Category: Antibiotics

Antibiotics, With or Without Delay!

This is a trial addressing a practice to which I’m not opposed, and recommended by some other experts: delayed antibiotic prescribing. Delayed prescribing, providing patients with an antibiotic to fill “just in case they get worse”, has seemingly reasonable fundamental components. An encounter with a patient is a single snapshot in time, frequently without a clear picture of the ongoing clinical course. Early bacterial illness may not be clearly apparent as infection, with subsequent days bringing the diagnosis into clearer focus. In the interests of respecting patients’ time and healthcare resource utilization, why not provide a provisional antibiotic prescription to be filled by the patient if they self-assess clinical worsening?

This specific delayed antibiotic prescribing trial was performed in children presenting with an acute, uncomplicated respiratory infection – which, by their inclusion criteria included acute otitis media, pharyngitis, rhinosinusitis, or acute bronchitis. These authors randomized 436 children to one of three arms: immediate antibiotics, delayed antibiotics, or no antibiotics. Parents whose children were enrolled in the delayed antibiotics arm were instructed to start the antibiotic if their children worsened or did not start feeling better within a few days to weeks, depending on the underlying illness at time of enrollment. The primary outcome for the trial was severity and duration of acute symptoms over the following month.

The good news – the trial was a “success”. Children randomized to the delayed antibiotics strategy reported similar numbers of symptom days as those randomized to the immediate antibiotics arm. Whether it was pharyngitis, otitis media, rhinosinusitis or bronchitis, children remained symptomatic – for 4 to 10 days – regardless of their treatment arm. Delayed antibiotic prescribing, then, was not clinically harmful with respect to the primary illness.

With respect to antibiotic use and adverse effects, within 30 days of enrolment nearly the entire immediate antibiotic arm used their prescriptions. In contrast, only 25% of those randomized to delayed antibiotics did so, along with 12% of those who had no antibiotic prescribed. As to be expected, those with fewer antibiotic exposures suffered fewer gastrointestinal side effects. Unscheduled primary care utilization was uncommon and similar across all treatment groups.

So, “success”!

Except for that other niggling, less-heralded study arm: the no antibiotics arm.

The authors conclude by saying “DAP compared to IAP led to greatly reduced antibiotic use and fewer gastrointestinal adverse effects associated with antibiotic intake.” While this is not untrue, the actual final conclusion might more appropriately be: “No practical advice can be provided regarding the appropriateness of a delayed antibiotic strategy, as this trial best demonstrates the no antibiotic strategy most likely the best choice.”

The entire premise of a delayed strategy is, in the context of clinical uncertainty, there is a substantial likelihood the underlying illness will ultimately require antibiotics for successful resolution. In this trial, the authors have selected a scenario where that is not the case – and, therefore, haven’t produced terribly generalizable information regarding delayed antibiotic prescribing strategies.

The authors have, at least, provided some useful insight into human behavior with respect to delayed antibiotics and the rate at which they are filled. But, mostly, they have best demonstrated, yet again, the vast majority of children evaluated for respiratory illnesses are best treated with supportive care and time, rather than antibiotics.

“Delayed Antibiotic Prescription for Children With Respiratory Infections: A Randomized Trial”
https://pediatrics.aappublications.org/content/early/2021/02/09/peds.2020-1323

APPAC II

The original APPAC was one of the first trials systematically testing an antibiotics-first strategy for appendicitis, demonstrating its feasibly and safety as an alternative to immediate surgery. Based on these and other data, reasonable differences of opinion exists regarding the favored approach. In Finland, however, where the original APPAC was performed, they’ve already moved on from the “if” question and onto “how best”.

In APPAC II, the “how best” question involves whether the initial treatment for uncomplicated appendicitis (no perforation, appendicolith, or tumor) need be intravenous, or whether a completely oral antibiotic strategy is noninferior. The intravenous strategy was comprised of two days of ertapenem, followed by five days of levofloxacin plus metronidazole, while the oral strategy was comprised of seven days of moxifloxacin monotherapy. All patients were hospitalized for observation for at least 20 hours, the minimum time necessary for two doses of intravenous antibiotics. The primary endpoint was treatment success at 1 year, defined as avoidance of surgery or recurrent appendicitis.

There were approximately 300 patients enrolled in each group, based on sample size estimates derived from their non-inferiority margin of -6% and an expected success rate of 73%. At one year follow-up, the success rate for the intravenous cohort was 73%, as compared with 70% for oral antibiotics. However, this did not meet their pre-defined margin for non-inferiority, as the difference of −3.6% had a one-sided 95% CI lower bound of -9.7%. This leads us into our favorite statistical wasteland, the land of not-non-inferior, yet also not inferior, nor equivalent.

