price agreement for liposomal amphotericin B in developing countries was key in the decision to conduct this trial. The results are impressive and should prompt a reevaluation of current treatment strategies for kala-azar.

Steroids for Pneumococcal Meningitis?

Although guidelines recommend routine use of adjunctive dexamethasone for adults with pneumococcal meningitis in high-income countries, clinical trials involving this practice have shown conflicting results, and the benefit remains unclear. Now, researchers have compared outcomes between adults (age, >16 years) in the Netherlands who received care for community-acquired pneumococcal meningitis between March 2006 and January 2009 (after implementation of these recommendations) and those who received such care between 1998 and 2002.

Using records from the Netherlands Reference Laboratory for Bacterial Meningitis, the researchers identified 352 eligible episodes of pneumococcal meningitis in 1998–2002 and 357 in 2006–2009. Clinical characteristics at admission and antibiotic treatment were similar between groups. Adjunctive dexamethasone was administered in 17% of episodes in 1998–2002 and 92% of those in 2006–2009. Compared with episodes in the earlier period, episodes in the later period were associated with significantly lower rates of neurological complications (60% vs. 75%), seizures (17% vs. 24%), cranial nerve palsy at discharge (17% vs. 28%), hearing impairment (12% vs. 22%), and death (20% vs. 30%).


Comment: These findings stem from a comparison of outcomes during different time periods in a high-income country. Still, they provide further support for the use of dexamethasone in adult patients with presumed pneumococcal meningitis in such countries.
Published in Journal Watch Infectious Diseases September 29, 2010

• Pyronaridine-Artesunate: Efficacious Against Falciparum Malaria

• In a clinical trial, this combination was as efficacious as artemether-lumefantrine for treating uncomplicated falciparum malaria.
• Artemisinin-based combination therapy is recommended for treating falciparum malaria, but the commonly used artemether-lumefantrine (AL) requires twice-daily dosing and a fatty meal to maximize absorption. Now, with partial industry support, investigators have conducted a phase III, double-blind, noninferiority trial to compare AL with another oral fixed-dose combination, pyronaridine-artesunate (PA).



A total of 1272 patients with uncomplicated falciparum malaria in Africa and Southeast Asia (44% aged 5–12 years; none aged <5 years) were randomized in a 2:1 ratio to receive a 3-day course of PA or AL. Dose was based on body weight. Patients were hospitalized for days 0–3 and followed through day 42. Polymerase chain reaction (PCR) analysis of blood samples obtained pre- and posttreatment was used to distinguish between reinfection and recrudescence.

In the per-protocol population, PCR-corrected adequate clinical and parasitological response rates were similar between PA and AL recipients at day 28 (99.5% and 99.2%, respectively). At day 42, this rate was significantly better with PA than with AL (93.2% vs. 88.1%).
In the intent-to-treat population, 95.5% of PA-group patients and 57.1% of AL-group patients cleared their parasites by 48 hours after the first dose. Reinfection rates at days 28 and 42 were significantly higher in the AL group than in the PA group; recrudescence rates were similar between groups at both time points.

No serious adverse events were attributed to the study treatments. The proportion of participants with drug-related adverse events was similar between groups, but transient increases in liver enzymes ( 5 times the upper limits of normal) were noted in 0.9% of PA-group patients and 0.5% of AL-group patients.

Comment: PA is highly efficacious for treating uncomplicated falciparum malaria. The lower rate of reinfection at day 42 in PA recipients may be attributable to pyronaridine's long half-life. As noted by the authors and an editorialist, efficacy may be lower in young children, who have less-well-developed immunity to malaria. (Children aged <5 years were not included in the study.) The once-daily dosing and low cost (<US$1.00 for adults and <$0.50 for children) make PA attractive, although the issue of elevated liver enzymes in a few recipients warrants scrutiny.
Published in Journal Watch Infectious Diseases May 5, 2010

Septic Shock, Insulin, and Steroids — Revisited

Intensive insulin therapy did not lower in-hospital mortality in septic shock patients who received hydrocortisone.
In a study published in 2002, patients with septic shock and impaired adrenal reserve appeared to benefit from 7-day courses of hydrocortisone (50 mg every 6 hours) plus the mineralocorticoid fludrocortisone (JW Gen Med Aug 30 2002). In contrast, hydrocortisone alone was not beneficial in the 2008 CORTICUS trial (JW Gen Med Jan 9 2008). Because patients in the 2002 trial were sicker and were treated earlier than those in CORTICUS, some experts still recommend low-dose hydrocortisone for patients with severe sepsis and refractory hypotension.


That hydrocortisone invariably induces hyperglycemia raises another question: Is intensive insulin therapy appropriate for hydrocortisone-treated patients with septic shock? To answer this question, researchers in France randomized 509 such patients to receive either intensive insulin therapy (target glucose level, 80–110 mg/dL) or usual care (target glucose level, around 150 mg/dL). In addition, to examine whether mineralocorticoid therapy is beneficial, the

researchers randomized the same patients to receive or not to receive fludrocortisone in a 2x2 factorial design. The outcome: Overall in-hospital mortality was 44%; neither intensive insulin nor fludrocortisone lowered mortality or any of numerous secondary endpoints.

Comment: In this multicenter study of hydrocortisone-treated patients with septic shock, intensive insulin therapy did not improve outcomes. An editorialist notes that
• mean glucose levels in intensively treated patients fell short of the intended target, reaching only about 120 mg/dL, which was not markedly different from the mean glucose level (about 150 mg/dL) of the control group; and
• the trial was underpowered to identify small differences in mortality.

Thus, she calls for a much larger trial. My own sense, however, is that intensive glycemic control is not the magic bullet that will improve outcomes in septic shock patients and that research should be directed toward other pathophysiologic mechanisms.
Published in Journal Watch General Medicine February 4, 2010

Hospital-acquired infections are most commonly associated with invasive medical devices or surgical procedures. Lower respiratory tract and bloodstream infections are the most lethal; however, urinary tract infections are the most common.
Recent data from the U.S. National Healthcare Safety Network indicate that gram-negative bacteria are responsible for more than 30% of hospital-acquired infections, and these bacteria predominate in cases of ventilator-associated pneumonia (47%) and urinary tract infections (45%).
NEJM May 13, 2010

In intensive care units (ICUs) in the United States, gram-negative bacteria account for about 70% of these types of infections, and similar data are reported from other parts of the world. A range of gram-negative organisms are responsible for hospital-acquired infections, the Enterobacteriaceae family being the most commonly identified group . Unfortunately, multidrug-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter baumannii, and extended-spectrum β-lactamase (ESBL)–producing or carbapenemase-producing Enterobacteriaceae, are increasingly being reported worldwide.

Mechanisms of Resistance in Gram-Negative Bacteria, and the Antibiotics Affected. Seven mechanisms of resistance are shown in the gram-negative bacterium, with some being mediated by a mobile plasmid. These mechanisms include the loss of porins, which reduces the movement of drug through the cell membrane; the presence of β-lactamases in the periplasmic space, which degrades the β-lactam; increased expression of the transmembrane efflux pump, which expels the drug from the bacterium before it can have an effect; the presence of antibiotic-modifying enzymes, which make the antibiotic incapable of interacting with its target; target site mutations, which prevent the antibiotic from binding to its site of action; ribosomal mutations or modifications, which prevent the antibiotic from binding and inhibiting protein synthesis; metabolic bypass mechanisms, which use an alternative resistant enzyme to bypass the inhibitory effect of the antibiotic; and a mutation in the lipopolysaccharide, which renders the polymyxin class of antibiotics unable to bind this target.

Pneumonia

Hospital-acquired pneumonia is the most common life-threatening hospital-acquired infection, and the majority of cases are associated with mechanical ventilation. Ventilator-associated pneumonia occurs in approximately 10 to 20% of patients who are on ventilators for longer than 48 hours and is associated with significant increases in length of hospital stay, mortality, and costs.9


Gram-negative organisms predominate in hospital-acquired pneumonia, particularly
P. aeruginosa, A. baumannii, and the Enterobacteriaceae.8 Between 1986 and 2003, acinetobacter species were the only gram-negative organisms that increased significantly as a cause of pneumonia in ICUs in the United States.8

Unfortunately, the resistance of these organisms to antibiotics, particularly to carbapenems, has posed important therapeutic challenges. In a recent survey, 26.4% of 679 P. aeruginosa isolates and 36.8% of 427 A. baumannii isolates that caused ventilator-associated pneumonia were resistant to carbapenems (imipenem or meropenem). Similar data have been reported from other parts of the world, with countries such as Greece reporting rates of carbapenem resistance of up to 85% among ICU isolates. Of greatest concern are reports of infections caused by organisms that are resistant to all currently available antibiotics, including the polymyxins.

