A Newborn Boy with Respiratory Distress

Posted by Carla Rothaus • April 17th, 2015

In the latest Case Record of the Massachusetts General Hospital, a newborn boy was admitted to the hospital because of respiratory distress and hypotension. At delivery, meconium was suctioned from the airway. Respiration and blood pressure improved after intervention, but lethargy and myoclonus developed.

Neonatal brain tumors are often not apparent in utero; only 18% are identified on prenatal ultrasound, even when polyhydramnios and hydrocephalus are present. This is because neonatal brain tumors tend to grow rapidly in the third trimester, after the period when prenatal ultrasonography is performed during uncomplicated pregnancies.

Clinical Pearls

- What is the mortality rate associated with meconium aspiration syndrome?

Meconium is present in 3 to 18% of term deliveries, and in such cases, the meconium aspiration syndrome develops in 2 to 9% of the neonates. The meconium aspiration syndrome accounts for 10% of all neonatal respiratory failure and is associated with a mortality rate of 39%.

- What is the mechanism of lung injury in meconium aspiration syndrome?

Meconium, which is thick and particulate, can physically obstruct the airways, causing a ball-valve phenomenon that then leads to air trapping and hyperinflation. Asymmetric lung inflation, with areas of collapse and hyperinflation, increases the likelihood of pneumothorax and of ventilation-perfusion mismatch. Meconium can cause surfactant inactivation and is also toxic to the type II cells, thereby decreasing production of surfactant. Meconium can also indirectly affect the lung tissue, by inducing inflammatory mediators and apoptosis and by inhibiting lung-fluid resorption.

Morning Report Questions

Q: What lesions are included in the differential diagnosis for congenital brain tumors?:

A: Congenital brain tumors are uncommon, accounting for only 1 to 2% of all brain tumors in pediatric patients (1 to 3 cases per 1 million live births). The differential diagnosis of brain tumors in infants differs from that in older children. Teratomas account for 35 to 45% of all brain tumors in newborns, whereas low-grade astrocytomas comprise the largest proportion of brain tumors affecting older children. Aggressive embryonal tumors — including medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid-rhabdoid tumors — account for nearly one quarter of all brain tumors in both infants and older children, with atypical teratoid-rhabdoid tumors occurring most frequently in infants and very young children. Tumors of the central nervous system in older children are more commonly infratentorial, whereas 60 to 70% of tumors of the central nervous system in neonates are supratentorial.

Q: What is the prognosis for an infant with a congenital brain tumor?

A: Given the large size of many neonatal tumors and the limited therapeutic options, the outcome for newborns and infants who receive a diagnosis of a brain tumor other than choroid plexus papilloma is very poor. The prognosis for neonates with a highly aggressive embryonal tumor is particularly poor; less than 20% of affected children survive. Patients who do survive typically have global impairments, including neurocognitive deficits (69% of affected children have a full-scale intelligence quotient of <85, and 54% have a full-scale intelligence quotient of <70, the standard threshold for mental retardation), motor delays (in 85%), visual impairment, hearing deficits and speech delays (in 50%), and feeding problems and endocrine deficits (in 25%).


Clostridium difficile Infection

Posted by Carla Rothaus • April 17th, 2015

A new review article on Clostridium difficile Infection covers the pathogenesis, epidemiology, diagnosis, and treatment of this nosocomial and potentially fatal infectious diarrhea, as well as the associated risk factors. New treatments include fecal microbiota transplantation for disease that is resistant to vancomycin.

Clostridium difficile is an anaerobic gram-positive, spore-forming, toxin-producing bacillus that is transmitted among humans through the fecal-oral route. C. difficile has emerged as a major enteric pathogen with a worldwide distribution. In the United States, C. difficile is the most frequently reported nosocomial pathogen.

Clinical Pearls

- Who is at risk for C. difficile infection?

