The high rate of influenza during the 2017-2018 influenza season brought into sharp focus the value of using standard microbiological and molecular detection techniques in tandem to help determine the best course of treatment for patients with viral infections, bacterial infections, or both. The problem of a bacterial co-infection with influenza is always a primary concern when treating influenza patients, but it is particularly worrying during a flu season like the one just passed, when the dominant strain is quite virulent and the influenza vaccine provides limited protection. When a suspected flu patient enters the ED or ICU of my institution, the University of Nebraska Medical Center, we first perform a rapid test for procalcitonin—a strong biomarker for bacterial infection—to help determine if the patient is at risk of a bacterial co-infection and requires antibiotics. We then also utilize a rapid, multiplexing PCR respiratory panel that detects 17 viruses and three bacteria that cause upper respiratory tract infections.
It is common for bacterial infections to complicate both seasonal and pandemic influenza and lead to hospitalization and mortality, as well as antibiotic therapy. Secondary bacterial respiratory infection typically occurs as either combined viral and bacterial pneumonia or as post-influenza pneumonia. It is widely suspected that post-influenza pneumonia results from the inflammation caused by the primary viral infection, which appears to compromise host immunity against the unrelated bacterial infection.1
Unfortunately, viral influenza, combined viral and bacterial pneumonia, and secondary bacterial infection following influenza are not always easy to distinguish, particularly early in the course of illness. For example, chest X-rays in critically ill patients with viral pneumonia typically reveal bilateral interstitial infiltrates that are indistinguishable from bacterial pneumonia.1 Secondary bacterial infections typically occur during influenza recovery, which makes these infections a bit easier to spot than combined viral and bacterial.2 However, in general, these infections present with very similar symptoms: cough, fever, and shortness of breath.
Secondary bacterial infection with influenza, or a bacterial superinfection, contributes greatly to the morbidity and mortality of influenza. It is a primary cause of hospitalization and is to blame for most pneumonia in those recovering from influenza, including otherwise healthy individuals.3 Although pandemic strains of influenza are usually more pathogenic than seasonal influenza strains, the excess mortality rates during pandemics is primarily caused by secondary bacterial pneumonia.1 An analysis of H1N1 influenza strains from the pandemic 2009 influenza season in the U.S. conducted by the Centers for Disease Control and Prevention (CDC) revealed that 29 percent of fatal H1N1 cases from May to August of 2009 were associated with secondary bacterial infection.4 Retrospective studies of tissue samples from both the 1918 and 1957 influenza pandemics reveal that most of these fatalities were associated with secondary bacterial infections.1 Two common and highly virulent pathogens that cause secondary pneumonia are Staphylococcus aureus and Haemophilus influenza.5 It should be noted that secondary bacterial pneumonia can occur with other respiratory viral infections besides influenza.
As a result of these overlapping symptoms and the high rate of mortality, there is a great temptation to routinely treat patients with viral infections, such as influenza, with antibiotics. In fact, before rapid microbial detection was available, this was often the practice due to concern for rapid development of critical illness if not properly treated.
Impact of antibiotic resistance
The reflexive prescription of antibiotics has had a severe cost: the rampant spread of antibiotic resistance during the past couple of decades. It is vital that we reduce the tremendous misuse of antibiotics in the clinical setting. Overuse of these drugs has played a major role in the acceleration of antibiotic resistance worldwide. In addition, providing antibiotics when a bacterial infection is not present will not benefit and can even harm a patient.
Studies suggest approximately half of all antimicrobial use in the inpatient setting is unneeded or inappropriate.6 For example, viruses are typically the cause of acute bronchitis, but in spite of this up to 80 percent of these patients will be prescribed antibiotics.7 Antibiotics are often used when they are not beneficial, and even when appropriate they may be provided for too long of a duration.8 Appropriate antimicrobial use is essential to avoid patient harm, including drug toxicity, increased drug resistance, and collateral damage such as Clostridium diffiicile-infection.9
According to the World Health Organization’s Global Strategy for Containment of Antimicrobial Resistance: “Antimicrobial resistance costs money, livelihood, and lives, and threatens to undermine the effectiveness of health delivery programs. It has been described as a threat to global stability and national security. Antimicrobial use is the key driver of resistance. This selective pressure comes from a combination of overuse…and misuse.”
A primary strategy to combat antibiotic resistance is antimicrobial stewardship. Antimicrobial stewardship is defined as a rational, systematic approach to the use of antimicrobial agents in order to achieve optimal outcomes. This means using the right agent, at the correct dose, for the appropriate duration in order to cure or prevent infection, while minimizing toxicity and emergence of resistance. The CDC recommends all facilities develop an antimicrobial stewardship program (ASP).
The University of Nebraska Medical Center has an an ASP which has been active since 2004. Its mission is to optimize the utilization of antimicrobial agents in order to realize improved patient outcomes, a positive effect on antimicrobial resistance, and an economic benefit.
An important component of antimicrobial stewardship is identifying the etiology of an infection so the most appropriate therapy can be rapidly initiated. As mentioned earlier, the clinical symptoms of viral and bacterial infection overlap significantly, making decisions regarding antibiotics difficult. To assist in this, since 2013 Nebraska Medical has relied on a PCR-based multiplexing respiratory panel that detects 20 common respiratory pathogens, including 17 viruses and three bacteria. The test provides highly reliable results in less than 45 minutes.
In contrast to the rapid methods for viral infection detection, the traditional methods for diagnosing bacterial infection take at least 48 to 72 hours. Because of this, even when a viral infection is identified, antibiotics are often started and continued until cultures return negative. A tool the Nebraska Medical ASP has been utilizing to rapidly identify bacterial infection is procalcitonin (PCT).
