What is the evidence to support the need to cover for anaerobes in aspiration pneumonia in children/adolescents?

Comment by InpharmD Researcher

Available evidence evaluating the need to cover for anaerobes in pediatrics treated for aspiration pneumonia is controversial. While one retrospective study demonstrated receiving anaerobic coverage in pediatrics has been associated with improved outcomes, another study revealed that antibiotic choice did not impact treatment failure rates (see Tables 1-2). However, the 2019 American Thoracic Society and Infectious Diseases Society of America guidelines for the treatment of community-acquired pneumonia do not suggest the routine use of adding anaerobic coverage in aspiration pneumonia unless lung abscess or empyema is suspected. Further prospective controlled studies are warranted to confirm these findings in pediatric population.

Background

The 2019 American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines for the treatment of community-acquired pneumonia (CAP) do not suggest the routine use of adding anaerobic coverage in aspiration pneumonia unless lung abscess or empyema is suspected (conditional recommendation, very low quality of evidence). The rationale for this recommendation is that although older studies showed higher isolation rates in this population, more recent literature have found anaerobes to be uncommon in hospitalized patients with suspected aspiration. This, in addition to the increasing prevalence of antibiotic-resistance pathogens and complications of antibiotics, highlights the need to employ a treatment approach that avoids the unnecessary use of antibiotics. There is a lack of discussion on addition of anaerobic coverage subsequent to culture results. [1]

The 2021 clinical pathway for patients with intra-abdominal infections was published by a collaboration from the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST). Initial antibiotic therapy is typically empiric due to urgency of treatment needs and delay in culture and susceptibility results. Empiric antibiotic therapy for patients with IAI should include agents with activity against aerobic gram-negative bacteria (e.g., Enterobacteriaceae), aerobic streptococci, and obligate enteric anaerobic organisms found in the gastrointestinal tract. Obtaining cultures allows for alteration of antimicrobial therapy spectrum, although the panel particularly stresses obtaining cultures in critically ill patients. There is a lack of discussion on continuation of antibiotics targeting anaerobes if cultures are negative. Conversely, the 2010 guidelines by the Surgical Infection Society and the Infectious Disease Society of America (IDSA) on management of complicated IAI suggests that cultures are not necessary for patients with community-acquired IAI if empiric antimicrobial therapy active against common anaerobic pathogens is provided. Notably, however, these guidelines are archived, and no further suggestions on tailoring antimicrobial therapy are provided on the basis of obtaining negative cultures. [2], [3]

A recent 2023 systematic review and meta-analysis investigates implementation of routine anaerobic blood cultures alongside aerobic cultures in a pediatric emergency department to enhance recovery of anaerobic pathogens. Treatment of anaerobic bacteria stems from their supposed role in pathogenesis of aspiration pneumonia; older studies from the 1970s had identified anaerobes as causative organisms in these infections, and routine anaerobic coverage was thus implemented in patients. However, the current study was conducted to verify this claim based on more recent data, which indicates decreased presence of anaerobes in community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). The review identified 3 relevant studies, all conducted in Japan, encompassing 941 adult patients. When assessing incidence of 30-day mortality, no significant difference was observed in patients receiving anaerobic coverage vs. those in the control group; notably, overall mortality was low. Similarly, no difference was observed in clinical cure rate when addition of anaerobic coverage. The authors discussed that previous reported rates of anaerobes in respiratory specimens from patients with aspiration pneumonia ranged from 73.9 to 100%, befitting the traditionally accepted practice of anaerobic coverage. More recent downtrends in identification of anaerobes may be related to earlier sampling and intervention as well as improvement in oral hygiene resulting in altered oral microbiota and potential causative organisms of aspiration pneumonia. Ultimately, the literature evaluated in this study was unable to identify clear evidence to recommend routine anaerobic coverage for treatment of aspiration pneumonia. [4]

A 2019 review article discusses the risk factors, bacteriology, clinical presentation, diagnosis, and management of bacterial infections in endocrinology. Bacterial infections of the pituitary gland often present with negative cultures in most cases; however, when positive, the most common organisms isolated include Streptococci and Staphylococci, alongside other bacteria such as Escherichia coli, Mycobacteria, Neisseria, and anaerobes. Due to the high rates of negative cultures, it is suggested that empirical antibiotic therapy should cover gram-positive, gram-negative, and anaerobic bacteria to ensure effective treatment. For adrenal abscesses, treatment typically involves drainage of the abscess and antibiotic therapy, with the choice of antibiotics guided by culture and sensitivity reports. Similarly, in cases where cultures are negative, treatment with broad-spectrum antibiotics covering gram-positive, gram-negative, and anaerobic organisms is suggested. [5]