A more recent clinical entity that physicians need to be aware of is health care–associated pneumonia — that is, cases of pneumonia acquired in the community by patients who have had direct or indirect contact with a health care or long-term care facility and are subsequently hospitalized. Such patients are more likely to have a coexisting illness and to receive inactive empirical antibiotic therapy and are at greater risk for death than patients who have true community-acquired pneumonia.

Apart from being associated with increased morbidity and mortality, suspected hospital-acquired pneumonia in the ICU can lead to the inappropriate use of antibiotic drugs, contributing to bacterial drug resistance and increases in toxic effects and health care costs. To optimize the appropriateness of antibiotic use, physicians must be aware of the management paradigms for hospital-acquired pneumonia .

The diagnosis of ventilator-associated pneumonia remains challenging, with no easily obtained reference standard. Apart from clinical criteria, microbiologic assessment is important to help guide therapy. For patients in whom ventilator-associated pneumonia is suspected, a sample from the lower respiratory tract should be obtained by means of endotracheal aspiration, bronchoalveolar lavage, or a protected specimen brush (depending on the resources available) for microscopy and culture before antibiotics are administered. Although each sampling method has its limitations, the most important point is to obtain the sample in a timely manner.

The alternative techniques appear to be associated with similar outcomes, on the basis of recent systematic reviews. When the patient is severely ill, the administration of empirical antibiotic therapy should not be delayed on account of the diagnostic procedure.

To assist the treating physician in determining whether a cultured organism signifies colonization or infection, it has been recommended that quantitative cultures be obtained, either by measuring the colony-forming units (CFU) per milliliter or by grading the bacterial growth as light, moderate, or heavy (semiquantified approach). In bronchoalveolar-lavage fluid, a cutoff value of less than 104 CFU per milliliter is more likely to indicate colonization; however, this information needs to be interpreted on the basis of the patient's clinical state.

Quantitative culture results are subject to possible sampling variability, and there is no evidence that quantitative cultures, as compared with qualitative cultures, are associated with reductions in mortality, the length of the ICU stay, the duration of mechanical ventilation, or the need to adjust antibiotic therapy.20 Nevertheless, quantitative cultures are more helpful in differentiating between colonization and true infection and thus are less likely to lead to unnecessary antibiotic therapy.

To further improve such differentiation in patients with ventilator-associated pneumonia, promising biomarkers are being studied in combination with clinical and microbiologic factors. These biomarkers include procalcitonin, C-reactive protein, and soluble triggering receptor expressed on myeloid cells.
Once a diagnosis of pneumonia has been made, empirical antibiotic therapy needs to be tailored to the institution's microbial ecology and the length of time the patient was in the hospital before pneumonia developed.

With a hospital stay of 5 days or longer, as compared with a shorter stay, the patient is at greater risk for infection with more resistant pathogens, and empirical treatment with broad-spectrum antimicrobial agents should be prescribed (see discussion of treatment below). Growing evidence suggests that early, appropriate antibiotic therapy improves outcomes, and such therapy should therefore be a goal; however, this strategy needs to be coupled with an early reassessment of both diagnosis and therapy, usually within 48 to 72 hours.


In the majority of cases, the antibiotic coverage can then be reduced to a more targeted regimen based on the results of respiratory cultures or even discontinued, if an alternative diagnosis is identified. When respiratory cultures are not available, therapy needs to be tailored to the most likely causative organisms for the given institution, with close monitoring for clinical failure, recently defined as lack of improvement in the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen and persistence of fever after 3 days of treatment.

When definitive antibiotic therapy is warranted, a relatively short course (8 days) should be prescribed for patients with uncomplicated ventilator-associated pneumonia who receive appropriate antibiotic therapy initially. For patients infected with nonfermenting gram-negative organisms such as P. aeruginosa, however, the rate of relapse is higher with short-course therapy, and thus the longer course of therapy (15 days) should be prescribed.

Finally, the importance of preventive measures for ventilator-associated pneumonia deserves specific mention, particularly a bundled approach .Institutions that adhere to such measures report a significant reduction in the rates of ventilator-associated pneumonia.

Bloodstream Infection

Infection of the bloodstream remains a life-threatening occurrence and is most commonly associated with the presence of a central vascular catheter but may also be associated with a gram-negative infection in other areas of the body, such as the lung, genitourinary tract, or abdomen. Approximately 30% of hospital-acquired bloodstream infections in ICUs in the United States are due to gram-negative organisms, although this proportion is lower when hospital-wide data are examined.

The most common organisms include klebsiella species, Escherichia coli, enterobacter species, and P. aeruginosa. As described above for organisms that cause hospital-acquired pneumonia, resistance is an emerging problem, particularly resistance against extended-spectrum cephalosporins and carbapenems. For example, of bloodstream isolates of Klebsiella pneumoniae from hospitals throughout the United States, 27.1% (from 483 isolates tested) were resistant to third-generation cephalosporins and 10.8% (from 452 isolates tested) were resistant to carbapenems.

The most recent challenge has been the spread of carbapenemase-producing Enterobacteriaceae. The β-lactamase responsible for this phenotype, also known as K. pneumoniae carbapenemase, or KPC, confers reduced susceptibility to all cephalosporins (including cefepime), monobactams (aztreonam), and the carbapenems.30 Carbapenemase-producing Enterobacteriaceae have now been identified in hospitals in at least 20 states in the United States, as well as in other parts of the world.

The genetic relatedness of the strains responsible for outbreaks within and between countries highlights the importance of strict infection control to prevent ongoing dissemination. These β-lactamases are encoded on mobile genetic elements, mostly plasmids and transposons, which probably explains their spread among gram-negative genera.

Furthermore, they often coexist with other resistance genes, including the most widespread of the ESBLs (the blaCTX-M-15 gene), aminoglycoside-resistance determinants, and plasmid-mediated quinolone-resistance genes (qnrA and qnrB), thus leaving the physician with few therapeutic options. As has been described for the nonfermenting gram-negative organisms, K. pneumoniae strains that are resistant to all currently available antibiotics, including the polymyxins, have been reported.

As with hospital-acquired pneumonia, delays in the administration of appropriate antibiotic therapy are associated with excess mortality among patients with hospital-acquired bloodstream infection,32 although the data reflect predominantly gram-positive infections. Data on the clinical effect of initial therapy for gram-negative bloodstream infection are more heterogeneous.

Empirical antibiotic coverage for gram-negative bacteria should be considered for patients who are immunosuppressed, those in the ICU, those with a femoral catheter, those with gram-negative bacterial infection at another anatomical site (particularly the lung, genitourinary tract, or abdomen), and those with other risk factors for resistant organisms .


Moreover, patients who present at the hospital with suspected bloodstream infection who have health care–associated risk factors should be treated initially with broad-spectrum empirical antibiotics, pending the results of blood cultures. Detailed guidelines for the management of central vascular catheter–related bloodstream infections have recently been published.

Prevention of bloodstream infections associated with central catheters is of paramount importance. Adherence to evidence-based interventions has proved highly successful ,and hospitals worldwide should be adopting such cost-effective, preventive measures. Evidence is also emerging in support of other interventions, such as the use of catheters impregnated with an antiseptic, an antibiotic, or both36 or the use of chlorhexidine-impregnated dressings37; however, when the described interventions for best practice are adhered to, the cost-effectiveness of these interventions is less clear.

Urinary Tract Infection

Gram-negative organisms predominate in hospital-acquired urinary tract infections, almost all of which are associated with urethral catheterization. After the second day of catheterization, it is estimated that the risk of bacteriuria increases by 5 to 10% per day. The majority of cases of bacteriuria are asymptomatic, and the most effective management is removal of the catheter rather than antibiotic treatment.

