INTRODUCTION
Snakebite is the only neglected tropical disease of noninfectious origin included in the WHO list.1–3 Although the ecoepidemiology of snakebite is similar to zoonotic infectious diseases,4 snakebite envenomation occurs after the inoculation of toxins into tissues by grooved fangs that may be contaminated by bacteria.5 Consequently, snake accidents are associated with significant general morbidity and mortality, producing secondary complications such as severe systemic and local septic infection.1,6
Animal venoms are considered sterile sources of antimicrobial compounds with intense bactericidal activity that disrupts the membrane of multidrug-resistant bacteria.7,8 In the case of snakebites, the cause of death is often due to a toxic hemorrhagic effect or a neurotoxic effect with a secondary bacterial infection.7,9
Of the five families of snakes that comprise the species capable of poisoning humans, Elapidae and Viperidae are the most important from a medical point of view.10 The Elapidae family includes cobras, kraits, mambas, coral snakes, Austro-Oceanic snakes, and sea snakes. The family Viperidae includes Old World vipers, rattlesnakes, moccasins, lancehead vipers, mamushis, habus, and other Eurasian vipers. Families of less medically critical venomous snakes are Lamprophiidae (Atractaspidinae; African/Middle Eastern burrowing asps) and Colubridae (now divided; snakes with opisthoglyphous dentition).10
Snakebites with cytotoxic and proteolytic effects cause lesion development and severe tissue necrosis at the bite site. In addition, dead tissue can become infected by bacteria from the oral cavity of the snake.11 The oral microbiota of snakes comprises a wide range of aerobic and anaerobic microorganisms, especially Gram-negative bacilli in the feces of snake-digested prey.12
The proteolytic properties of snake venom cause extensive tissue destruction and devitalization, predisposing the wound to bacterial infection.12 Wound infection after snakebite occurs in 9% to 77% of bitten individuals.12 The principal microorganisms responsible are Aeromonas hydrophila, Morganella morganii, Klebsiella pneumoniae, Bacillus sp., and Enterococcus spp.13
It has been reported that the oral cavity of the Russell’s viper harbors a diverse array of pathogenic bacteria, including Gram-negative genera (Proteus sp., Pseudomonas sp., Salmonella sp., Providencia sp., Alcaligenes sp., Morganella sp., and Escherichia coli) and Gram-positive genera (Bacillus and Enterococcus sp., Staphylococcus sp. and Lysinobacillus sp.).14 Another study identified a wide range of pathogenic bacteria, including Salmonella arizonae, Pseudomonas stutzeri, Proteus penneri, Alcaligenes faecalis, Citrobacter diversus and Citrobacter freundii, Enterococcus faecalis, Bacillus anthracis, Staphylococcus sciuri, and Achromobacter xylosoxidans were isolated as new additions to the floral diversity of the scale viper.15
Other authors analyzed tusk, tusk sheath, and venom cultures from 15 healthy, newly captured Bothrops jararaca. The bacteria most frequently found were group D streptococci (12 snakes), Enterobacter sp. (six), Providencia rettgeri (six), Providencia sp. (four), E. coli (four), M. morganii (three) and Clostridium sp. (five). The bacteria identified were similar to those found in the abscesses of patients bitten by Bothrops. Because these snake mouth bacteria can be inoculated during a snakebite, bacterial multiplication and infection can occur under favorable conditions.16
The objective of the present systematic review was to determine the prevalence of snakebite infections and the bacteria isolated.
MATERIALS AND METHODS
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In addition, the protocol of this study was registered in the PROSPERO database (ID: CRD42023391691).
Information sources and search strategy.
The PubMed, Scopus, Web of Science, SciELO, and Embase databases were searched, with no language or geographic location restrictions (Supplementary Table 1). The search strategy was developed using the Peer Review of Electronic Search Strategies (PRESS) Checklist.16 Initially, the strategy was built in PubMed and was later modified to be adapted to other databases. Literature was searched from inception of the databases to December 22, 2022.
Study selection and data extraction.