A 2018 review article highlights the significance of early and appropriate antimicrobial therapy in the management of sepsis and septic shock. Antimicrobial selection should be guided by patient-specific factors, predicted pathogens, and local resistance patterns, with a focus on prompt administration of broad-spectrum antibiotics to patients meeting criteria for sepsis or septic shock. Empirical antibiotic regimens should cover typical gram-positive and gram-negative microorganisms, with additional anaerobic coverage for infections where anaerobes are significant pathogens (eg., intra-abdominal infections). Empiric antibiotic therapy for septic patients with skin and soft tissue infections should target gram-positive, gram-negative, and occasionally anaerobic pathogens. However, necrotizing infections, which are associated with high morbidity and mortality, require aggressive surgical debridement and broad-spectrum antibiotics. These infections can be categorized into Type I polymicrobial, Type II monomicrobial (typically caused by Streptococcus pyogenes or Staphylococcus aureus), and Type III associated with Vibrio spp., or monomicrobial infections such as gas gangrene caused by Clostridium spp. Regardless of classification, it is suggested that initial empiric antibiotic therapy for necrotizing soft tissue infections should cover gram-positive, gram-negative, and anaerobic organisms. Importantly, the authors highlight that de-escalation of antimicrobial therapy can generally be considered after 48-72 hours once culture and susceptibility data are available. [6]

A 2010 expert review article aimed to describe the challenges in diagnosing and treating infected pancreatic necrosis in severe acute pancreatitis. In cases of infected pancreatic necrosis, diagnosis often relies on clinical findings; however, in most patients, confirmation through abdominal CT scan is necessary for diagnosis. Notably, the authors highlight that prophylactic antibiotics fail to reduce peri-pancreatic in severe acute pancreatitis. Due to this, it is recommended to reserve antibiotics for documented infections, with empiric coverage encompassing gram-negative, gram-positive, and anaerobic microorganisms. While cultures should be obtained, it is suggested that treatment decisions should not be delayed awaiting their results. [7]

A 2004 review article discusses the consequences of inadequate antibiotic coverage in orofacial odontogenic infections, emphasizing the need to minimize the risk of resistance in responsible organisms. The authors suggest that selected antibiotics should effectively target both viridans streptococci and anaerobes to ensure successful treatment outcomes. Broad-spectrum antibiotics like clindamycin, cefoxitin, and imipenem, as well as combinations of beta-lactam agents with a beta-lactamase inhibitor, are recommended due to their effectiveness against both viridans streptococci and anaerobes. Additionally, fluoroquinolones with anaerobic spectrum have expanded the therapeutic options, demonstrating exceptional anti-anaerobic activity in odontogenic infections. Initial antimicrobial therapy for odontogenic infections is typically empirical due to the known composition of the underlying flora and the time needed for definitive microbial information. However, in specific scenarios (e.g., rapidly spreading infections, patients not responding to empirical therapy, immunocompromised patients) culture and sensitivity may be necessary to guide antimicrobial therapy effectively. Overall, optimal anaerobic coverage is crucial in the treatment of orofacial odontogenic infections to minimize the risk of therapy failure and ensure better patient outcomes. [8]

A 2024 retrospective cohort study aimed to investigate whether a difference exists between antibiotic therapy with limited anaerobic coverage (LAC) versus extended anaerobic coverage (EAC) in terms of in-hospital mortality and risk of Clostridioides difficile colitis among patients admitted to the hospital for community-acquired aspiration pneumonia. A total of 3,999 patients were included, with 2,683 patients in the LAC group and 1,316 patients in the EAC group. Patients were grouped based on the initial antibiotic administered within 48 hours of admission. Ceftriaxone, cefotaxime, and levofloxacin were classified as having LAC due to their coverage of some oral anaerobes such as Peptostreptococcus species. Conversely, amoxicillin-clavulanate, moxifloxacin, metronidazole, and clindamycin were considered EAC due to their ability to cover most oral and gut anaerobes. The findings revealed that in-hospital mortality rates were 30.3% in the LAC group and 32.1% in the EAC group (adjusted risk difference [RD] 1.6%; 95% confidence interval [CI] –1.7% to 4.9%). Additionally, C. difficile colitis occurred in 5 or fewer patients (≤0.2%) patients in the LAC group and in 11-15 patients (0.8%-1.1%) in the EAC group (adjusted RD 1.05; 95% CI 0.3%-1.7%). Based on these results, it was suggested that EAC is likely unnecessary in aspiration pneumonia as it is not associated with any additional mortality benefit, but rather poses an increased risk of C. difficile colitis. The authors note that the majority of the included patients did not have a bacterial pathogen identified, highlighting the low microbiological yield in aspiration pneumonia. Importantly, this aligns with current guidelines suggesting empirical treatment without extensive microbiological workup.