These are interesting data, and, cutting through the statistical chicanery, it is most likely the outcomes in each arm are virtually indistinguishable. It is hard to tell, however, the advantage of adopting the oral strategy, as implemented, in the face of even a small amount of potential harm. Because all patients were hospitalized and observed inititally, the oral strategy does not avoid unnecessary bed utilization. It is not clear whether this initial hospitalization could be avoided; this initial timeframe constituted the greatest percentage of treatment failures, although this can also be potentially confounded by conservative clinical judgement and readily available operative resources.

The choice of moxifloxacin monotherapy as the comparator is interesting, as it is not strictly equivalent to levofloxacin plus metronidazole with respect to its anaerobic efficacy. It is rather baffling not to simply use levofloxacin plus metronidazole as the oral therapy in each group. The authors cite several publications demonstrating the viability of moxifloxacin monotherapy for intra-abdominal infections, but it seems to muddle the comparison unnecessarily.

In the end, these represent yet another interesting permutation in the approach to the non-surgical management of appendicitis. From a pragmatic standpoint, it seems rather mooted until such data exist showing patients can be managed without hospitalization. Then, if an acute emergency department evaluation is being performed, this provides plenty of opportunity to give at least a single intravenous dose of antibiotics, if warranted, rather than hewing dogmatically to oral-only – admitting fluoroquinolones have identical oral and intravenous bioavailability. These data raise as many follow-up questions as answers, unfortunately.

Finally, tucked into this publication is an even more interesting tidbit: APPAC III. Characterizing diverticulitis as “left-sided appendicitis”, and noting the relative inessential nature of antibiotics for diverticulitis, this currently-enrolling trial tests antibiotics versus placebo for uncomplicated appendicitis. In a world where others are slow to move beyond mandatory operative intervention, this group is testing zero intervention at all – fascinating!

“Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis”
https://jamanetwork.com/journals/jama/fullarticle/2775227

More Anti-Antibiotics in Diverticulitis

It’s hard to believe I’ve covered this topic – the evidence for reducing antibiotic exposure in diverticulitis – as long ago as 2013. While it might not be the prudent thing to be the first adopter of a new medical practice, I’d have thought this idea could have had more traction, sooner.

This latest piece of evidence is a “pragmatic” randomized, placebo-controlled, double-blind trial of patients admitted for “non-complicated” diverticulitis. “Non-complicated” in this context means, effectively, non-perforated, and explicitly defined as Hinchey 1a grade. Patients were also excluded if they had multiple systemic inflammatory response criteria, immunosuppression, or other comorbid physical status. Those who received antibiotics were given a regimen including cefuroxime, metronidazole, and amoxicillin/clavulanic acid, while the opposing side received matching placebo.

The trial was rolled out across four hospitals between 2015 and 2019, including three in Auckland, New Zealand, and one in Sydney, Australia and ultimately included 180 participants. The primary outcome was length of hospital stay, the difference for which was not statistically significant at 40 hours for the antibiotic cohort and 46 hours for placebo. The authors tracked many adverse events, discontinuation reasons, and protocol terminations, and there was no clear pattern or apparent trend favoring either cohort, within the scope of the small sample.

After so many years, it would be lovely to finally see better guideline uptake in support of antibiotic stewardship for mild diverticulitis. It certainly seems consistent across all the various trials and cohorts by multiple groups across the world, now, there is minimal, if any, additive benefit – or, at the least, the harms from antibiotic use are similar to those whose diverticulitis progresses left untreated.

“Antibiotics Do Not Reduce Length of Hospital Stay for Uncomplicated Diverticulitis in a Pragmatic Double-Blind Randomized Trial”
https://reader.elsevier.com/reader/sd/pii/S1542356520304262

Potpourri

Just a quick-hit collection of articles I’ve wanted to highlight/catalogue for future reference, but couldn’t find the time for deep dives into each:

Shared Decision Making in Patients With Suspected Uncomplicated Ureterolithiasis: A Decision Aid Development Study.
For this common clinical scenario in the Emergency Department, the authors have developed a patient-facing packet to facilitate shared decision-making. However, more important than the product, is the process these authors have described for its creation. A similar roadmap could be followed to address similar opportunities in your department.