The following inclusion criteria were considered: 1) studies that assessed the prevalence of infection in snakebites; 2) studies that assessed the prevalence of the different bacteria identified in snakebites; 3) studies that assessed the prevalence of surgical intervention (including wound incision, pus drainage, debridement, and fasciotomy for necrotizing fasciitis or compartment syndrome) secondary to snakebite infections; 4) cohort, case–control, and cross-sectional studies; and 5) carried out in people of any age. We excluded the following studies: systematic reviews, scoping reviews, narrative reviews, conference abstracts, and case reports.
The bibliographic search results were uploaded to Rayyan QCRI software. Two researchers (A. Al-kassab-Córdova and E. A. Hernandez-Bustamante) independently screened all titles and abstracts. The remaining studies were retrieved in full text and independently assessed by the same researchers (see excluded articles by full text in Supplemental Table 2). Discussion with a third party (V. A. Benites-Zapata) resolved any reviewer disagreement. Articles that met the selection criteria were included in the systematic review. For each article selection phase, the Cohen’s kappa coefficient (Cohen’s κ) was used to determine the degree of agreement between the authors who screened the articles.17
The information on the selected articles was collected in a data extraction table developed in Microsoft Excel by two researchers (E. A. Hernandez-Bustamante and A. Siddiq). Finally, the extracted information was compared, and consensus resolved disagreements. The following information was collected: title, country, age, study design, gender, number of people presenting snakebite infection, bacteria identified in snakebite infection, and number and type of surgical interventions secondary to snakebite infection.
Quality assessment of studies and publication bias.
Four researchers (J. R. Ulloque-Badaracco, A. Al-kassab-Córdova, and E. A. Hernandez-Bustamante) independently evaluated the included studies using the Newcastle–Ottawa Scale (NOS) for cohorts/case controls and the adapted NOS for cross-sectional studies.17,18 In both cases, a study with seven or more stars was deemed to be of high methodological quality or low risk of bias. In contrast, studies with fewer than seven were considered to be of low methodological quality or high risk of bias.
The current literature does not recommend the evaluation of publication bias in the case of systematic reviews of prevalence studies because there are no tests that correctly fit the proportional data.19,20
STATISTICAL ANALYSES
The quantitative analyses were performed with Stata 16.0 (Stata Corporation, College Station, TX). A combined analysis of the studies that evaluated the prevalence of snakebite infection with its corresponding 95% CI was carried out. The random effects model (Dersimonian and Laird) was used. The 95% CI was calculated using the Clopper–Pearson method. Heterogeneity between studies was assessed using the I2 statistic and Cochran’s Q test. In the case of the I2 statistic, values greater than 60% were considered high heterogeneity. On the other hand, a P-value <0.05 was considered a sign of heterogeneity in the Cochran’s Q test.
Following the same methodology, meta-analyses of the prevalence of bacteria identified in snakebites and the prevalence of surgical intervention secondary to snakebite infection were also performed. In addition, subgroup analyses were carried out according to continents and snake families. Finally, sensitivity analyses were performed, excluding studies with a high risk of bias.
RESULTS
Study selection.
The literature search identified 2,200 records, of which 1,675 were removed due to duplication. After screening the studies by title/abstract (Cohen’s κ: 0.34), 83 articles remained. Finally, after full-text assessment (Cohen’s κ: 0.53), 62 studies were included in the meta-analysis and quantitative synthesis.9,12,21–80 References to the analyzed studies are usually not included. The selection process is summarized in Figure 1.
PRISMA flow diagram.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 5; 10.4269/ajtmh.23-0278
Study characteristics.
The characteristics of the studies included are summarized in Table 1. Sixty-two studies (N = 84,296) were conducted between 1989 and 2022 in the following continents: Asia (33 studies), America (24 studies), Africa (four studies), and Europe (one study). All the studies defined the diagnosis of snakebite infection from a physical examination of the area affected by the bite with signs of an infected wound or progressive tissue necrosis. All the studies defined the diagnosis of snakebite infection as signs of an infected wound or progressive tissue necrosis on physical examination of the area affected by the bite.