A 2022 retrospective study evaluated anaerobic coverage adjunct to first-generation cephalosporin prophylaxis in patients with soft tissue sarcoma resections to determine whether spectrum broadening would affect major wound complications or reduce surgical site infections after resection. A total of 579 patients were analyzed between January 2008 and January 2021, with 497 patients receiving a standard antibiotic regimen that usually entailed use of a first-generation cephalosporin, and 82 patients receiving an antibiotic regimen with anaerobic coverage, often metronidazole. Follow-up was within 120 days of the initial resection. Major wound complications resulted in 150 patients (26%) altogether, of which 27% and 17% were in the standard and augmented antibiotic cohorts, respectively (p= 0.049). Although anaerobic coverage was not associated with lower odds of anaerobic or polymicrobial infections due to small sample sizes, it was associated with smaller odds of wound complications after controlling for patient factors (odds ratio [OR] 0.36; 95% CI 0.18 to 0.68; p= 0.003). Further evaluation in prospective controlled trials is required to substantiate these findings. [10]

Furthermore, although not specific to pediatrics, a 2013 review article aimed to evaluate the significance of anaerobic bacteria in the development of aspiration pneumonia and its severe complications such as lung abscess, necrotizing pneumonia, and empyema. The optimal antibiotic and duration of treatment for aspiration pneumonia are unknown due to a lack of literature and guidance. Animal studies demonstrated that anaerobes are causative organisms in these infections and were generally necessary to replicate aspiration pneumonia leading to lung abscesses, highlighting a model of bacterial synergy. Despite anaerobic bacteria being infrequent pulmonary pathogens, they can cause severe diseases, particularly in the context of aspiration events. Effective treatment strategies encompass drainage of pleural collections and the administration of antimicrobials such as clindamycin or a beta-lactam/beta-lactamase inhibitor. Despite advancements in diagnosing and treating anaerobic pulmonary infections, the importance of exploring and addressing these pathogens is underscored by their potential to cause serious disease. Given the scarcity of studies in the pediatric population, further quality evidence is warranted to confirm the need for anaerobe coverage in pediatrics treated for aspiration pneumonia. [11]

References:

[1] Metlay JP, Waterer GW, Long AC, et al. 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. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST
[2] Sartelli M, Coccolini F, Kluger Y, et al. WSES/GAIS/SIS-E/WSIS/AAST global clinical pathways for patients with intra-abdominal infections. World J Emerg Surg. 2021;16(1):49. Published 2021 Sep 25. doi:10.1186/s13017-021-00387-8
[3] Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America [published correction appears in Clin Infect Dis. 2010 Jun 15;50(12):1695. Dosage error in article text]. Clin Infect Dis. 2010;50(2):133-164. doi:10.1086/649554
[4] Yoshimatsu Y, Aga M, Komiya K, et al. The Clinical Significance of Anaerobic Coverage in the Antibiotic Treatment of Aspiration Pneumonia: A Systematic Review and Meta-Analysis. J Clin Med. 2023;12(5):1992. Published 2023 Mar 2. doi:10.3390/jcm12051992
[5] Scott LJ. Eravacycline: A Review in Complicated Intra-Abdominal Infections [published correction appears in Drugs. 2019 Apr 11;:]. Drugs. 2019;79(3):315-324. doi:10.1007/s40265-019-01067-3
[6] Buckman SA, Turnbull IR, Mazuski JE. Empiric Antibiotics for Sepsis. Surg Infect (Larchmt). 2018;19(2):147-154. doi:10.1089/sur.2017.282
[7] De Waele JJ. Use of antibiotics in severe acute pancreatitis. Expert Rev Anti Infect Ther. 2010;8(3):317-324. doi:10.1586/eri.10.3
[8] Stefanopoulos PK, Kolokotronis AE. The clinical significance of anaerobic bacteria in acute orofacial odontogenic infections. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98(4):398-408. doi:10.1016/j.tripleo.2004.01.016
[9] Bai AD, Srivastava S, Digby GC, Girard V, Razak F, Verma AA. Anaerobic Antibiotic Coverage in Aspiration Pneumonia and the Associated Benefits and Harms: A Retrospective Cohort Study. Chest. Published online February 20, 2024. doi:10.1016/j.chest.2024.02.025
[10] Ramsey DC, Walker JR, Wetzel R, Gundle KR, Hayden JB, Doung YC. Is the Addition of Anaerobic Coverage to Perioperative Antibiotic Prophylaxis During Soft Tissue Sarcoma Resection Associated With a Reduction in the Proportion of Wound Complications?. Clin Orthop Relat Res. 2022;480(12):2409-2417. doi:10.1097/CORR.0000000000002308
[11] Bartlett JG. How important are anaerobic bacteria in aspiration pneumonia: when should they be treated and what is optimal therapy. Infect Dis Clin North Am. 2013;27(1):149-155. doi:10.1016/j.idc.2012.11.016