The most important risk factor for C. difficile infection remains antibiotic use. Ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are the antibiotics that are most frequently associated with the disease, but almost all antibiotics have been associated with infection. The risk of C. difficile infection and the severity of infection increase as age increases. In one study, the risk of contracting C. difficile during an outbreak was 10 times as high among persons older than 65 years of age as among younger inpatients. The majority of C. difficile infections are hospital-acquired, but community-acquired infection has increased dramatically in the past decade and may now account for up to a third of new cases. Other documented risk factors for infection include advanced age, inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, immunodeficiency, and exposure to an infant carrier or infected adult.

Table 1. Antibiotic Classes and Their Association with Clostridium difficile Infection.

- How is C. difficile infection diagnosed?

Stool culture for C. difficile requires anaerobic culture and is not widely available. Enzyme immunoassay used to be the mainstay of testing for C. difficile infection, since it is rapid and easily performed. Recently, many hospital laboratories have adopted DNA-based tests that detect toxigenic strains and provide higher sensitivity and specificity than does enzyme immunoassay.

Morning Report Questions

Q: What is the recommended treatment for acute C. difficile infection?

A: Metronidazole and oral vancomycin have been the mainstays of treatment for C. difficile infection since the 1970s. For the treatment of severe disease, vancomycin is better than metronidazole, but for mild-to-moderate infection, the two antibiotics have been considered to be equivalent. However, a marked rise in clinical failure associated with metronidazole, especially in patients with the BI/NAP1/027 strain, has been seen in the past decade. Previous studies were underpowered to evaluate differences between metronidazole and vancomycin in cases of nonsevere infection, but recent data suggest an overall superiority of vancomycin. In 2011, fidaxomicin, a poorly absorbed, bactericidal, macrocyclic antibiotic with activity against specific anaerobic gram-positive bacteria, was approved by the Food and Drug Administration for the treatment of C. difficile infection. In phase 3 clinical trials, the cure rate for acute infection was nearly equivalent among patients receiving fidaxomicin and those receiving vancomycin (approximately 90% for each), but the risk of recurrence was 15% among patients receiving  fidaxomicin, as compared with 25% among those receiving vancomycin. However, a reduced risk of recurrence was not seen among patients infected with BI/NAP1/027 strains, which were found in 38% of isolates. The markedly higher cost of fidaxomicin has limited its use, despite its superiority to vancomycin in reducing the risk of recurrence.

Q: How are recurrent C. difficile infections treated?

A: Treatment of a first episode of recurrent infection with a repeat course of either metronidazole or vancomycin for 10 to 14 days is successful in approximately 50% of patients. Second and subsequent recurrences can be difficult to cure, primarily because of the persistence of spores in the bowel or environment and the inability of the patient to mount an effective immune response to C. difficile toxins, rather than to antibiotic resistance. Second recurrences can be treated with fidaxomicin or by a vancomycin regimen involving tapered and pulsed dosing. Recent data suggest that fidaxomicin may be more effective than vancomycin at preventing further episodes of C. difficile after an initial recurrence. Fecal microbial transplantation, a procedure that was first reported in 1958, has recently emerged as an accepted, safe, and effective treatment for recurrent C. difficile infection.

Table 2. Treatment of Clostridium difficile Infection.

Inflammatory Bowel Disease

Posted by Carla Rothaus • April 9th, 2015

A new review article covers the wide range of cancers associated with inflammatory bowel disease and the drugs used to manage them. Surveillance recommendations are presented.

Cancers complicating inflammatory bowel disease can be attributed to chronic intestinal inflammation or to the carcinogenic effects of the immunosuppressive drugs used to treat inflammatory bowel disease.

Clinical Pearls

- What is the epidemiology of colorectal cancer in patients with inflammatory bowel disease?