Characteristics of the studies included
| Author | Year | Country | Participants (male/female) | Median/Mean/ Range Age (IQR/SD) | No. of Participants with SI | Prevalence of SI | No. of Participants Requiring Surgical Intervention for SI | Types of Bacteria in SI (n/N) | Bacteria Isolated in SI (n/N) |
|---|---|---|---|---|---|---|---|---|---|
| Chen et al. | 2011 | Taiwan | 231 (144/87) | 4–95 | 59 | 25.50% | 26 | -Gram-positive bacteria: 14/61 -Gram-negative bacteria: 39/61 -Anaerobic bacteria: 8/61 |
-Enterococcus species: 12/61 -Morganella morganii: 14/61 -Proteus species: 5/61 -Pseudomonas aeruginosa: 5/61 -Shewanella species: 3/61 -Citrobacter species: 4/61 -Escherichia coli: 2/61 -Bacteroides fragilis: 6/61 -Klebsiella pneumoniae: 1/61 -Serratia species: 2/61 |
| Wagener et al. | 2017 | South Africa | 164 (NR/NR) | NR | 40 | 24.39% | NR | -Gram-positive bacteria: 13/48 -Gram-negative bacteria: 35/48 -Anaerobic bacteria: 0/48 |
-Morganella morganii: 20/48 -Enterococcus species: 15/48 -Proteus species: 12/48 -Escherichia coli: 2/48 -Citrobacter species: 2/48 -Klebsiella pneumoniae: 2/68 |
| Huang et al. | 2012 | Taiwan | 121 (74/47) | 4–90 | 34 | 28.00% | 24 | -Gram-positive bacteria: 7/41 -Gram-negative bacteria: 33/41 -Anaerobic bacteria: 1/41 |
-Morganella morganii: 15/41 -Aeromonas hydrophila: 8/41 -Enterococcus species: 5/41 -Proteus species: 3/41 -Escherichia coli: 1/41 -Shewanella species: 1/41 -Pseudomonas aeruginosa: 1/41 -Serratia species: 2/41 -Staphylococcus aureus: 2/41 |
| Blaylock et al. | 1999 | South Africa | 310 (NR/NR) | NR | 17 | 5.48% | 14 | -Gram-positive bacteria: 2/20 -Gram-negative bacteria: 18/20 -Anaerobic bacteria: 0/20 |
-Morganella morganii: 4/20 -Proteus species: 4/20 -Escherichia coli: 2/20 -Serratia species: 3/20 -Citrobacter species: 3/20 |
| Ngo et al. | 2020 | Vietnam | 46 (NR/NR) | NR | 36 | 78.00% | NR | -Gram-positive bacteria: 26/46 -Gram-negative bacteria: 20/46 |
-Enterococcus species: 25/46 -Morganella morganii: 11/46 -Proteus species: 2/46 -Klebsiella pneumoniae: 1/46 -Staphylococcus aureus: 1/46 |
| Hsieh et al. | 2017 | Taiwan | 148 (100/48) | NR | 42 | 28.00% | NR | -Gram-positive bacteria: 11/30 -Gram-negative bacteria: 16/30 -Anaerobic bacteria: 3/30 |
-Morganella morganii: 12/30 -Aeromonas hydrophila: 1/30 -Bacteroides fragilis: 3/30 -Proteus species: 3/30 -Enterococcus species: 11/30 |
| Mao et al. (Cohort A) | 2018 | Taiwan | 183 (116/67) | 51.5 (18.5) | 148 | 80.90% | 21 | -Gram-positive bacteria: 11/35 -Gram-negative bacteria: 24/35 -Anaerobic bacteria: 1/35 |
-Morganella morganii: 12/35 -Aeromonas hydrophila: 1/35 -Enterococcus species: 10/35 -Proteus species: 4/35 -Escherichia coli: 1/41 -Shewanella species: 1/35 -Pseudomonas aeruginosa: 1/35 -Bacteroides fragilis: 1/35 -Serratia species: 2/35 |
| Mao et al. (Cohort B) | 2016 | Taiwan | 112 (NR/NR) | NR | 86 | 76.78% | NR | NR | |
| Houcke S et al. | 2022 | French Guiana | 172 (119/53) | 41 (28–52) | 55 | 31.97% | 43 | -Gram-positive bacteria: 2/17 -Gram-negative bacteria: 15/17 |
-Morganella morganii: 12/17 -Aeromonas hydrophila: 1/17 -Escherichia coli: 1/17 -Pseudomonas aeruginosa: 1/17 -Staphylococcus aureus: 2/17 |