Reduction of Inappropriate Antibiotic Use and Improved Outcomes by Implementation of an Algorithm-Based Clinical Guideline for Nonpurulent Skin and Soft Tissue Infections.
Amazing – using the correct antibiotics reduces treatment failures and, likewise, treatment failures necessitating admission to the hospital. This is an effort-intensive intervention featuring provider education and individual prescribing feedback, but, given the limitations, can be considered a change management success. Whether this can be replicated at your institution will depend on many cultural factors.

Utility of INR For Prediction of Delayed Intracranial Hemorrhage Among Warfarin Users with Head Injury.
Here’s a topic with a ton of practice variation – do you admit patients with closed head injury on anticoagulation for observation? This retrospective review of those patients just on warfarin tries to make the case patients with INR <2 are safe for discharge, whereas those with higher scores are not. Again, however, the yield of observation is somewhere south of 1% in their entire therapeutic cohort, making it truly challenging to find the inflection point of value. Another opportunity for shared decision-making?

Performance of Novel High-Sensitivity Cardiac Troponin I Assays for 0/1-Hour and 0/2- to 3-Hour Evaluations for Acute Myocardial Infarction: Results From the HIGH-US Study.
A detailed look at high-sensitivity Troponin I rule-in/rule-out algorithms suggests a 0/1-hour strategy is similar to a 0/3-hour strategy. Overall, while the disposition of patients is likely to be more rapid from the 0/1 hour strategy, a greater proportion of patients ultimately fall into the “intermediate” zone requiring further observation and diagnostics. Certainly, combinations of hsTnI and other risk-stratification instruments ought to mean the majority of patients with straightforward chest pain presentations may be discharged from the Emergency Department.

Randomized Clinical Trial of IV Acetaminophen as an Adjunct to IV Hydromorphone for Acute Severe Pain in Emergency Department Patients.
In this trial, patients receiving hydromorphone were randomized to receive adjunctive treatment with IV acetaminophen or placebo. With 159 patients, they found advantages to the multi-modal approach favoring the addition of acetaminophen – but the confidence interval for their primary outcome crossed unity by 0.01. The authors conclude this is a negative trial, but it rather seems to me there’s certainly no harm in adding acetaminophen (it need not be IV) – adding it likely has a favorable effect, even if the effect size may not be large.

Effect of No Prehydration vs Sodium Bicarbonate Prehydration Prior to Contrast-Enhanced Computed Tomography in the Prevention of Postcontrast Acute Kidney Injury in Adults With Chronic Kidney Disease: The Kompas Randomized Clinical Trial.
In news surprising no one, another trial fails to show benefit of prehydration in staving off post-contrast exposure acute kidney injury. As seen on Twitter, rather than “contrast-induced nephropathy”, the clinical paradigm is effectively “contrast-adjacent nephropathy.” The impairment in renal function is associated with the underlying medical illness and not the exposure to IV contrast. Thus, no intervention – such as prehydration – can prevent such.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.
This interesting observational study evaluated patients with a diagnosis of non-ST elevation acute coronary syndrome using coronary CT angiography prior to invasive coronary angiography. The good news: CT angiography was probably useful at excluding obstructive coronary disease. The bad news: nearly 70% of patients had a coronary stenosis identified on invasive angiography, so patient selection prior to CT angiography will be important to improve the value of using it as a screen to prevent invasive angiography.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.
As we watch our healthcare delivery system struggle and groan under the various strains and burdens, one of the culprits has always been the influence of pharmaceutical/device manufacturers targeting investments to improve uptake of their products. In this observational analysis of the OpenPayments database, these authors identified the recipients of financial support from the manufacturers of endovascular devices. About 16% of vascular neurologists received funding from industry, but over 75% could be identified as “influencers” – chiefs of staff, department chairs, or similar. Pharma et al should always be remembered they are serving the interests of owners and shareholders, and not patients and our healthcare system.

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

  • Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
  • Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
  • Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
  • The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
  • Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
  • No routine empiric anerobic coverage for suspected aspiration pneumonia.
  • No routine steroids for CAP, even severe.
  • Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
  • No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

It’s Lefamulin Time

New antimicrobials – particularly those with novel mechanism of action – are rare. Lefamulin, a pleuromutilin class antibiotic, is not new, but it’s new to humans – or, even more specifically, new to oral and intravenous availability in humans.