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence to support the need to cover for anaerobes in aspiration pneumonia in children/adolescents?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Antibiotics for Aspiration Pneumonia in Neurologically Impaired Children

Design

Multicenter, retrospective cohort study

N= 4,733 

Objective

To compare hospital outcomes associated with commonly used antibiotic therapies for aspiration pneumonia in children with neurologic impairment (NI)

Study Groups

Anaerobic coverage alone (n= 724)

Gram-negative coverage alone (n= 503)

Anaerobic and Gram-negative coverage (n= 2,740)

Anaerobic, Gram-negative, and P. aeruginosa coverage (n= 766)

Inclusion Criteria

Children aged 1-18 years with a diagnosis of NI, a principal diagnosis of aspiration pneumonia, and received antibiotics within the first two days of admission

Exclusion Criteria

Children transferred from another hospital, with tracheostomy or chronic ventilator dependence, diagnosed with HIV or tuberculosis, or received chemotherapy during hospitalization

Methods

Eligible children from 44 hospitals received antibiotic therapy in the first two days of admission. Empiric antibiotic therapy classified by antimicrobial activity. Chart review was performed to compare outcomes across groups in children who received anaerobic and Gram-negative coverage and those who received anaerobic therapy alone. Multivariable regression adjusted for confounders.

Duration

July 1, 2007 to June 30, 2015

Outcome Measures

Primary: Acute respiratory failure, intensive care uni (ICU) transfer, length of stay (LOS)

Baseline Characteristics

 

Anaerobic (n= 724)

Gram-negative (n= 503)

Anaerobic and Gram-negative (n= 2,740)

Anaerobic, Gram-negative, and P. aeruginosa  (n= 766) p-value 

Median age, years

5 4 5 8 < 0.001

Male

52.6% 51.3% 54.8% 53.9% 0.247

Severity of illness on presentation

Acute respiratory failure

Pleural drainage

Receipt of vasoactive agents

Transfusion of blood product

 

18.1%

0.1% 

6.5%

0.3%

 

21.9%

0.4%

11.3%

1.4%

 

23.4%

0.2%

8.1%

0.9%

 

41.5%

0.9%

12.5%

2.9%

 

< 0.001

0.022

< 0.001

< 0.001

Results

Endpoint

Anaerobic (n= 724) Gram-negative (n= 503) Anaerobic and Gram-negative (n= 2,740) Anaerobic, Gram-negative, and P. aeruginosa (n= 766)

p-value

Unadjusted Outcomes

Acute respiratory failure

ICU transfer

Median LOS, days (interquartile range)

 

14%

3.5%

4 (2 to 7)

 

23.7%

6%

7 (3 to 13)

 

21.1%

4%

5 (3 to 9)

 

34.5%

2.2%

7 (4 to 12)

 

< 0.001

0.007

< 0.001

Adjusted analysis: children receiving Gram-negative coverage alone had two-fold greater odds of respiratory failure (odds ratio [OR] 2.15; 95% CI 1.41-3.27), greater odds of ICU transfer (OR 1.80; 95% CI: 1.03-3.14), and longer LOS (adjusted rate ratio [RR] 1.28; 95% CI: 1.16-1.41] than those receiving anaerobic coverage alone.

Children receiving anaerobic and Gram-negative coverage had higher odds of respiratory failure (OR 1.65; 95% CI: 1.19-2.28) than those receiving anaerobic coverage alone, but ICU transfer (OR 1.15; 95% CI: 0.73-1.80) and length of stay (RR 1.07; 95% CI: 0.98-1.16) did not statistically differ.

For children receiving anaerobic, Gram-negative, and P. aeruginosa coverage, LOS was shorter (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone; odds of respiratory failure and ICU transfer rates did not significantly differ.

Adverse Events

N/A

Study Author Conclusions

Anaerobic therapy appears to be important in the treatment of aspiration pneumonia in children with NI. While Gram-negative coverage alone was associated with worse outcomes, its addition to anaerobic therapy may not yield improved outcomes.