| Lin et al. | 2020 | Taiwan | 726 (506/220) | 51.88 (17.42) | 163 | 22.45% | NR | -Gram-positive bacteria: 11/20 -Gram-negative bacteria: 5/20 -Anaerobic bacteria: 4/20 |
-Morganella morganii: 3/20 -Enterococcus species: 3/20 -Bacteroides fragilis: 1/20 -Aeromonas hydrophila: 1/20 -Staphylococcus aureus: 2/20 |
| Sasa et al. | 2020 | Costa Rica | 475 (NR/NR) | NR | 33 | 6.90% | NR | NR | NR |
| Weed et al. | 1993 | United States | 72 (63/9) | NR | 0 | 0% | NR | NR | NR |
| Clark et al. | 1993 | United States | 41 (32/9) | NR | 3 | 7.30% | NR | NR | NR |
| Kouyoumdjian et al. | 1989 | Brazil | 22 (NR/NR) | NR | 4 | 18.18% | NR | NR | NR |
| Magalhães et al. | 2019 | Brazil | 70,816 (55,557/ 15,248) | NR | 2639 | 3.72% | NR | NR | NR |
| Kriengkrairut et al. | 2021 | Thailand | 123 (83/40) | 52 (36–66) | 8 | 6.50% | NR | NR | NR |
| Osmani et al. | 2007 | Pakistan | 110 (72/38) | 11-80 | 62 | 56.36% | NR | NR | NR |
| Nascimento et al. | 2022 | Brazil | 3,297 (0/3,297) | 28.3 (10.7) | 178 | 5.90% | NR | NR | NR |
| Mendes et al. | 2022 | Brazil | 127(101/26) | 64 (50.4) | 127 | 23.30% | NR | NR | NR |
| Sachett et al. | 2017 | Brazil | 153/33 | NR | 74 | 39.80% | NR | -Gram-positive bacteria: 1/6 -Gram-negative bacteria: 5/6 |
-Morganella morganii: 5/6 -Staphylococcus aureus: 1/6 |
| Ruha et al. | 2017 | United States | 450 (312/138) | 1-89 | 2 | 0.40% | NR | NR | NR |
| Hansdak et al. | 1998 | Nepal | 52 (36/16) | 13-64 | 10 | 19.00% | NR | NR | NR |
| Villanueva Forero et al. | 2004 | Peru | 170 (107/63) | 26.2 (17.95) | 14 | 8.20% | NR | NR | NR |
| Otero et al. (Cohort A) | 2002 | Colombia | 39 (31/8) | 15–70 | 12 | 30.8% | NR | -Gram-positive bacteria: 9/10 -Gram-negative bacteria: 1/10 |
-Morganella morganii: 2/10 -Proteus species: 1/10 -Aeromonas hydrophila: 2/10 -Staphylococcus aureus: 2/10 -Klebsiella pneumoniae: 1/10 |
| Otero et al. (Cohort B) | 1992 | Colombia | 524 (NR/NR) | 27 (NR) | 56 | 10.60% | NR | NR | NR |
| Lopez et al. | 2008 | Colombia | 48 (6/42) | 24.6 (8–61) | 16 | 33.30% | NR | -Gram-positive bacteria: 2/11 -Gram-negative bacteria: 9/11 |
-Morganella morganii: 5/11 -Proteus species: 1/11 -Escherichia coli: 1/11 -Enterococcus species: 1/11 |
| Yeh et al. | 2021 | Taiwan | 195 (144/51) | 49.97 (17.42) | 53 | 27.20% | NR | NR | NR |
| Frangides et al. | 2005 | Greece | 147 (85/62) | 48.11(17.71) | 20 | 13.60% | NR | NR | NR |
| Silva et al. | 2020 | Brazil | 144 (NR/NR) | NR | 11 | 9.00% | NR | NR | NR |
| White et al. | 2018 | Myanmar | 948 (580/368) | NR | 82 | 8.80% | NR | NR | NR |
| Yakubu et al. | 2018 | Ghana | 119 (83/36) | 26.38 ± 16.46 | 42 | 35.30% | NR | NR | NR |
| Bhalla et al. | 2014 | India | 150 (99/51) | NR | 4 | 2.60% | NR | NR | NR |
| Looareesuwan et al. | 1988 | Thailand | 46 (NR/NR) | 1–81 | 6 | 13.00% | NR | NR | NR |
| Kumar et al. (Cohort A) | 2019 | India | 58 (NR/NR) | NR | 55 | 94.00% | NR | NR | NR |
| Tan et al. | 2010 | Singapore | 52 (43/9) | 13–69 | 2 | 3.84% | NR | NR | NR |
| Mohammed et al. | 2022 | Ethiopia | 250 (202/48) | 24 (22–26) | 130 | 62.80% | NR | NR | NR |
| Murugan et al. | 2015 | India | 82 (64/18) | 14 − 65 | 48 | 58.54% | NR | NR | NR |