This article in JAMA details LEAP-2, the sequel (of course) to LEAP-1. This clinical trial demonstrates the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of generally mild community-acquired pneumonia. LEAP-1, as I’m certain you recall, demonstrated its non-inferiority as an intravenous-to-oral regimen for slightly-less-mild CAP in whom hospitalization was reasonable. Without belaboring the results too greatly, “early clinical response in the intention to treat population” and “test of cure in modified intention to treat populations” were generally similar, with response rates of about 90% for each arm. However, lefamulin is certainly less well-tolerated – diarrhea, nausea, and vomiting far exceeded the frequency observed in the moxifloxacin cohort.

These are likely valid results with respect to efficacy and a 10% non-inferiority margin, considering pleuromutilin antibiotics have been used effectively in animals for decades. This was, however, a tightly-controlled trial, narrowly targeted at meeting the threshold for approval in Europe and the United States (i.e., 50% of patients required to be PORT Class II, so 50.4% of them were). All authors, study procedures, and analyses were overseen by the sponsor, and trial sites were scattered across the (somewhat) developing world. Irregularities regarding efficacy differences and assessments were seen at several sites and addressed in the supplementary appendix, noting mostly the exclusion of results from these sites would not have affected the overall trial outcome. All these signals, however, do raise concerns regarding underreporting of adverse events and systematic minimization of any efficacy differences.

It’s splendid to have a new option for cases of multidrug resistance. For $200 to $300 a day, however, no need to indulge unnecessarily – or be the first on your block to drive the new hotness.

“Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia”
https://jamanetwork.com/journals/jama/fullarticle/2752331

The Antibiotic Penalty on Blood Cultures

As the administrative team likes to remind us: blood cultures before antibiotics.

Blood cultures before antibiotics.

Blood cultures? Before antibiotics.

What’s the point, we say – aren’t the antibiotics the actual life-saving intervention? And the answer, when relevant, ties into identifying the specific susceptibility of the infective agent, such that antibiotics may ultimately be narrowed to the minimum necessary for cure. It’s a noble premise, at least.

But, so, what does happen when you give antibiotics first?

At least one recent retrospective study has pulled data from their health system showing a clear decrease in blood culture positivity following administration of antibiotics, but these results may be limited by potential differences between groups. In contrast, this clever little study looks at it prospectively: the same 325 Emergency Department patients with “severe manifestation of” sepsis – hypotensive or lactate >4 mmol/L – received blood culture draws both prior to, and just following, antibiotic administration.

Before antibiotics: 31.4% positive blood cultures.

After antibiotics: 19.4% positive blood cultures.

It is not a perfect study by any means, but a long story short: if you’re going to go to the trouble of drawing and processing blood cultures, draw them before you start antimicrobial treatment. But, clearly, the antimicrobials are doing their job – do it expeditiously such that your patient does not suffer from unwanted delay.

“Blood Culture Results Before and After Antimicrobial Administration in
Patients With Severe Manifestations of Sepsis”
https://annals.org/aim/fullarticle/2751453/blood-culture-results-before-after-antimicrobial-administration-patients-severe-manifestations

Let’s Not Treat the Asymptomatic (Urine)

It’s a fairly common picture: the altered/declining/demented/elderly, with a small leukocytosis, and some positive elements on a urinalysis – but no clear symptoms of urinary tract infection. For lack of a better explanation, perhaps, treatment is begun with antibiotics. The benefit is uncertain, but, at the least it is more likely to benefit than harm?

This retrospective study, within the scope of its limitations, finds no reliable benefit to treatment, and more likely harms. This study performed chart reviews on 2,733 hospitalized patients with “asymptomatic bacteriuria”, as defined as a positive urine culture in the absence of documented Infectious Diseases Society of America criteria for UTI. Constitutional or non-specific symptoms in those unable to specifically report (e.g, dementia, AMS) were not considered as consistent with UTI unless multiple systemic signs of infection were also present.

Not only did nearly 80% of patients identified as ASB receive antibiotics, these authors were unable to shed light on any value of treatment. Treatment of ASB was more common in the scenario above, but was also widespread in patients capable of reporting symptoms yet having none documented. The dependence on retrospective chart abstraction limits the accuracy of their observations, but they have face validity.

Patient-oriented outcomes associated with either antibiotic treatment or non-treatment were 30-day mortality, 30-day readmission, 30-day post-discharge Emergency Department visit, C. diff infection, and duration of hospitalization. Most adjusted and unadjusted odds ratios for poorer outcomes were associated with treating ASB, but these differences were generally not statistically significant. Duration of hospitalization, however, was statistically associated with antibiotic treatment. This may be a spurious finding relating to contextual clinical confounders, but it may also represent an element of diagnostic inertia distracting from the true underlying etiology relating to hospitalization.

