Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
- Measles Vaccination in Infants Younger than 9 Months
- Studies Shed Light on Oral Antibiotic Strategies for Gram-Negative Infections
- Your Hunch Was Right: Blood Cultures After Antibiotics Aren’t as Good
Did you miss the previous edition of Journal Club? You can find it and other past installments in the IDSA News archives. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, M.D., FIDSA, in each issue of Clinical Infectious Diseases.
Measles Vaccination in Infants Younger than 9 Months
Reviewed by Zeina A. Kanafani, M.D., M.S., FIDSA
Recent years have witnessed a surge in cases of measles, both in endemic as well as in low-risk countries leading to various outbreaks. Current guidelines recommend the administration of measles containing vaccines (MCVs) starting at 9 or 12 months of age. In the wake of increased concern for transmission of measles, there is an interest in evaluating whether vaccination earlier than 9 months of age is effective and safe, and whether it influences the response to further MCV administrations.
Two World Health Organization-funded meta-analyses recently published in Lancet Infectious Diseases aimed to answer these questions. The authors included clinical trials, outbreak investigations, and cohort and case-control studies where the first dose of MCV (referred to as MCV1) was administered before 9 months of age.
In the first meta-analysis, evaluating immunogenicity, effectiveness, and safety data, 56 studies were included in the analysis. The overall seroconversion rate with MCV1 was 50% at 4 months and increased progressively to reach 85% at 8 months of age. Based on data from five studies, the pooled vaccine effectiveness estimate of MCV1 was 51% in infants younger than 9 months vs 83% in those aged 9 months or older (P < 0.0001). There was some variability in seroconversion rates with different vaccine strains, with more infants showing seroconversion at 6 months with the Edmonston-Zagreb strain than with the Schwarz strain. The presence of maternal antibodies was also associated with a reduced seroconversion by 33%. Adverse events after MCV1 were similar among both age groups.
The purpose of the second meta-analysis was to estimate the effect of MCV1 earlier than 9 months on the immune response to subsequent MCV doses. Based on data from 13 studies, the pooled proportion of seropositivity after two MCV doses was 98% with MCV1 before 9 months of age. In studies that compared both age groups, the pooled proportion of seropositive infants was not statistically different (pooled estimated difference 4%; P = 0.087). Four studies found early vaccination schedules resulted in lower geometric mean titers after MCV2, with the difference reaching statistical significance in one study. Additionally, measles virus-specific cellular immune responses were determined in five studies, finding that age at MCV1 did not have an effect on T-cell responses after two or three MCV doses.
Based on both analyses, the authors conclude that early measles vaccination is effective and safe. However, there is concern about the blunting effect of early vaccination on antibody titers after subsequent vaccination. Future randomized trials should address these findings in order to determine the best age of first administration of the measles vaccine, both in outbreak and non-outbreak settings.
(Lochlainn et al. Lancet Infect Dis. 2019;19:1235–45.)
(Lochlainn et al. Lancet Infect Dis. 2019;19:1246–54.)
Studies Shed Light on Oral Antibiotic Strategies for Gram-Negative Infections
Reviewed by Manie Beheshti, M.D.
Owing to an increasing number of studies, we are gaining a better understanding of step-down therapy from intravenous to oral antibiotics. Two recent articles address this strategy in patients with Gram-negative infections.
A randomized, controlled study in Clinical Infectious Diseases compared intravenous and oral therapy for patients with Klebsiella pneumonia liver abscess. In this 4-year study at three academic centers in Singapore, adult patients with radiographic evidence of liver abscess and K. pneumoniae isolated from cultures of either the blood or liver aspirate who had been on 7 or less days of effective therapy were randomized 1:1 to continue oral or intravenous therapy. The primary endpoint was based on predefined “clinical cure” at week 12. Excluded were patients with severe sepsis, central nervous system abscess, or endophthalmitis.
The primary endpoint was met in 71/74 (oral antibiotics group, all ciprofloxacin) and 72/78 (intravenous antibiotics group, all ceftriaxone) patients, demonstrating the predetermined non-inferiority criteria at 12 weeks. Similar results were found with the per-protocol population and univariate analysis adjusting for abscess size, drainage, age, and diabetes exhibited no significant change in findings. Similar rates of antibiotic extension beyond week 4 were noted in both groups with a median antibiotic duration of 29.0 days. Rates of serious adverse events were similar between the two groups. Similar to previously published data, the overall cure rate was 93%. As expected, costs were higher in the intravenous antibiotic group.
In another study, published in Open Forum Infectious Diseases, a systematic review and meta-analysis aimed to compare step-down oral therapy for Enterobacteriaceae bacteremia. Data from eight studies involving 2,289 total adult patients with a variety of sources of infection were utilized to determine mortality and reinfection rates comparing high versus low bioavailability oral antibiotics, namely fluoroquinolones (FQs) or trimethoprim-sulfamethoxazole (TMP-SMX) versus β-lactams (BLs).
All-cause mortality was not significantly different in the two groups. Of the 1,666 patients transitioned to FQs or TMP-SMX, 85 (5.1%) died compared to 22 of 623 (3.5%) patients transitioned to BLs. Although low patient numbers limited analysis of BLs compared to TMP-SMX, recurrent infection was twice as likely with BLs when compared to FQs. The authors posited that factors such as underdosing of BLs and lower medication adherence owing to the more frequent dosing of BLs may have contributed to the increased recurrence.
These studies shed further light on an area being more widely addressed by the literature. While many challenges remain in determining optimal therapeutics, these studies show that in patients with Enterobacteriaceae bacteremia or K. pneumoniae liver abscesses, treatment strategies utilizing step-down strategies to oral antibiotics can be successful.
(Molton et al. Clin Infect Dis. Published online: Oct. 23, 2019.)
(Punjabi et al. Open Forum Infect Dis. 2019;6(10):ofz364.)
Your Hunch Was Right: Blood Cultures After Antibiotics Aren’t as Good
Reviewed by Nirav Patel, M.D.
In the era of time critical management for sepsis, ensuring that the box is checked can take priority over true diagnostic accuracy. Furthermore, timely antibiotic administration remains critical to patient outcomes in sepsis and unwarranted delays increase mortality. Nonetheless, there is uncertainty about the impact of drawing blood cultures shortly after antibiotic administration, which most clinicians would assume would reduce diagnostic sensitivity. However, this had not been strongly established prior to this study recently published in the Annals of Internal Medicine.
The study evaluated adult patients presenting with concern for severe sepsis to seven emergency departments in the United States and Canada. Blood cultures were obtained prior to antibiotic administration and between 30 and 240 minutes after. Three hundred and twenty-five patients were included in the study. Cultures were positive in 102 of 325 patients (31%) prior to antibiotic administration and in 63 of 325 patients (19%) after, resulting in a sensitivity of 53% of postantibiotic cultures.
Infectious disease practitioners may benefit from the knowledge that there is an approximately 50% reduction in diagnostic sensitivity of blood cultures when obtained after antibiotic administration. This study provides a robust directive to frontline practitioners and designers of sepsis quality improvement programs to ensure prioritization of blood culture draw prior to antibiotic administration.
(Cheng et al. Ann Intern Med. 2019;171(8):547-554.)