In rare cases, local and systemic complications ensue, and antibiotic treatment should be initiated for asymptomatic bacteriuria in patients who are about to undergo urologic surgery or implantation of a prosthesis.
Such therapy should also be considered in immunocompromised patients. Bloodstream infection appears to be a well-defined but rare complication of catheter-associated urinary tract infection.

Recent U.S. data indicate that E. coli is the most common etiologic gram-negative organism, followed in descending order of frequency by P. aeruginosa, klebsiella species, enterobacter species, and A. baumannii.7 Uropathogenic E. coli strains infect the urinary tract through a range of mechanisms, including specialized adhesins, fimbriae, biofilm, and aversion of host responses.40 The emergence of resistance to quinolones and extended-spectrum cephalosporins remains a considerable challenge, since these agents are often used as first-line therapy., respectively.

Traditionally, the SHV-type and TEM-type ESBLs have predominated among hospital-acquired organisms, and this is still the case in the United States. The epidemiology of ESBLs is changing, however, and CTX-M–type ESBLs are becoming more common worldwide. In particular, CTX-M-15 is the most widespread, and this β-lactamase has frequently been associated with a uropathogenic E. coli clone known as sequence type 131.41 Unfortunately, the plasmids carrying these ESBL genes often carry resistance determinants targeting fluoroquinolones as well.

To reduce the morbidity associated with hospital-acquired urinary tract infections and prevent the dissemination of drug-resistant gram-negative organisms, adherence to evidence-based prevention guidelines is strongly recommended. Until further data are available, we do not recommend the use of antibiotic-impregnated or silver-coated urinary catheters.

Treatment Options

The importance of knowing local antimicrobial susceptibility to direct empirical antibiotic therapy cannot be overemphasized.

The polymyxins (colistin and polymyxin B) are an older antibiotic class that has seen a resurgence of use in recent years and deserves mention. Discovered in the late 1940s, polymyxins have specificity for lipopolysaccharides on the outer cell membrane of gram-negative bacteria. Organisms inherently resistant to polymyxins include serratia, proteus, Stenotrophomonas maltophilia, Burkholderia cepacia, and flavobacterium. Their use was initially hampered by nephrotoxicity and then rapidly declined with the advent of newer antibiotics.



NEJM May 13, 2010

However, this class of antibiotic has been reinstated as a key therapeutic option for carbapenem-resistant organisms, particularly P. aeruginosa, A. baumannii, and carbapenemase-producing Enterobacteriaceae.

It is still a challenge to determine the appropriate dosage, since the polymyxins were never subjected to the rigorous drug-development process we now expect for new antimicrobial agents. Despite in vitro data suggesting that colistin's antimicrobial activity is dependent on the peak blood concentration and that its effectiveness could be enhanced by once-daily administration, selection for colistin-resistant mutants, regrowth, and increased toxicity in an animal model have been reported with this dosing frequency. Therefore, two to four divided doses per day are currently recommended.

Recently licensed agents with activity against gram-negative bacteria include tigecycline, which is a parenteral glycylcycline antibiotic, and doripenem, which is a parenteral carbapenem that appears to have activity similar to that of meropenem. Tigecycline, a minocycline derivative with a broader spectrum of activity, is approved for the treatment of complicated skin, soft-tissue, and intraabdominal infections.

In vitro activity of tigecycline against a range of troublesome gram-negative organisms, including ESBL-producing and carbapenemase-producing Enterobacteriaceae, acinetobacter species, and Stenotrophomonas maltophilia, has been reported (P. aeruginosa and proteus species are intrinsically resistant to the drug). Clinical experience with treating these multidrug-resistant bacteria remains limited, however. The urine concentrations of tigecycline are low, so it is not suitable for the treatment of urinary tract infections.

Furthermore, it was shown to be inferior to imipenem–cilastatin for the treatment of ventilator-associated pneumonia in a randomized, double-blind trial. Given its rapid movement from the bloodstream into tissues after administration, peak tigecycline serum levels are low (0.63 µg per milliliter) with standard dosing (a 100-mg loading dose followed by 50 mg every 12 hours). Thus, its use for bloodstream infection due to organisms with a minimum inhibitory concentration of 1 µg per milliliter or more also remains limited and requires caution.

There is still much debate about the role of combination therapy versus monotherapy for gram-negative infections. The results of earlier studies and meta-analyses are difficult to interpret, but more recent evidence is starting to clarify this issue. For empirical treatment, combination therapy improves the likelihood that a drug with in vitro activity against the suspected organism is being administered (often defined as appropriate therapy).47 This effect is more pronounced in institutions with a greater prevalence of multidrug-resistant organisms.

The antibiotics selected for the combination, however, need to be tailored to local susceptibility data, because the benefits can be lost in the presence of high cross-resistance, such as to fluoroquinolones and third-generation cephalosporins. When the antibiotic susceptibilities of the infecting organism are known, monotherapy and combination therapy have similar outcomes, including rates of emergence of resistance and recurrence of infection.

Exceptions include monotherapy with aminoglycosides for P. aeruginosa, which is inferior to any other monotherapy regimen, and possibly monotherapy for patients who have cystic fibrosis. Therefore, we recommend institution-tailored combination therapy for the empirical treatment of serious hospital-acquired gram-negative infections, followed by de-escalation to monotherapy once susceptibilities have been determined. Although clinicians have historically preferred dual therapy for serious pseudomonal infections, the data support single-agent therapy as long as an active β-lactam can be chosen.

Other strategies currently used to treat multidrug-resistant gram-negative infections include prolonged infusion (3 to 4 hours) or continuous infusion of β-lactams and aerosolized antibiotics for the treatment of ventilator-associated pneumonia. These strategies are particularly useful for infections caused by multidrug-resistant organisms .

For example, according to pharmacokinetic and pharmacodynamic data in hospitalized patients, prolonging the infusion of β-lactams such as cefepime, piperacillin–tazobactam, and the carbapenems significantly improves bactericidal target attainment (i.e., time above the minimum inhibitory concentration for at least 50% for cefepime and piperacillin–tazobactam and 40% for the carbapenems), especially for organisms with an elevated minimum inhibitory concentration (8 to 16 µg per milliliter).


Furthermore, the emergence of resistance has been prevented in in vitro models.50 Clinical data for extended-infusion β-lactams remain sparse, with some retrospective studies showing improved outcomes, but results of prospective trials are less consistent. Nebulized antibiotics such as tobramycin, amikacin, and colistimethate sodium attempt to minimize systemic toxicity and improve drug delivery at the site of infection. For severe or refractory cases of pneumonia or those caused by highly drug-resistant organisms,
nebulized antibiotics given as an adjunct to systemic antibiotics should be thought of as a therapeutic option .

Respiratory toxicity such as bronchospasm has been reported and may be diminished or prevented by the administration of bronchodilators before dosing. Moreover, a recent Food and Drug Administration alert informed physicians about the importance of using aerosolized colistimethate sodium soon after preparation to prevent lung toxicity from the active colistin form. Prospective studies should be focused on determining the clinical benefits and safety of nebulized antibiotics and extended-infusion β-lactams, especially for infections caused by nonfermenting gram-negative.

Septic shock is traditionally viewed as an excessive systemic inflammatory reaction to invasive microbial pathogens, yet efforts to improve the outcome of patients with sepsis by means of inhibitors of proinflammatory cytokines and mediators have been unsuccessful. Occasionally, patients present with an exaggerated systemic inflammatory response to highly virulent pathogens (such as in cases of meningococcemia) and rapidly succumb.
Immunotherapy for Sepsis — A New Approach against an Ancient Foe
NEJM July 1, 2010

However, the vast majority of patients with sepsis survive the initial insult, only to end up in the intensive care unit with sepsis-induced multiorgan dysfunction days or weeks later. Sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients.

The clinical relevance of this immunosuppressed state is evidenced by the frequent occurrence of infection with relatively avirulent and often multidrug-resistant bacterial, viral, or fungal pathogens such as species of stenotrophomonas, acinetobacter, candida, pseudomonas, enterococcus, and cytomegalovirus.