Regardless, consistent with this journal’s series feature “Less is More”, yet another instance in which common practice does not easily lend itself to confirmation of value.

“Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2748454

CRP for COPD

If you follow this blog, you’ve probably read various critiques of the use of procalcitonin to guide antibiotic prescribing. Procalcitonin, a non-specific inflammatory marker, provides a small amount of informational value regarding the underlying etiology of infection, but my underlying criticism of its envisioned use is:

  • The baseline rate of antibiotic prescribing is so poor, and the likelihood of poor outcomes so low, a safe reduction in prescribing is guaranteed.
  • It provides about the same area-under-the-curve for predicting bacterial etiologies as C-reactive protein.
  • The pro-procalcitonin studies and contributions are effectively covered in the fingerprints of the manufacturers of the assay.

So, then, replace the above complaints with – well, mostly just the top one, because here we are with CRP doing the same things for which procalcitonin is advertised, and the apparent conflict-of-interest is turned down a few notches.

In this study, 86 primary care clinics in England and Wales randomized patients with a diagnosis of COPD and a clinical diagnosis of an acute exacerbation to use of point-of-care CRP testing versus usual care. Similar to those studies seen with procalcitonin, prescribers were provided guidance with respect to various CRP levels and recommendations for either prescribing, possible prescribing, or do not prescribe. The primary outcome and secondary outcomes were associated with receipt of any antibiotics, quality of life, and adverse health outcomes.

Over the course of two years, 649 patients were randomized to the two arms, with a handful of each failing to properly undergo initial study procedures. The prescribing rate at the index visit in the “usual care” group: 69.7%. The prescribing rate with CRP: 47.7%. A winner is CRP!

Except that 76% of patients had CRP less than the threshold at which antibiotics were recommended. Another 12% were in the “antibiotics maybe” group. Thus, nearly 90% of the entire cohort were suspected of having no or limited benefit to antibiotics – so, of course any safety margin to deprescribing would be satisfied. And, considering the baseline rate of prescribing was 70%, again, there is basically no possible way a stewardship intervention could fail.

The editorial accompanying this article is darkly amusing, stating “the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD”. However, it also goes on to note these data hardly identify “which patients (if any) truly benefit from antibiotic therapy”(emphasis mine). Some trials testing 100% antibiotic prescribing vs. zero prescribing (e.g., placebo) have found minimal, or no, benefit. As with procalcitonin, our problem is a pervasive culture of over-prescribing, and ultimate answer is the same for CRP: we don’t need to introduce a marginally informative test into this low-stakes patient population, we simply need to snap out of our collective insanity.

“C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations”
https://www.nejm.org/doi/10.1056/NEJMoa1803185

Antibiotics & Hospitalization for Asthma

Reactive airway disease and asthma exacerbations. The mainstays of treatment are beta-agonist bronchodilators, systemic corticosteroids, and other adjunctive therapies as indicated. Conspicuously absent from treatment guidelines is any role for antibiotics – but that’s not stopping folks from using them.

In this retrospective data on inpatient hospitalizations comprised of 19,811 patients with acute asthma, 8,788 (44%) received antibiotics within the first two days of hospitalization. Patients receiving early antibiotics were mildly more ill than those who did not, and in their unadjusted analysis “treatment failure” was more common and length-of-stay was longer, as were antibiotic-associated adverse effects. The authors then performed a more evenly-matched propensity score analysis, featuring comparing 6,833 patients in each cohort – and find roughly the same associations, again favoring those who were not treated with antibiotics.

As usual, the limitations are the retrospective nature of a data-dredging exercise such as this, and potential for unmeasured confounders. I wouldn’t make much of the association between no-antibiotics and decreased length-of-stay, as it’s reasonable to expect confounding from selection bias at play for those receiving antibiotics and those who do not. Regardless, antibiotics were frequently used – and rather than wait for proof they are unhelpful, it seems more prudent to wait for proof they are.

There’s also been a fair bit of talk about the so-called anti-inflammatory effect of macrolides, specifically azithromycin. These represented about half the antibiotics used in these patients, and, obviously, there weren’t any further hypothesis-generating signals of benefit along that line of physiologic plausibility.

“Association of Antibiotic Treatment With Outcomes in Patients Hospitalized for an Asthma Exacerbation Treated With Systemic Corticosteroids”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2721036