InpharmD Researcher Critique

In addition to limitations inherent to the retrospective nature, the results are limited by various sampling techniques, absence of administration data, and lack of validated clinical criteria for the diagnosis of aspiration pneumonia.



References:

Thomson J, Hall M, Ambroggio L, et al. Antibiotics for Aspiration Pneumonia in Neurologically Impaired Children. J Hosp Med. 2020;15(7):395-402. doi:10.12788/jhm.3338

Evaluation of the Treatment of Aspiration Pneumonia in Hospitalized Children

Design

A single-center, retrospective review

N= 355 (419 treatment courses )

Objective

To evaluate the impact of antibiotic regimen and duration on treatment failure for aspiration pneumonia (AP) in children and to correlate the effects of antimicrobial stewardship program (ASP) interventions on treatment duration

Study Groups

≤7 days of antibiotics (n= 228)

>7 days of antibiotics (n= 191)

Inclusion Criteria

Hospitalized children diagnosed with AP, confirmed through ASP documentation with either an ICD-9/10 code or physician diagnosis of AP

Exclusion Criteria

Patients with infectious diseases service consultation, concomitant infection requiring antibiotic treatment, or missing pertinent data points

Methods

Patients were identified through an ASP repository. Diagnosis was confirmed with ICD-9/10 codes or physician diagnosis. Treatment failure was compared between shorter (≤7 days) vs longer (>7 days) antibiotic courses and various empiric/final antibiotic regimens. ASP interventions on treatment duration were also evaluated.

Duration

Antibiotic duration ranged from 1.4 to 24.8 days, with an average of 7.4 days of total antibiotic treatment.

Outcome Measures

Primary Outcome: Incidence of treatment failure (necrotizing pneumonia, lung abscess, empyema, or retreatment)

Secondary Outcomes: Variability among antibiotic treatment regimens, impact of ASP intervention on treatment duration

Baseline Characteristics  

≤7 days of antibiotics (n= 228)

>7 days of antibiotics (n= 191) N = 419
Female, n (%) 97 (42.5%) 94 (49.2%) 191 (45.6%)
Median age

Chronic conditions 147 (64.5%) 130 (68.1%)

277 (66.1%)

Mechanical ventilation

74 (32.5%) 45 (23.6%) 119 (28.4%)

Severity

Acute

Chronic

 

67 (29.4%)

7 (3.1%)

 

27 (14.1%)

18 (9.4%)

 

94 (22.4%)

25 (6.0%)

ICD code for aspiration pneumonia 150 (65.8%) 146 (76.4%) 296 (70.6%)

Feeding tube/tracheostomy

Feeding tube

Neither

Both

 

134 (58.8%)

87 (38.2%)

7 (3.1%)

 

102 (53.4%)

71 (37.2%)

18 (9.4%)

 

236 (56.3%)

158 (37.7%)

25 (6.0%)

The majority of AP cases were treated empirically with an IV or oral aminopenicillin plus beta-lactamase inhibitor (BLI) (47.2%) or a third-generation cephalosporin plus clindamycin (30.8%) and the remaining 22% of patients received a combination of broad-spectrum antibiotics, clindamycin, or third-generation cephalosporin plus clindamycin alone.

Results Course Length Total Aspiration Pneumonia Cases (N= 419) Treatment Failure No Treatment Failure Odds Ratio (95% confidence interval) p-value
Short course (≤7 days) 228 8 (3.5%) 220 (96.5%) -ref- 0.27
Long course (>7 days) 191 11 (5.7%) 180 (94.3%) 1.7 (0.7 to 4.3) 0.30
Adverse Events

No specific adverse events were reported in the study.

Study Author Conclusions Shorter courses (≤7 days) of antibiotics for AP in hospitalized pediatric patients did not result in more treatment failure compared with longer treatment regimens. Neither antibiotic choice nor route impacted treatment failure rates. ASP interventions for shortening therapy resulted in a significant decrease in antibiotic duration.
Critique

Single-center, retrospective design limits the generalizability of the results. There was a potential for misclassification of AP due to reliance on EMR documentation. Furthermore, the results are limited by the exclusion of certain antibiotic courses as well as heterogeneous study groups without separate analyses for patients with chronic conditions.

References:

Streck HL, Goldman JL, Lee BR, Sheets JM, Wirtz AL. Evaluation of the Treatment of Aspiration Pneumonia in Hospitalized Children. J Pediatric Infect Dis Soc. 2022;11(3):102-107. doi:10.1093/jpids/piab122