| Enzenhofer et al. | 2018 | Argentina | 67 (51/47) | 15-49 | 15 | 22.00% | NR | NR | NR |
| Ho et al. | 2019 | Taiwan | 125 (88/38) | NR | 0 | 0% | NR | NR | NR |
| Chew et al. | 2011 | Malaysia | 260(154/106) | NR | 13 | 5.00% | NR | NR | NR |
| Pradhan et al. | 2022 | India | 88 (48/40) | NR | 24 | 27.27% | NR | NR | NR |
| Kim K et al. | 2020 | Korea | 61 (36/25) | 61 (56 − 71) | 6 | 9.80% | NR | NR | NR |
| Bhelkar et al. | 2017 | India | 156 (100/56) | 37.78 (14) | 75 | 66.96% | NR | NR | NR |
| Lai et al. | 2022 | Taiwan | 161 (114/47) | 50.4 (17.7) | 80 | 49.68% | 72 | -Gram-negative bacteria: 33/34 -Anaerobic bacteria: 1/34 |
-Enterococcus species: 12/34 -Morganella morganii: 11/34 -Serratia species: 2/34 -Shewanella species: 2/34 -Aeromonas hydrophila: 1/34 -Citrobacter species: 1/34 -Proteus species: 3/34 -Bacteroides fragilis: 1/34 |
| Monteiro et al. | 2012 | India | 31 (18/13) | 19–65 | 29 | 93.50% | NR | NR | NR |
| Garg A et al. | 2009 | India | 43 (31/12) | NR | NR | NR | NR | -Gram-positive bacteria: 17/53 -Gram-negative bacteria: 25/53 |
-Staphylococcus aureus: 17/53 -Enterococcus species: 4/53 -Escherichia coli: 8/53 -Klebsiella pneumoniae: 4/53 -Proteus species: 3/53 -Morganella morganii: 3/53 -Pseudomonas aeruginosa: 3/53 |
| Lath et al. | 2015 | India | 454 (312/142) | NR | 138 | 30.39% | NR | NR | NR |
| Liu et al. | 2012 | Taiwan | 10 (4/6) | 42.5 (26–88) | NR | NR | NR | -Gram-negative bacteria: 24/24 | -Shewanella species: 10/24 -Morganella morganii: 4/24 -Enterococcus species: 3/24 -Bacteroides fragilis: 2/24 -Aeromonas hydrophila: 1/24 -Proteus species: 1/24 |
| Dookeram et al. | 2022 | Trinidad and Tobago | 28 (22/6) | NR | 1 | 3.4% | NR | NR | NR |
| Kumar et al. (Cohort B) | 2021 | India | 300 (209/91) | NR | 18 | 6.00% | NR | NR | NR |
| Chatterjee et al. | 2022 | India | 94 (58/36) | 7.4 (NR) | 16 | 17.02% | NR | NR | NR |
| Ashok et al. | 2021 | India | 91 (NR/NR) | NR | 32 | 35.1%% | NR | NR | NR |
| Miah et al. | 2009 | Bangladesh | 46 (36/10) | 34.9 (16.2) | 7 | 15.2%% | NR | NR | NR |
| Reddy et al. | 2019 | India | 60(25/35) | NR | 10 | 17.00% | NR | NR | NR |
| Chinga et al. | 2004 | Ecuador | 41 (NR/NR) | NR | 29 | 70.73% | NR | NR | NR |
| Kerrigan (Cohort A) et al. | 1997 | Ecuador | 114 (63/51) | 3–84 | 9 | 8.00% | NR | -Gram-positive bacteria: 4/11 -Gram-negative bacteria: 7/11 |
-Escherichia coli: 3/11 -Staphylococcus aureus: 4/11 -Proteus species: 1/11 -Klebsiella pneumoniae: 2/11 |
| Saravu et al. | 2012 | India | 76 (46/30) | 16–82 | 8 | 10.52% | NR | NR | NR |
| Morejon-Garcia et al. | 2006 | Brazil | 30 (23/7) | NR | 3 | 10.00% | 3 | NR | NR |
| Matute-Martinez et al. | 2016 | Honduras | 59 (NR/NR) | 24 (NR) | 6 | 10.16% | NR | NR | NR |
| García-Willis et al. | 2009 | Mexico | 171 (NR/NR) | 0–15 | 36 | 21.00% | NR | NR | NR |
| Avila-Agüero et al. | 2001 | Costa Rica | 82 (55/27) | NR | 37 | 45.12% | NR | NR | NR |
| Kerrigan (Cohort B) et al. | 1992 | Ecuador | 312 (NR/NR) | NR | 38 | 12.17% | NR | -Gram-positive bacteria: 8/11 -Gram-negative bacteria: 3/11 |
-Proteus species: 1/11 -Escherichia coli: 4/11 -Serratia species: 3/11 -Staphylococcus aureus: 3/11 |
IQR = interquartile range; NR = not reported; SI = snakebite infection.