Patients with inflammatory bowel disease without colonic inflammation and patients with ulcerative colitis limited to the rectum are not at excess risk for colorectal cancer. In contrast, patients with primary sclerosing cholangitis associated with inflammatory bowel disease are at high risk for colorectal cancer, beginning at the time of the diagnosis. In other patients with inflammatory bowel disease, the excess risk of colorectal cancer, as compared with the risk among persons of the same age and sex without inflammatory bowel disease, is driven by the extent, duration, and severity of colonic inflammation.

Table 1. Risk Factors for Colorectal Cancer in Patients with Inflammatory Bowel Disease.

Table 2. Crude Incidence Rate and Standardized Incidence Ratio of Colorectal Cancer in Patients with Inflammatory Bowel Disease.

- How do the precursor colitis-associated dysplastic lesions compare with the dysplastic lesions seen in sporadic colorectal cancer?

As in sporadic colorectal cancer, in which the precursor dysplastic lesion is usually a visible polyp, in colitis, most dysplasia is also visible in the colon. However, colitis-associated dysplastic lesions are often flatter and have less distinct borders, and they can even be invisible when standard endoscopic techniques are used. This has prompted the recommendation to perform extensive biopsies throughout the colorectum, taking care to target any raised or suspicious lesions. Newer endoscopic techniques, especially high-definition white-light colonoscopy and chromoendoscopy with mucosal dye-spraying, enhance the detection of dysplasia, as compared with standard-light colonoscopy. This is why most international authorities now favor chromoendoscopy with targeted biopsies over random biopsies, although the latter approach, alone or in combination with targeted biopsies, has not yet been fully abandoned.

Figure 1. Pathogenesis of Colorectal Carcinoma.

Morning Report Questions

Q: What is the relative risk of cancer in patients with inflammatory bowel disease treated with thiopurines as compared to TNF-alpha antagonists?

A: After adjustment for confounders, current use of thiopurines for inflammatory bowel disease has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7 in adequately powered cohort studies. This excess risk is reversible after thiopurine withdrawal. There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for inflammatory bowel disease, but a long-term excess risk due to accumulated doses cannot yet be ruled out because of the relatively recent use of biologics.

Q: What is the most common type of lymphoma induced by thiopurines in this population?

A: Thiopurines were shown in the 1970s to increase the incidence of non-Hodgkin’s lymphoma after kidney transplantation. This phenomenon was established in the early 2000s in patients with inflammatory bowel disease. Most of the lymphomas induced by thiopurines are posttransplant-like EBV-associated B-cell lymphomas. These lymphomas may occur in patients seropositive for EBV (i.e., almost all adults >30 years of age); in these patients, non-Hodgkin’s lymphoma is attributed to the cytotoxic effects of thiopurines on EBV-specific immune cells that prevent the proliferation of EBV-infected B lymphocytes.

Table 3. Risks of Cancer in Patients with Inflammatory Bowel Disease Exposed to Thiopurines and TNF-alpha Antagonists.

Take the New Interactive Medical Case!

Posted by Karen Buckley • April 9th, 2015

A 43-year-old man with a 6-week history of abdominal pain and diarrhea. The pain was initially epigastric and occurred after eating but then became more constant and diffuse.  The patient rated the pain at 7 on a scale of 0 to 10, with 10 being the most severe pain.  The diarrhea began gradually and was watery, occurred six or seven times daily (including when the patient fasted, at night), and was associated with urgency and tenesmus.

Test your diagnostic and therapeutic skills with this latest Interactive Medical Case, and earn CME credit or MOC points.

Interactive Medical Cases are online simulations based on a real patient’s experience of illness. You follow interactive steps through an evolving patient’s history, diagnosis, and management, from presentation to outcome. During the presentation of the case, you access videos, lab results and brief commentary that explain concepts important for diagnosis and treatment.

You may also wish to browse the list of 35 previous Interactive Medical Cases.

A Woman with Headache and Fever

Posted by Carla Rothaus • April 9th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 28-year-old woman was seen in the emergency department of this hospital because of the acute onset of headache, fever, rash, and myalgias. On examination, she had petechiae on the chest, abdomen, and thighs and a purpuric lesion on the right shoulder.