In light of progressive antimicrobial resistance and the paucity of new antimicrobial agents entering the developmental pipeline, the care of patients with sepsis is increasingly challenging. Sepsis can be considered to represent a race between the pathogens and the host immune response; pathogens seek an advantage by incapacitating various aspects of host defenses

For example, they induce the apoptotic depletion of immune effector cells, suppress the expression of major-histocompatibility-complex class II molecules, increase expression of negative costimulatory molecules, increase antiinflammatory cytokines, and augment levels of regulatory T cells and myeloid-derived suppressor cells .The prevention of sepsis-induced immunosuppression, or its treatment if it occurs, is a research priority

• Reversal of Immunosuppression in Sepsis.

• In many cases of sepsis, the immune system fails to eradicate the infectious pathogens, and a prolonged phase of sepsis-induced immunosuppression begins, characterized by a failure to eradicate the primary infection and by development of secondary nosocomial infections.

This immunosuppression is mediated by multiple mechanisms, including massive apoptosis-induced depletion of lymphocytes and dendritic cells, decreased expression of the cell-surface antigen–presenting complex HLA-DR, and increased expression of the negative costimulatory molecules programmed death 1 (PD-1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) and their corresponding ligands (e.g., PD-1 ligand [PD-L1]).


Furthermore, the numbers of regulatory T cells and myeloid-derived suppressor cells (MDSCs) are increased, and there is a shift from a phenotype of inflammatory type 1 helper T (Th1) cells to an antiinflammatory phenotype of type 2 helper T (Th2) cells characterized by the production of interleukin-10. The net result is a severely compromised innate and adaptive immune system with poorly functional "exhausted" CD8 and anergic CD4 T cells.

Targets of potential immunotherapeutic approaches (shown in red) include agents that block apoptosis, block negative costimulatory molecules, decrease the level of antiinflammatory cytokines, increase HLA-DR expression, and reactivate "exhausted" or anergic T cells. FLT-3L denotes Fms-related tyrosine kinase 3 ligand, GM-CSF granulocyte–macrophage colony-stimulating factor, LFA-1 lymphocyte function–associated antigen 1, and TNF- tumor necrosis factor .

• A recent study by Said and colleagues3 provides insights into the molecular mechanisms that underlie immune depression following sustained inflammation, such as occurs in patients with either chronic viral infections or protracted sepsis. These investigators studied a critical monocyte–macrophage protein known as programmed death 1 (PD-1), which is found in patients infected with the human immunodeficiency virus (HIV). PD-1, a negative costimulatory molecule expressed on immune effector cells, is up-regulated along with its cognate ligand PD-L1 (also expressed on effector cells) during chronic HIV infection.

NEJM July 1, 2010

Said and colleagues found that microbial mediators translocate across the intestinal epithelium in chronic HIV-induced inflammation and are recognized by toll-like receptors. Persistent activation of the innate immune system by these intestinally derived microbial products up-regulates the expression of PD-1 and PD-L1 on various immune cells.

PD-1 impairs immunity by inducing apoptosis, increasing production of interleukin-10 (a key antiinflammatory cytokine increased in sepsis), preventing T-cell proliferation, and causing T cells to become nonresponsive ("exhausted"). Said and colleagues described a new mechanism by which the interaction between PD-1 and PD-L1 induces immunosuppression in patients with HIV. They found that PD-1 activation results in the increased production of interleukin-10 by monocytes from persons infected with HIV.

Moreover, the PD-1–induced inhibition of CD4 T cells was itself inhibited by the blocking of the interleukin-10 receptor. Thus, PD-1 affects immunosuppression through its effect on interleukin-10 expression. These results suggest that blocking PD-1 may improve the prognosis of patients with any of a variety of chronic infections. These findings are consistent with the improved survival in mice with fungal infections, and in mice with bacterial sepsis, in which PD-1 was inhibited.4

Although it is possible that immunostimulatory therapy exacerbates the hyperinflammatory phase of sepsis or induces autoimmunity, clinical trials of interferon- , a potent immunostimulatory agent, and granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor (GM-CSF) in patients with various systemic inflammatory states did not elicit unbridled inflammatory reactions. Most patients with refractory sepsis are so severely immunosuppressed that the development of hyperinflammation or autoimmunity is unlikely.

To prevent the extensive apoptosis-induced depletion of immune effector cells in patients with sepsis, one potential strategy is use of the antiapoptotic, immunostimulatory cytokines interleukin-7 and interleukin-15; both agents have shown efficacy in models of infection, including sepsis. These cytokines, in preventing cell death, diminish the immunosuppressive effect on phagocytic cells (which are relieved from disposing of increased numbers of apoptotic cells).


Interleukin-7
also restores the effector function of lymphocytes and improves lymphocyte migration by increasing the activity of integrins.
Interleukin-7 is currently in clinical trials to treat cancer , hepatitis C virus and HIV.

In the future, immunotherapy will probably be tailored to the individual patient on the basis of specific laboratory or clinical findings. For example, a recent trial of GM-CSF to treat sepsis tested the effect only on patients in whom monocyte HLA-DR expression was significantly depressed. Flow-cytometric studies quantitating the level of expression of negative costimulatory molecules (such as PD-1 and PD-L1) on leukocytes, or rapid whole-blood stimulation assays of cytokine secretion, could be used to guide immunotherapeutic decisions.

Patients with cytomegalovirus infection or reactivation of herpes simplex virus type 1 and those with sepsis due to infection with opportunistic pathogens (such as stenotrophomonas or acinetobacter) are good candidates for immunoenhancing therapy.
An old saying goes, "Desperate diseases are cured by desperate means or not at all."

Trials of immunostimulatory agents should be undertaken, with close monitoring of innate and adaptive immune function, in patients with demonstrable immunosuppression. Many potentially beneficial immunomodulatory agents are currently in clinical trials for other indications and have reasonable safety profiles. We speculate that such approaches will have wide-ranging effects and could represent a major advance in the field of infectious disease.

These findings are consistent with the improved survival in mice with fungal infections, and in mice with bacterial sepsis, in which PD-1 was inhibited.
Although it is possible that immunostimulatory therapy exacerbates the hyperinflammatory phase of sepsis or induces autoimmunity, clinical trials of interferon- , a potent immunostimulatory agent, and granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor (GM-CSF) in patients with various systemic inflammatory states did not elicit unbridled inflammatory reactions.

Most patients with refractory sepsis are so severely immunosuppressed that the development of hyperinflammation or autoimmunity is unlikely.
To prevent the extensive apoptosis-induced depletion of immune effector cells in patients with sepsis, one potential strategy is use of the antiapoptotic, immunostimulatory cytokines interleukin-7 and interleukin-15; both agents have shown efficacy in models of infection, including sepsis.

These cytokines, in preventing cell death, diminish the immunosuppressive effect on phagocytic cells (which are relieved from disposing of increased numbers of apoptotic cells). Interleukin-7 also restores the effector function of lymphocytes and improves lymphocyte migration by increasing the activity of integrins. Interleukin-7 is currently in clinical trials to treat cancer and infection with hepatitis C virus and HIV.

In the future, immunotherapy will probably be tailored to the individual patient on the basis of specific laboratory or clinical findings. For example, a recent trial of GM-CSF to treat sepsis tested the effect only on patients in whom monocyte HLA-DR expression was significantly depressed.5 Flow-cytometric studies quantitating the level of expression of negative costimulatory molecules (such as PD-1 and PD-L1) on leukocytes, or rapid whole-blood stimulation assays of cytokine secretion, could be used to guide immunotherapeutic decisions.


Patients with cytomegalovirus infection or reactivation of herpes simplex virus type 1 and those with sepsis due to infection with opportunistic pathogens (such as stenotrophomonas or acinetobacter) are good candidates for immunoenhancing therapy.

An old saying goes, "Desperate diseases are cured by desperate means or not at all." Trials of immunostimulatory agents should be undertaken, with close monitoring of innate and adaptive immune function, in patients with demonstrable immunosuppression. Many potentially beneficial immunomodulatory agents are currently in clinical trials for other indications and have reasonable safety profiles. We speculate that such approaches will have wide-ranging effects and could represent a major advance in the field of infectious disease.

"Desperate diseases are cured by desperate means or not at all."

Changes in Rabies Postexposure Prophylaxis Regimen
The CDC recommends changing the vaccination schedule from five to four doses.
In October 2008, the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices convened a panel, reviewed all relevant evidence, and changed the recommendations for rabies PEP to the following:
Unvaccinated people with bite or nonbite exposures should receive human rabies immune globulin and vaccination.
Vaccination should consist of four 1-mL intramuscular doses of human diploid cell vaccine or purified chick embryo cell vaccine; the first dose should be given as soon as possible after exposure (day 0), and additional doses should be given on days 3, 7, and 14 after the first dose.