PCT is a 116 amino-acid precursor of calcitonin which under normal circumstances is produced by the thyroid C-cells. Serum concentrations of PCT are normally <0.05 ng/mL, but in circumstances of systemic inflammation, particularly bacterial infection, PCT is produced in large quantities by many body tissues. It is usually detectable within two to four hours and peaks within six to 24 hours (as opposed to C-reactive protein, or CRP, which begins to rise after 12 to 24 hours and peaks at 48 hours).10-12 PCT levels generally parallel the severity of the inflammatory insult or infection; that is, patients with more severe disease have higher levels. Furthermore, PCT has a predictable half-life (roughly 24 hours), which also usually mirrors clinical improvement..
Excellent evidence supports the use of PCT for assisting clinicians in antibiotic management in lower respiratory tract infections (LRTI) including pneumonia, exacerbations of chronic bronchitis, and other assorted infections (bronchitis, asthma exacerbation, etc.). A meta-analysis of eight studies with 3,431 patients found the use of PCT in LRTI resulted in a 31 percent decrease in antibiotic prescriptions and a decrease in antibiotic duration of 1.3 days.13 A second meta-analysis with >6700 patients found that PCT-based management of LRTI not only decreased antibiotic use and antibiotic side effects significantly, but was associated with decreasedmortality compared to usual care.14
Procalcitonin testing in patients with LRTI using a rapid PCT assay has been a core element of the ASP for many years. The FDA recently cleared the PCT test for antibiotic stewardship in LRTI and sepsis patients. We encourage PCT testing in LRTI patients to assist in deciding whether antimicrobial therapy will be useful and when it can be safely stopped.
Decisions regarding antimicrobial therapy should be placed into the clinical context of each patient scenario, considering the site of possible infection, the likelihood of bacterial infection, and the severity of illness. PCT levels may not rise with localized infections (osteomyelitis, localized abscess, etc.), and there are some non-infectious causes of elevated PCT levels, such as recent surgery or trauma and fungal infections.
Serial PCT testing
At Nebraska Medical, when a patient presents with cough, fever, body aches, and suspicious infiltrates on a chest X-ray—particularly during the flu season—we encourage PCT testing, coupled with rapid viral testing. If PCT levels are above 0.25 ng/mL, we encourage antibiotic therapy immediately, and if influenza testing is positive, usually initiate antiviral therapy.
Once the patient is admitted, we also perform serial PCT testing to track PCT as a surrogate for the efficiency of the selected antibiotic therapy. If antibiotics are initiated, PCT testing is repeated roughly every 24 to 72 hours, and once levels drop below 0.25 ng/mL or 80 pecent to 90 percent of the peak value, it is recommended that antibiotics be stopped. If antibiotics are not started but significant concern for bacterial infection is still present, a repeat PCT at six to 12 hours is very useful in determining if withholding antibiotics was appropriate. This allows customization of the antibiotic regimen and results in shorter courses of antibiotic therapy, which is a key benefit of our testing regimen. We have seen a significant reduction in antibiotic overuse not only from reducing antibiotic treatment at the outset of therapy, but also from early discontinuation.
Both rapid viral identification and PCT testing have been valuable tools for determining which patients are likely to have a bacterial co-infection and benefit from antibiotics and when antibiotics can be safely withheld. The accuracy and rapidity of these tests provide a great deal of reassurance regarding treatment decisions in those with suspected influenza and LRTI and allow us to provide optimal, patient specific care.
- van der Sluijs K. Bench-to-bedside review: Bacterial pneumonia with influenza – pathogenesis and clinical implications. Crit Care. 2010;14(2):219.
- Canadian Critical Care Trials Group H1N1 Collaborative. Critically illpatients with 2009 influenza A(H1N1) infection in Canada. JAMA. 2009;302:1872-1879.
- Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis. 2008;198:962-970.
- Centers for Disease Control and Prevention (CDC) Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) – United States, May-August 2009. MMWR. 2009;58:1071-1074.
- Grabowska K, Hogberg L, Penttinen P, Svensson A, Ekdahl K. Occurrence of invasive pneumococcal disease and number of excess cases due to influenza. BMC Infect Dis. 2006;6:58.
- John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis. 1997;24(3):471-485.
- Wenzel RP, Fowler AA. Acute bronchitis. N Engl J Med. 2006;355:2125-2130.
- Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis. 2011;52(10):1232-1240.
- Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008;29(12):1099-1106.
- Christ-Crain, Muller B. Biomarkers in respiratory tract infections:diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J. 2007;30(3):556-573.
- Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011;66(S2):33-40.
- Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Medicine. 2011;9:107.
- Li H, Luo YF, Blackwell TS, Xie CM. Meta-analysis and systematic review of procalcitonin-guided therapy in respiratory tract infections. Antimicrob Agents Chemother. 2011;55(12):5900-5906.
- Schuetz P, Wirz Y, Sager R, et al; Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis, Lancet Infect Dis. 2018;18(1):95-107. doi: 10.1016/S1473-3099(17)30592-3. Epub 2017 Oct 13.
Trevor Van Schooneveld, MD, FACP, serves as Associate Professor, Department of Internal Medicine, at the Nebraska Medical Center, as well as Director of Infectious Diseases Fellowships and Medical Director of the Antimicrobial Stewardship Program. His professional interests include antimicrobial stewardship, C. diff infections, multi-drug resistant gram negative pathogens, and infection biomarkers.