Neisseria meningitidis is the second most common cause of bacterial meningitis in adults, and most cases occur sporadically.

Clinical Pearls

- What clinical and laboratory findings are often associated with bacterial meningitis?     

The following clinical findings are often associated with bacterial meningitis: mental-status changes, a CSF neutrophil count of greater than 1000 cells per cubic millimeter, visible organisms on Gram’s staining, hypoglycorrhachia (a low CSF glucose level), and an elevated CSF protein level. However, it is important to recognize that one or more clinical or laboratory signs or symptoms that are typical of meningitis — such as fever, nuchal rigidity, altered mental status, and a CSF white-cell count of greater than 1000 per cubic millimeter — may be absent in a substantial number of patients with this diagnosis, and the CSF glucose and protein levels may be normal.

- What microbiologic findings are characteristic of Neisseria meningitidis?

Gram-negative diplococci with a coffee-bean shape are characteristic of N. meningitidis.

Figure 3. Microbiologic Study.

Morning Report Questions

Q: Describe some of the features associated with meningococcal meningitis.

A: N. meningitidis is associated with a rapidly progressive, sometimes fulminant illness characterized by sepsis, petechial rash, purpura, and meningitis. Of adults with meningococcal meningitis, 49% seek medical attention less than 24 hours after the onset of symptoms and 64% have a rash, of whom the majority have petechiae and one fourth have purpura, ecchymoses, or both; impaired consciousness may be absent in 49% and Gram’s staining of CSF may be negative for organisms in 11%.

Q: What disorder has been associated with recurrent meningococcal meningitis?

A: A deficiency in one of the terminal complement components, with the exception of C9, has been associated with recurrent meningococcal meningitis. Although low-grade or transient meningococcal bacteremia can be overcome by opsonization and subsequent phagocytosis, higher-grade or persistent bacteremia requires the complement system for eradication. Vaccination is performed in an attempt to boost the early opsonophagocytic response. Ultimately, however, an intact and a sufficient response of the terminal complement components is crucial in overwhelming the defense mechanisms of this microorganism and in protecting against invasive disease. The risk of N. meningitides infection among persons with a terminal complement deficiency is 7000 to 10,000 times as high as the risk among persons without such a deficiency; furthermore, approximately 50% of persons with a terminal complement deficiency who have had N. meningitidis infection have recurrent infections. However, N. meningitidis infection is often milder and associated with lower mortality among persons with a terminal complement deficiency than it is among persons without such a deficiency.

Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery

Posted by Chana Sacks • April 8th, 2015

“Age,” the great boxer Muhammad Ali famously said, “is whatever you think it is. You are as old as you think you are.”

The role that aging plays in vitality, strength, and wisdom has long been debated, but more recently the question of whether younger is better has been raised about red blood cells.  Currently, blood bank regulations allow for storage of red cells for up to 6 weeks before transfusion.   Some observational studies, including data published in the Journal, suggest this might be too long, finding an association between red cell units stored for more than 2 to 3 weeks and serious adverse events.

Given the confounding inherent in observational data, Steiner and colleagues designed a randomized controlled trial to more definitively explore this question.   Their findings, now published in the Journal, call the conclusions of these prior observational studies into question.

Investigators enrolled participants 12 years of age or older who were undergoing complex cardiac surgery and were deemed likely to undergo red blood cell transfusions.  For all intraoperative and postoperative transfusions, participants were randomized to either a shorter storage group (RBCs stored for 10 days or less) or a longer storage group (RBCs stored for 21 days or more).   The primary outcome was the change in the Multiple Organ Dysfunction Score (MODS), a measure from 0-24 that is sensitive to minor changes in clinical status and incorporates mortality, through day 7, death or discharge.