The vaccine should be administered intramuscularly in the deltoid area (the anterolateral thigh is acceptable in children).As much of the human rabies immune globulin dose as possible should be infiltrated around the site of the wound; the remainder should be administered intramuscularly at a site distant from the first vaccine.Persons who have been vaccinated previously should receive two doses of vaccine — 1 mL in each deltoid, with the first dose on day 0 and the second on day 3.Comment: These updated recommendations will be welcomed by both providers and patients (1 less injection) but will not be reflected in the product labels on the vaccine vials, at least not for some time.
Published in Journal Watch Emergency Medicine April 2, 2010

“Infectious” vs. “contagious”

• Infectious
• 1. A disease capable of being transmitted from person to person, with or without actual contact. 2. Denoting a disease due to the action of a microorganism.

Contagious

Relating to contagion; communicable or transmissible by contact with the sick or their fresh secretions or excretions.
Anthrax, for example, is infectious but not contagious. It is caused by a microorganism, the bacterium Bacillus anthracis, but it’s not “communicable or transmissible by contact with the sick or their fresh secretions or excretions”. People most often get anthrax from contact with infected hides or other animal products, and from soil where the hardy spores of the bacterium can remain for decades after being deposited by infected animals.


There’s some confusion inherent in these terms because it seems that the “contact with the sick or their fresh secretions or excretions” part only applies to sick humans. You might get rabies from breathing in droplets of the saliva of an infected animal, but that is not considered to be contagion. As near as I can tell, anyway. So, since a human being with rabies doesn’t infect others, the disease is considered non-contagious.

An important factor in any contagious disease is how easily it is transmitted from one person to another. You can’t get HIV from touching the skin of an infected person, but influenza and the common cold can be transmitted that way. Shake hands with someone who just sneezed into his or her hand, and the bacteria are on your hand; when you touch your mouth, nose or eyes, the microorganisms can enter your system. TB is contagious, as is leprosy, but they are not transmitted by brief casual contact.

Prevention and medical management of Clostridium difficile infection

• Summary points
• The incidence of Clostridium difficile infection has increased in the past decade
• National and local surveillance of C difficile infection is crucial to guide implementation of control measures
• Prudent antibiotic prescribing, correct hand hygiene, use of personal protective equipment, environmental decontamination, and isolation or cohort nursing may prevent infection
• Treatment is with oral vancomycin or metronidazole, according to disease severity, with escalation of treatment in the event of non-response
BMJ 12 March2010;340

The incidence of Clostridium difficile infection in the United Kingdom has increased since the late 1990s.1 High profile outbreaks in the United States, Canada, and northern Europe have been associated with a previously uncommon but highly virulent strain known as ribotype 027. A recent review in the BMJ examined the role of surgery in treating C difficile colitis.2 This review focuses on the prevention and medical management of C difficile infection.

Who becomes infected with C difficile?

C difficile can be cultured from the stool of 3% of healthy adults and as many as 35% of hospital inpatients. Most colonised people remain asymptomatic. Clinical disease develops when the normal gut flora is disrupted, usually by antibiotic exposure, thereby creating conditions that favour C difficile proliferation within the colon. Elderly hospital inpatients are the main group affected, but the epidemiology of the disease is changing. Community associated infections have been increasingly recognised, as have infections in pregnant women and children, populations previously regarded as being at low risk.

How does C difficile infection present and how is it diagnosed?

Gastrointestinal diseases associated with C difficile infection range from mild diarrhoea to fulminant colitis. Some "silent" infections present with abdominal pain and distension, in the absence of appreciable diarrhoea. These features may indicate severe disease, which in turn causes ileus or toxic megacolon. UK national guidelines define C difficile infection as one episode of unformed stool, not attributable to any other cause, occurring at the same time as a positive C difficile toxin assay.

The toxin may be detected by commercial immunoassay kits, nine of which were tested against a "gold standard" cytotoxin or toxigenic culture assay.5 Compared with the cytotoxin assay, sensitivities ranged from 67% to 92% and specificities from 91% to 99%. When C difficile infection is uncommon or clinically unlikely, positive test results must therefore be interpreted with care and a confirmatory test should be considered. In suspected cases of silent infection, endoscopy or abdominal computed tomography may be needed. Characteristic findings includethickening of the colonic wall, dilation, and pseudomembrane formation.


• How can it be prevented?
• Prevention has two aspects—prevention of acquisition of C difficile and prevention of infection in colonised people. This requires a multifaceted approach based on the five main strategies outlined in the UK Department of Health Saving Lives campaign .prudent antibiotic prescribing, hand hygiene, use of personal protective equipment, environmental decontamination, and isolation or cohort nursing. In the UK, reporting of C difficile infections to the HPA is mandatory. Locally, surveillance of C difficile infections is key to identifying outbreaks and initiating control measures in a timely fashion.

How can antibiotic stewardship help prevent C difficile infection?Many authors have produced "hit lists" of antibiotics with the potential to cause C difficile infection, but this approach has problems.w6 Classification into low, medium, and high risk antibiotics is practically useful, but any antibiotic, at any dose, for any length of time, will alter the colonic microbiota, potentially allowing C difficile to proliferate and cause disease.

Prospective observational cohort studies suggest that restricting the use of the high risk agents, clindamycin and third generation cephalosporins, results in fewer cases of C difficile infection. Although use of fluoroquinolones has been linked to the spread of the ribotype 027 strain, riskanalyses have been confounded by antibiotic polypharmacy, duration of antibiotic treatment, and infection control practices. In addition, observational data suggest that different fluoroquinolones differ in propensity to cause C difficile infection, with gatifloxacin having the highest risk.

To reduce overprescribing and inappropriate antibiotic use, the Saving Lives campaign makes the following "best practice" recommendations for antimicrobial prescribing: antibiotics should be prescribed according to local policies and guidelines for treatment and prophylaxis, avoiding broad spectrum agents; the indication for starting an antibiotic should be documented in the medical record, along with a stop or review date; intravenous
antibiotics should be avoided, and the shortest treatment course likely to be effective should be prescribed.

Hospital initiatives focusing on antibiotic stewardship include antibiotic ward rounds, antibiotic care bundles, electronic prescribing, restricted antibiotics that require microbiology approval, and computerised decision support networks. Antibiotic pharmacists may play a major role in this regard.

What infection control measures should be instituted?C difficile infection has been estimated to increase hospital stay by an average of 21 days, While in hospital, infected patients may continue to excrete infective C difficile spores. Hand washing is paramount in preventing hospital acquired infections. Alcohol based hand gels are highly effective against non-spore forming organisms, but they do not kill C difficile spores or remove them from hands.

Experimental studies have shown that alcohol based hand gels are significantly less effective at reducing contamination with C difficile spores than washing with soap and water. UK national guidelines recommend that healthcare workers wash their hands before and after contact with patients with suspected or confirmed C difficile infection, and that disposablegloves and aprons are used when handling body fluids and caring for such patients.1

C difficile spores can survive in the environment for months or years, and environmental contamination has been linked to the spread of C difficile infection in healthcare settings. UK national guidelines therefore recommend various forms of environmental decontamination1: rooms or bed spaces of infected patients should be cleaned daily using chlorine containing cleaning agents; commodes, toilets, and bathrooms should be cleaned after each use; and after discharge of an infected patient, the room and mattress should be thoroughly cleaned using chlorine containing cleaning agents or vaporised hydrogen peroxide.

Replacing electronic oral and rectal thermometers (which may be contaminated with C difficile spores) with disposable thermometers can significantly reduce rates of C difficile infection. A prospective randomised crossover study of 20 nursing unitsreported a significantly lower rate of nosocomial C difficile infection with use of disposable thermometers (0.16/1000 patient days) compared with electronic thermometers (0.37/1000 patient days; relative risk 0.44; 95% confidence interval 0.21 to 0.93),19 and a similar reduction was seen by an observational study that compared rates before and after the introduction of tympanic thermometers.