Fourteen hundred and eighty-one participants underwent randomization, with 1098 who ultimately received red cell transfusions included in the analysis. Participants had a median age in their early 70s, were about 40% male, and 90% white; there was no significant difference in baseline MODS between groups. The median storage time of RBCs was 7 days in the short storage group and 28 days in the longer storage group.

The results: there was no significant difference in the primary endpoint, with a mean change in MODS of 8.5 in the shorter storage group versus 8.7 in the longer storage group (p = 0.44).  There were no differences in either serious or non-serious adverse events except that hyperbilirubinemia was more common in the longer storage group, likely attributable to hemolysis in older red blood cells.  While statistically significant, the absolute change in total serum bilirubin was 1.5mg/dL in the longer storage group versus 0.8 in the shorter-term storage group — a difference that seems unlikely to be highly clinically significant.

NEJM Deputy Editor Dr. Dan Longo describes this trial as “an important study that demonstrates no clinical benefit to the preferential transfusion of younger red blood cells.” He cautions, however, against overstating this conclusion: given that the older blood group used red cells stored for a median of 4 weeks and current regulations allow storage up to 6, he notes, “This trial doesn’t address whether 5- or 6-week-old blood might be more harmful.”

With that caveat in mind, age as studied here doesn’t seem to make a difference. When we here at the Now@NEJM blog called Mr. Ali for comment about the fact that he had been right all along, he didn’t seem surprised: “It’s hard being humble,” he says, “when you’re as great as I am.”

See also: NEJM Quick Take video summary on this trial

NEJM Group Open Forum – Take part in the conversation!

Posted by Karen Buckley • April 7th, 2015

These active and engaging discussions are happening now on the NEJM Group Open Forum on Medstro.com. Read the questions and answers posted so far, like, share and comment to become a part of the conversation.

Women Transforming the Culture of Medicine: How do women physicians communicate with each other and with their male colleagues? Can the culture of medicine be improved by more inclusion of women in leadership roles? Part 4 of a 6 part discussion series featuring women physicians, brought to you by the NEJM CareerCenter, starts today on the NEJM Group Open Forum, and continues through April 16.

Extracting the Benefits of a Mentorship:  How do you find the right mentor? We’re talking to successful mentor/mentee pairs to see how they made it happen in part 3 of the NEJM CareerCenter discussion series featuring women physicians.  This discussion is ongoing through April 9.

Detecting Trisomies in a General Population: Ask the authors about a new study that confirms cell-free DNA (cfDNA) testing is superior to routine screening for detecting trisomies among pregnant women in a general prenatal screening population.  This discussion is ongoing through April 10.

Free registration is required. Social login is now available through Facebook, Twitter, Google, and LinkedIn.

Emergency Contraception

Posted by Carla Rothaus • April 3rd, 2015

Ulipristal and levonorgestrel pills are the most commonly used form of emergency contraception; ulipristal is slightly more effective, but levonorgestrel is available over the counter in the United States. The most effective approach is insertion of a copper IUD.  Read the new Clinical Practice review article on Emergency Contraception.

Unintended pregnancy is common; in 2008, the most recent year for which data are available, half the 6.8 million pregnancies reported in the United States were unintended.

Clinical Pearls

- Describe the oral emergency contraceptive pills that are available in the United States.

Oral emergency contraceptive pills are the most commonly used form of emergency contraception. Two regimens are currently marketed in the United States: ulipristal acetate (30 mg) and levonorgestrel (1.5 mg). In 39 clinical trials that included a combined total of more than 18,000 women, rates of pregnancy after use of one of these two regimens ranged from 0 to 6.5%. Interpretation of these numbers is problematic because the likelihood of pregnancy in the absence of emergency contraception was not directly assessed; estimates that were based on the days of the menstrual cycle on which the participants had sex suggest that use of each of these regimens reduces the risk of pregnancy after a single sex act by 40 to 90%. In the United States, products containing 1.5 mg of levonorgestrel in one tablet may legally be sold over the counter to women and men of all ages. Although the ulipristal regimen was recently approved for nonprescription sale in Europe, it still requires a prescription in the United States; consequently, use of this regimen in the United States is limited. Some but not all data suggest reduced efficacy of the levonorgestrel regimen in obese women.

- How should oral emergency contraceptives be used?

The levonorgestrel regimen is effective for at least 4 or 5 days after sex but may be more effective the sooner it is taken; data on the ulipristal regimen have not indicated a decrease in efficacy through 120 hours after sex. However, since both regimens work largely by delaying or inhibiting ovulation, and since women are usually unaware of whether ovulation is imminent, prompt use is prudent. Neither of these two oral emergency contraceptive regimens has any recognized contraindications.

Morning Report Questions

Q: How does the copper intrauterine device (IUD) compare with the oral regimens for emergency contraception?

A: The most effective form of emergency contraception is the copper IUD. A review of 42 studies showed that, of 7034 women who received IUDs up to 10 days after unprotected sex, only 0.09% subsequently became pregnant. Recent analyses suggest that the IUD is effective for emergency contraception throughout the menstrual cycle and can be inserted at any point if pregnancy is ruled out. A key advantage of the IUD over oral emergency contraceptive pills is that the IUD can provide ongoing contraception for at least 10 years. Almost all women can safely use an IUD for emergency contraception; the only recognized contraindications are pregnancy, cancer of the genital tract, uterine malformation preventing device placement, copper allergy, mucopurulent cervicitis, current pelvic inflammatory disease, and known current cervical infection with chlamydia or gonorrhea. These conditions can be reasonably ruled out on the basis of interview, examination, and, if indicated, pregnancy test; routine testing for cervical infection is not necessary.

Q: Are these forms of emergency contraception associated with serious complications?

A: No deaths or serious complications have been causally linked to either oral emergency contraception regimen. Previous studies over the past decades have not revealed adverse effects of levonorgestrel exposure during pregnancy on either the woman or the conceptus. Data on ulipristal exposure during pregnancy are limited, but combined data from postmarketing surveillance and clinical trials showed that among 232 pregnancies with a known outcome in which the woman and conceptus were exposed to ulipristal, no teratogenic effects were seen. The incidence of pelvic inflammatory disease after IUD insertion is less than 5% even when the device is inserted through an infected cervix; whether IUD insertion itself increases this incidence has not been definitively established. IUD insertion can be uncomfortable, and some women have vaginal bleeding and cramping after insertion. In the one published study of IUD insertion for emergency contraception, which was conducted in community clinics, the IUD insertion attempt was unsuccessful in 18% of women; this proportion is higher than that reported in clinical trials of IUD insertion for routine contraception.

Table 1. Situations in Which Emergency Contraception May Be Indicated in a Woman Using Routine Contraception.

Community-Acquired Pneumonia in Adults

Posted by Carla Rothaus • April 3rd, 2015

Antimicrobial choices for community-acquired pneumonia in hospitalized patients who do not require ICU-level care continue to be debated. In a new trial, empirical beta-lactam–based therapy with or without a macrolide was compared with fluoroquinolones as initial treatment.

The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. Postma et al. conducted a cluster-randomized crossover trial in the Netherlands to assess whether a strategy of preferred empirical treatment with beta-lactam monotherapy is noninferior to either preferred beta-lactam-macrolide combination therapy or preferred fluoroquinolone monotherapy, with regard to 90-day all-cause mortality among adults with clinically suspected CAP who are admitted to non-ICU wards.

Clinical Pearls

- What do current guidelines recommend for the empirical treatment of adult patients with suspected CAP who are admitted to non-intensive care unit wards?

For patients with clinically suspected CAP who are admitted to a non-intensive care unit ward, guidelines recommend either combination therapy with a beta-lactam plus a macrolide or plus ciprofloxacin or monotherapy with moxifloxacin or levofloxacin for empirical treatment.