No RCTs or systematic reviews have assessed the value of isolation measures in preventing C difficile infection, but a systematic review of isolation in the hospital management of meticillin resistant Staphylococcus aureus(MRSA) suggested it was effective as part of a broader infection control strategy.20 UK national guidelines recommend that patients with potentially infective diarrhoea should be moved immediately into a single room withen suite facilities,1 but this practice has difficulties. For example, moving frail elderly patients may increase the risk of delirium.w16


In a large outbreak, isolating affected patients in single rooms may not be possible. The creation of C difficile isolation wards in hospitals with high levels of disease was successful in certain outbreaks. Because the positive predictive value of the toxin immunoassays is suboptimal, however, transferring patients to cohort areas risks putting people without C difficile (false positives) at increased risk of acquiring the infection.

Are there any other ways of preventing C difficile infection?The rising incidence of C difficile infection since the late 1990s has coincided with the widespread use of proton pump inhibitors (use increased 10-fold in the UK from 1992 to 1995), raising concerns that the two may be linked. Hospital and community studies have produced conflicting results, but a meta-analysis of case-control and cohort studies including 126 999 patients suggested a significant association between proton pump inhibitors and C difficile infection (odds ratio 2.05; 1.47 to 2.85).

Probiotics

(live micro-organisms such as Lactobacillus
or Bifidobacterium taken as supplements or in yoghurt drinks to rebalance the gut flora) and prebiotics (carbohydrates such as oligofructose, inulin, and other non-digestible foodstuffs that stimulate the growth or activity of gut bacteria) have been proposed as preventive methods for C difficile infection. A recent double blind RCT showed that a probiotic Lactobacillus preparation helped prevent C difficile infection in a highly selected subgroup of patients receiving antibiotics,23 but the findings may not be generalisable.

• How is C difficile managed medically?

• Patients with C difficile infection may develop electrolyte imbalance, dehydration, malnutrition, and pressure sores, so their supportive medical care must be optimised. After outbreaks at Maidstone and Tunbridge Wells NHS Trust in 2005-6, the UK Healthcare Commission criticised the general management of infected patients for inadequate monitoring and doctor review, poor fluid replacement and nutritional support, and lack of multidisciplinary assessment.

In early studies, 15-23% of patients who developed C difficile infection became asymptomatic through stopping the offending antibiotic alone—allowing normal flora to recolonise the colon—whereas continuing systemic antibiotics has been associated with a poor response to treatment.3 When treatment cannot be stopped, because of concurrent infection that requires ongoing systemic antibiotics, an antibiotic with a low risk of causing C difficile infection may be substituted . The use of antimotility agents during active infection has been associated with toxic megacolon.3

Which antibiotics are used to treat

C difficile infection?Oral vancomycin was the first drug shown to be effective for C difficile infection, followed by oral metronidazole, and these agents remain the mainstay of treatment.3 Whereas intravenous vancomycin is almost exclusively excreted in the urine, oral vancomycin achieves faecal concentrations many times higher than the minimum inhibitory concentrations of C difficile strains reported to date.

After ingestion by healthy volunteers,metronidazole is completely absorbed from the gastrointestinal tract, and is undetectable in the faeces. When diarrhoea is present, however, metronidazole may achieve therapeutic values in faeces when given orally or intravenously, perhaps because of seepage across inflamed colonic mucosa. UK surveillance data support the emergence of reduced susceptibility to metronidazole in some C difficile isolates, but the clinical importance ofthis is unclear.

What is the appropriate choice for initial antibiotic treatment?In patients with severe C difficile infection (any of white blood cell count >15x109/l, acutely rising serum creatinine (>50% above baseline), temperature over 38.5°C, or clinical or radiographic evidence of severe colitis), UK national guidelines recommend initial treatment with oral vancomycin, on the basis of evidence from two recent RCTs that compared vancomycin and metronidazole.

These trials, which stratified for disease severity,showed a lower rate of treatment failure with vancomycin in patients with severe C difficile infection. Only one has been fully published; it found cure rates of 76% with metronidazole versus 97% with vancomycin (P=0.002) in patients with severe disease. Retrospective and prospective observational studies have also shown that response time is shorter for vancomycin than for metronidazole, which may be important in patients withsevere disease.


In patients with mild or moderate disease, neither RCT showed that vancomycin was significantly superior. UK national guidelines therefore still recommend oral metronidazole for initial treatment in these patient groups, because it is cheaper than oral vancomycin, and because of concern that overuse of vancomycin may result in the selection of vancomycin resistant enterococci.1 Observational data suggest, however,that metronidazole, as well as vancomycin, may promote persistent overgrowth of vancomycin resistant enterococci.2

• What if the patient fails to respond to initial treatment?Treatment failure is defined as no response after one week, although most patients show signs of improvement within 48-72 hours. UK national guidelines recommend that antibiotics be reviewed daily and a plan agreed for escalating treatment in the event of non-response. If diarrhoea does not improve, patients initially treated with metronidazole may be changed to vancomycin.

In severe disease, aggressive treatment with escalating doses of vancomycin, up to 500 mg four times daily, may be used, although no robust evidence supports this approach, and an early randomised trial comparing vancomycin 500 mg four times daily with 125 mg four times daily in 46 inpatients found no difference in outcomes. In patients with adynamic ileus (which may reduce passage of oral preparations to the colon), intravenous metronidazole may be added, but the efficacy of this route of administration is unclear.w26

Vancomycin administered as a retention enema may increase colonic antibiotic exposure, and in a recent case series examining this as adjunctive treatment, eight of nine patients completely recovered. Finally, surgery may be life saving in severe disease.

Are there any other treatment options for refractory disease? UK national guidelines suggest considering the addition of rifampicin 300 mg twice daily for severe disease,1 although the only RCT assessing rifampicin as an adjunct to metronidazole for C difficile infection was halted early because of lack of efficacy. A recent case series described the successful use of intravenous tigecycline for C difficile infection in fourpatients refractory to vancomycin and metronidazole. UK national guidelines also recommend the use of intravenous immunoglobulin (400 mg/kg) in selected severe cases,1 although results from case reports and small series have been inconsistent and no RCTs are available to support this position.

How is recurrent C difficile infection diagnosed?Recurrent C difficile infection (relapse of diarrhoea after initial resolution of symptoms) usually occurs within one to three weeks but has been described up two months after the initial episode. The risk of recurrence after a single episode is high, with 8-50% of patients having at least a second episode after treatment with metronidazole or vancomycin. Risk factors include previous relapses, age greater than 65 years, severe underlying illness, and additional antibiotic use after treatment for C difficile infection has been stopped.

Paradoxically, the antibiotics used to treat C difficile infection may themselves interfere with the re-establishment of the normal colonic flora, contributing to the propensity for recurrent disease.
Patients may remain positive for C difficile toxin despite clinical cure, and UK Department of Health surveillance regards serial positive results within 28 days of the first specimen as a single episode. UK national guidelines do not recommend retesting for C difficile toxin within 28 days if patients remain symptomatic, but repeat testing may be appropriate at any time if symptoms relapse after resolution and recurrence needs to be confirmed.

How do recommendations differ for recurrent disease?Because recurrence may represent reinfection rather than relapse, and because evidence for clinically relevant resistance to metronidazole or vancomycin is lacking, the antibiotic that was used to treat the initial episode may be used for the first recurrence (unless this is metronidazole and the recurrence meets criteria for severe C difficile infection) In second and subsequent recurrences, however, vancomycin is recommended.

This is because stool concentrations of metronidazole wane during recovery, with much lower concentrations in formed than in watery or semiformed stools, and because long term use of metronidazole may be associated with adverse effects, such as peripheral neuropathy.

Observational studies have examined the use of long term, tapering, or pulsed courses of vancomycin. Slowly falling concentrations of antibiotics in the colon may suppress C difficile proliferation, while allowing normal colonic flora to recover, or allow C difficile spores to germinate, making them susceptible to subsequent intermittent doses.32 None of the proposed regimens has been tested in an RCT, and they may all apply considerable selection pressure for vancomycin resistant enterococci.


Other antimicrobial regimens, such as a short course of vancomycin and rifampicin, or rifaximin (a poorly absorbed rifamycin derivative not licensed in the UK) used as a "chaser" after vancomycin, have been reported to be successful in small numbers of patients. Low concentrations of serum antibodies against C difficile toxin A correlate with the risk of recurrent C difficile infection, and a recent phase II RCT found a significant reduction in C difficile recurrence in patients treated with experimental monoclonal antibodies against toxins A and B.

Pooled intravenous immunoglobulin may also neutralise these toxins, and a small case series reported a successful clinical response to intravenous immunoglobulin in three of five patients with recurrent infection.35 Although recommended in the UK Department of Health clinical guidelines for immunoglobulin use for selected patients with multiple recurrent C difficile infection in whom all other treatments have failed or are inappropriate, no RCTs support the use of intravenous immunoglobulin, and cost and availability may preclude its widespread adoption.

Finally, evidence is emerging for the efficacy of faecal transplantation in patients with relapsing C difficile infection, mostly from small retrospective case series.
Fresh stool from a healthy donor is administered by enema or nasogastric tube in an effort to reconstitute the normal colonic flora. Concerns remain about the safety of this approach, as well as its acceptability.

Conclusions

Many cases of C difficile infection could be prevented by prudent antibiotic prescribing and vigorous infection control measures, which may also reduce other healthcare associated infections and limit the spread of multiresistant organisms such as MRSA and vancomycin resistant enterococci. Although evidence from RCTs supports guidance on the initial antibiotic treatment of C difficile infection, more data are urgently needed on the management of refractory, fulminant, and recurrent disease.

• Tips for non-specialists

• Avoid antibiotics with a high risk of inducing Clostridium difficile infection, especially in patients with a history of infection
• Isolate patients with suspected C difficile infection, use gowns and gloves when seeing them, and remember to wash hands rather than use alcohol gel
• Pay careful attention to the supportive care (such as fluid and electrolyte replacement) of infected patients
• Stop precipitating antibiotics if possible, and if not, substitute with a lower risk agent
• Reserve metronidazole for initial treatment of patients with mild or moderate disease, then escalate treatment according to agreed local and national protocols
• Discuss patients with recurrent infection with your local microbiology department

• Ongoing research

• To determine the epidemiology of community acquired Clostridium difficile infections in younger patients who have not received antibiotics or had contact with the healthcare system
• To determine the contribution of factors such as C difficile in food animals, salads and other food stuffs, pets, soil, and water
• To define diagnostic algorithms that optimise test combinations for the laboratory diagnosis of C difficile infection
• There is considerable interest in the development of monoclonal antibodies and toxin specific vaccines to prevent or treat C difficile infection, and tolevamer, a novel toxin binding polymer, is undergoing clinical trials
• Randomised controlled trials (RCTs) are urgently needed to examine treatment for fulminant, refractory, and recurrent C difficile infection, including new antibiotics such as tigecycline, and non-antimicrobial agents such as intravenous immunoglobulin
• An RCT examining faecal transplantation is under way in the Netherlands


New WHO guidelines for the treatment of malaria
Quality assured diagnosis of malaria in Africa is a major challenge.
The publication of a second edition of the World Health Organization’s guidelines for the treatment of malaria in March 2010 just four years after the first is testament to how quickly malaria control has developed in the past few years. This is not so much the result of new tools for control, but rather the changing use of existing tools, whose more effective application over the past 10 years has resulted in a marked reduction in the global burden of malaria.2
BMJ 28 May 2010

Both the first (2006) and new (2010) editions of the guideline provide a clear account of evidence and recommendations for the treatment of severe and non-severe malaria caused by Plasmodium falciparum and the other four species of Plasmodium known to infect humans
(P knowlesi now being recognised as an important zoonosis). In addition, annexes provide scientific detail and references, and the new edition has used the GRADE system, which details the strength of evidence behind each recommendation.

The 2010 edition differs from the first edition in four important areas—refining and improving treatment of malaria, minimising the risk of resistance to artemisinin-based combination treatments, using drugs to reduce transmission, and malaria diagnosis.

The choice of partner drug with artemisinin derivatives continues to be refined, and piperaquine, which is attractive because of its low cost and co-formulation, is now recommended alongside lumefantrine, amodiaquine, sulfadoxine-pyrimethamine, and mefloquine. The new guideline places greater emphasis on completing courses of these combined treatments to minimise selection pressure for resistance to artemisinins, which is now a major concern after reports of partial resistance to artemisinin monotherapy in South East Asia.4

For severe malaria, intravenous artesunate is recommended in preference to quinine in adults, and it has at least equal preference to quinine in children. The results of the AQUAMAT trial (quinine v artesunate for severe malaria in African children), which are expected in early 2011, may guide a more definitive policy.5 The 2006 guideline included useful advice on the use of antimicrobials in severe malaria, but this section has been removed, possibly because of the lack of evidence from clinical trials. However, this leaves an important gap in recommendations for the treatment of malaria-bacterial co-infection, which is present in 14-25% of inpatient deaths from malaria in children.

In areas where reduction in transmission is a priority, a single dose of primaquine is now recommended at the end of a course of artemisinin based combination treatment. This recommendation is based on its historical use and a single trial that showed excellent clearance of gametocytes, although a transient fall in haemoglobin was noted. Mass drug administration to reduce transmission is not supported because it has only ever resulted insustained malaria control on the small Pacific island of Aneityum.

The single most important operational change in the new guideline is the replacement of "presumptive treatment" in young children (treatment of any childhood fever with no obvious alternative cause as malaria, a cornerstone of WHO policy for the past 20 years) with parasitological diagnosis wherever possible. There is already a consensus that parasitological diagnosis of malaria is highly desirable, but opinion differs on the speed with which this can be achieved in resource poor settings.9

The evidence needed to guide this decision is limited, and being largely operational, might be inconclusive even if it did exist. So the new guideline has taken a bold step and the question now has to shift from whether we are ready to abandon presumptive treatment to how we can provide a quality assured parasitological diagnosis where infrastructure is weak and the burden of disease is high.

The challenges to achieving parasitological diagnosis of malaria are immense, especially in many areas of Africa where routine slide results compare badly with malaria rapid diagnostic tests or quality assured microscopy. The scaling up of rapid diagnostic tests has progressed rapidly in recent years. Many countries now have substantial rapid diagnostic test programmes supported by the Global Fund, but important areas still need urgent attention. These include selection and cost of tests (more than 80 are now available), establishment of quality assurance systems, and prescriber use and adherence to results.11


Slide microscopy remains a key element in parasitological diagnosis of malaria, both for clinical care and quality control of malaria rapid diagnostic tests, but the limited evidence available suggests that the quality of slide results in routine care in Africa is poor, with estimates of sensitivity and specificity often falling below 70% (WHO sets a minimum standard of 90% specificity and 95% sensitivity). Although quality assurance schemes forroutine slide microscopy in Africa exist in policy, they rarely operate in practice, and major efforts are urgently needed to correct this.

Targeting antimalarial treatment on those who actually have malaria is an important objective, and the 2010 WHO guideline sets a challenging task to provide accurate parasitological tests for malaria at all levels of the health system. However, the difficulties in translating the aspiration to reality should not be underestimated. Strong leadership is needed from WHO, international funders, and ministries of health if it is to succeed.

Management of malaria and other severe infections in rural Africa and Asia

Delays to treatment cost lives and quick fixes are not the answer
The winner of the Research Paper of the Year category in the 2010 BMJ Group Awards was a paper that described the use of pre-referral rectal artesunate (a rapidly effective antimalarial) in patients with severe malaria.1This remarkable study conducted in Bangladesh, Ghana, and Tanzania randomised 17 826 patients with suspected malaria in rural areas to rectal artesunate or placebo before referral to a health facility.
BMJ 17 March 2010

Although mortalitydid not differ between groups, the composite of death and disability was significantly reduced in people who received artesunate, in an analysis that was restricted to those with confirmed malaria. The effect was largely limited to participants who were delayed for more than six hours before arriving at a health facility, in whom the risk ratio was 0.49 (95% confidence interval 0.32 to 0.77). The findings suggest that in patients with severemalaria in whom treatment is likely to be delayed, pre-referral treatment with rectal artesunate could reduce the risk of mortality and disability.

The study was an outstanding logistical feat and clearly confirmed the principle that treatment of severe malaria in remote areas can reduce morbidity and mortality. The paper has generated much debate since publication about its methods and implications for practice, and it has raised ethical concerns.2 3 It identified important differences between Asia and Africa, and between children and adults.