- Is there evidence in support of these recommendations?

These guidelines have increased the use of macrolides and fluoroquinolones, although these antibiotic classes have been associated with increased development of resistance. The evidence in support of these recommendations is limited. The recommendation to  add a macrolide to a beta-lactam is based on observational studies, which are prone to confounding by indication. Although fluoroquinolones have been evaluated in randomized, controlled trials, their superiority over beta-lactam monotherapy has not been shown.

Morning Report Questions

Q: Is empirical treatment with beta-lactam monotherapy noninferior to beta-lactam-macrolide combination therapy or fluoroquinolone monotherapy with respect to 90-day all-cause mortality among this population?

A: In the trial by Postma et al., the absolute difference in the adjusted risk of death between the beta-lactam strategy and the beta-lactam-macrolide strategy was 1.9 percentage points (90% confidence interval [CI], −0.6 to 4.4) in favor of the beta-lactam strategy, and the absolute difference between the beta-lactam strategy and the fluoroquinolone strategy was −0.6 percentage points (90% CI, −2.8 to 1.9) in favor of the fluoroquinolone strategy. These confidence intervals do not include the prespecified margin of a 3-percentage-point higher 90-day mortality, thus demonstrating the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies.

Figure 2. Noninferiority Plots.

Q: Is a strategy of empirical treatment with beta-lactam monotherapy associated with a higher rate of complications as compared with beta-lactam-macrolide combination therapy or fluoroquinolone monotherapy?

A: In the Postma study, there were no significant differences among the three strategies in the incidence of major or minor complications.

Initial Antibiotic Choice for Community Acquired Pneumonia

Posted by John Staples • April 2nd, 2015

The basic symptoms which occur in pneumonia … are as follows: acute fever, sticking pain in the side, short rapid breaths, serrated pulse and cough.

  – Maimonides (1138–1204 AD)

Antibiotic treatment of community-acquired pneumonia (CAP) is one of the most remarkable medical developments of the 20th century, yet the choice of initial antibiotics is not without controversy. Current guidelines advise coverage for atypical organisms, but some investigators have pointed to the low incidence of atypical pathogens, the risk of fostering antibiotic resistance, and the specter of increased cardiac events with macrolides. What’s a clinician to do?

In an effort to shed light on this dilemma, Drs. D.F. Postma and C.H. van Werkhoven (University Medical Center, The Netherlands) and colleagues report on the results of the CAP-START study in this week’s NEJM. Seven Dutch hospitals were randomly assigned to treat patients admitted to non-ICU wards with CAP according to one of three antibiotic strategies: Beta-lactam monotherapy (such as ceftriaxone alone), beta-lactam/macrolide combination therapy (such as ceftriaxone plus azithromycin), or fluoroquinolone monotherapy (such as levofloxacin alone). Physicians could deviate from the strategy at their discretion. Hospitals crossed over to a different strategy every four months until trial completion, at which time a total of 2,283 patients had been recruited.

The investigators found that beta-lactam monotherapy was non-inferior to the other strategies, with similar crude 90-day mortality rates for all three groups (9%, 11%, and 9%, respectively). Median hospital length of stay was 6 days for all strategies.

“The non-inferiority of beta-lactam monotherapy for CAP is intriguing and should be considered in light of the risk of side effects (albeit small but not inconsequential) and the increasing burden of antimicrobial resistance,” says infectious disease specialist and NEJM Deputy Editor Dr. Lindsey Baden. “But readers should note that deviations from the recommended strategy for medical reasons occurred in about 25% of patients – suggesting there’s still a need for clinical judgment based on local and clinical factors.”

Unlike the pre-antibiotic era (when Sir William Osler called pneumonia “the Captain of the Men of Death”), modern medicine has a panoply of effective antibiotics from which to choose when a patient is admitted with CAP. What is the take-home message from CAP-START? Perhaps beta-lactam monotherapy is an adequate first volley to fire at the Captain.