Three challenging clinical questions arising from the study do not currently have clear answers.
Firstly, can the approach of giving rectal antimalarials in remote areas where malaria is endemic be operationalised? It is currently unclear if giving rectal artesunate (or equivalent effective antimalarials4) can be made to work outside a trial setting, but the findings of this study suggest that we should try. As with many interventions, deprived communities in rural areas some distance from formal health care have the most to gain but are also those most difficult to reach.

It would be inappropriate to set up a parallel system only to deliver rectal antimalarial, which should be delivered through existing community based systems providing care. It cannot be assumed that improving care in the community will lead to reduced mortality at a population level, and this would have to be tested.5 The cost of delivering rectal antimalarials for pre-referral use must be weighed against the cost of improving speed of access to good quality health care.

Secondly, how can we enhance the rapid referral of severely sick children and adults to health facilities? The need for rapid referral extends beyond malaria. Delivering rectal artesunate is not a substitute for formal care, but a way to reduce the effect of delayed treatment in cases of severe malaria, and the sooner correct treatment is started the lower the risk of death. The study adds to the overwhelming evidence that delays in treating severe infections kill, and it highlights differences between Asia and Africa.

Barriers to rapid referral include inadequate information and cultural beliefs about illness, as well as factors such as transport, distance, direct and indirectcosts, relationships within households and between carers and professionals, and patients’ or carers’ impressions of quality of care at health facilities.6 7 8 The successful management of illness in the community is usually dependent on functioning health systems. Dealing with any one barrier to referral in isolation will therefore have limited impact without changes to the health system as a whole.


Thirdly, what should we do for patients who have severe febrile disease but do not have malaria? How best to manage severe non-malarial illness is complex. In many areas of Africa and Asia where malaria is endemic, it is common to treat most severe febrile illnesses as if they were malaria.9 Malaria is, however, only one severe infection that may cause mortality. In some areas of Africa and Asia the proportion of severe illness attributable to malaria is decreasing,10 and the relative importance of non-malarial causes of illness is therefore increasing.

Alternative causes vary by geographical area, age, and HIV prevalence, but bacterial infections make up a substantial proportion of treatable causes in many settings.11 One approach is to improve diagnosis; the World Health Organization now recommends parasitological testing before antimalarial treatment, and this is a major shift in case management. Rapid diagnostic testing to guide treatment is gaining momentum in remote areas, although introducing tests does not in itself immediately solve the problem of misdiagnosis because clinicians’ prescribing behaviour is complex and tests are only one element of this.12

An alternative response is to use syndromic treatment, which combines an antibiotic with an antimalarial in probable severe infection, but the impactof this approach has yet to be tested, and it is not clear which antibiotic is best.
The award winning study clearly shows that substantial delays in obtaining treatment have serious effects on seriously ill patients in Africa and Asia even when effective antimalarial drugs are available. The failure of healthcare systems to deliver effective treatment early contributes substantially to avoidable mortality and morbidity. Fixing this system failure will not be easy or quick, but it must be a priority.

BCG vaccination in developing countries

Important interactions occur with other vaccines, vitamin A, and the organisms that cause fatal pneumonia
BCG vaccine is given to more than 100 million infants each year, making it one of the most widely used vaccines. Roth and colleagues assess whether revaccinating children at 19 months reduces overall child mortality.
BMJ 15 March 2010

A single dose of BCG provides useful protection against systemic mycobacterial infections, such as tuberculous meningitis, miliary tuberculosis, and leprosy. It is less effective against pulmonary tuberculosis—effectiveness varies greatly between trials, but geographical latitude and study validity explained 66% of this variance in one meta-analysis. BCG was less effective near the equator, in lower quality trials, and in rural areas, but effectiveness was not influenced by age at vaccination or the strain of BCG used.

BCG may be of less benefit to people living in tropical or rural areas because they have greater contact with environmental mycobacteria. These organisms may have heterologous (non-specific) immunological effects that provide some protection against tuberculosis but also reduce the effectiveness of BCG.

Because BCG provides useful protection against tuberculous meningitis and miliary tuberculosis in children, the WHO recommends that it be given as soon as possible after birth to all infants living in areas where tuberculosis is highly endemic. WHO also recommends that BCG be given only once, largely because of the lack of evidence that revaccination is beneficial. Two randomised controlled trials, a case-control study, and a cohort study have suggested that revaccination with BCG does not reduce the incidence of pulmonary tuberculosis.

However, all these studies were performed in countries near the equator, where BCG is likely to have little effect on pulmonary tuberculosis.5 The two randomised trials and the case-control study were confined to people with at least one BCG scar, so we do not know whether a second dose of BCG is helpful in people with no scar, although the presence of a scar and the reaction to purified protein derivative are probably not a reliable guide to immunity to tuberculosis.

Revaccination with BCG may still be beneficial even if it does not provide extra protection against pulmonary tuberculosis.
Attenuated Mycobacterium bovis (BCG) has potent heterologous effects on the immune response to many organisms other than M tuberculosis, including other mycobacteria (M avium intracellulare, M leprae, M microti, M ulcerans), other bacteria (Brucella, Coxiella, Listeria, Salmonella), protozoa (Babesia, Leishmania,Plasmodium, Toxoplasma), and vaccinia virus.


These heterologous effects have an important influence on human infections other than tuberculosis. Randomised trials of a single dose of BCG in the United States and the United Kingdom published in the 1940s and 1950s showed that it substantially reduced mortality even after excluding deaths from tuberculosis and accidents.

Two randomised trials have shown that revaccination with BCG provides protection against non-tuberculous infections. One trial of 121 020 people in Malawi showed that revaccination increased protection against leprosy by about 50% compared with a single BCG vaccination, even though it did not protect against pulmonary tuberculosis. In the other trial, 41 302 children born in Algeria between 1935 and 1947 were given BCG orally at birth and then alternately allocated to receive no further doses or three extra doses at 1, 3, and 7 years of age; revaccination reduced total mortality between 1 and 11 years of age by 27% (95% confidence interval 22% to 31%).

Although BCG reduces mortality from diseases other than tuberculosis, diphtheria-tetanus-pertussis (DTP) vaccine may increase mortality from infections other than diphtheria, tetanus, and pertussis in some circumstances. To assess whether BCG can counteract these harmful non-specific effects of DTP, Roth and colleagues randomised children to receive either no vaccine or a second dose of BCG at 19 months of age, one month after they should have received a booster dose of DTP (DTP4).2 All the children had been given BCG in infancy. No significant difference in mortality was seen between the groups (hazard ratio 1.20, 0.77 to 1.89).

Unfortunately, the trial was inconclusive for several reasons. Firstly, as discussed in the paper, monitoring of the progress of the trial was not ideal. Secondly, mortality during the trial was lower than expected, which is a common finding when free medical care is provided during a study in an area with high mortality. Thirdly, and most importantly, major interactions occurred between BCG, vitamin A, and DTP. Sixty per cent of the children had not received the DTP4 booster at the time of enrolment, and importantly many of these children were given DTP after they had been vaccinated with BCG at 19 months of age..

Children who received BCG had a lower mortality than the controls if they had received DTP4 before enrolment (hazard ratio 0.36, 0.13 to 0.99) and a higher mortality if they had not received DTP4 before enrolment (hazard ratio 1.78, 1.04 to 3.04). Mortality was 0.36 per 100 person years if DTP4 had been given before BCG revaccination, 1.02 in controls who were not revaccinated with BCG (mortality was not affected by DTP4 status at enrolment), and 1.83 if DTP4 had not been given before BCG revaccination. These findings suggest that it may be beneficial to give BCG after a booster dose of DTP, but that it may be harmful to revaccinate with BCG if this is followed by a dose of DTP.

Children were not randomised to receive DTP4 before or after BCG revaccination in this study, so the apparent interaction between DTP and BCG may have been the result of confounding, although this seems unlikely. Similar positive and negative heterologous interactions are common in the immunological literature.

The study adds to the existing evidence that BCG, DTP, and measles vaccines have important heterologous interactions with each other as well as with the pathogens that cause fatal pneumonia in children in developing countries, and that the order in which vaccines are given is important. This raises the exciting prospect that we may be able to reduce child mortality substantially by revising the current immunisation schedule, and it suggests that new vaccines should be tested for their effects on total mortality and not just their effects on the target diseases