In the quality assessment of the studies with the NOS-CS, four studies had a high risk of bias, and the remaining 58 had a low risk of bias (Supplementary Table 3).
Prevalence of snakebite infection.
All the meta-analyses are summarized in Table 2. The prevalence of snakebite infection was 27.0% (95% CI: 22.0–32.0%), with high heterogeneity among studies (I2 = 99.7%). In the subgroup analysis according to continents, high heterogeneity was found, and the prevalence of snakebite infection in the Asian, American, and African continents was 32%, 21%, and 29%, respectively. There was also high heterogeneity in the subgroup analysis according to snake families (Figure 2), and the prevalence of infection after a bite by Elapids and Vipers was 62% and 31%, respectively. After removing the studies with a high risk of bias, the prevalence of snakebite infection in the sensitivity analysis was 28.0% (95% CI: 23.0–33.0%); however, there was no decrease in heterogeneity (I2 = 99.72%). On the other hand, the prevalence of surgical intervention in patients with snakebite infection was 68% (95% CI: 37.0–98.0%, I2 = 98.28%) (Figure 3).
Results of meta-analyses of snakebite infection
| Meta-Analysis | No. of Studies | Pooled Prevalence (%) | 95% CI | I2 | P-Value |
|---|---|---|---|---|---|
| Meta-analysis of snakebite infection | |||||
| Overall prevalence | 59 | 27.0% | 22.0–32.0% | 99.7% | <0.001 |
| Continents | – | – | |||
| Asia | 31 | 32.0% | 24.0–40.0% | 99.08% | <0.001 |
| America | 24 | 21.0% | 13.0–29.0% | 99.86% | <0.001 |
| Africa | 4 | ||||
| Family of snakes | – | – | |||
| Elapids | 5 | 62.0% | 40.0–85.0% | 97.91% | <0.001 |
| Vipers | 12 | 31.0% | 19.0–42.0% | 97.48% | <0.001 |
| Sensitivity analysis | 55 | 28.0% | 23.0–33.0% | 99.72% | <0.001 |
| Meta-analysis of surgical interventions in snakebite infection | |||||
| Prevalence | 7 | 68.0% | 37.0–98.0% | 98.28% | <0.001 |
| Meta-analysis of bacteria isolated in snakebite infection | |||||
| Gram-positive | 16 | 40.0% | 21.0–58.0% | 96.59% | <0.001 |
| Gram-negative | 16 | 63.0% | 50.0–76.0% | 91.76% | <0.001 |
| Anaerobes | 8 | 4.0% | 1.0–7.0% | 54.19% | <0.001 |
| Morganella morganii | 15 | 32.0% | 22.0–41.0% | 83.59% | <0.001 |
| Enterococcus spp. | 11 | 23.0% | 15.0–32.0% | 98.28% | <0.001 |
| Staphylococcus aureus | 9 | 15.0% | 6.0–23.0% | 72.52% | <0.001 |
| Proteus spp. | 14 | 8.0% | 5.0–10.0% | 0.0% | <0.001 |
| Shewanella spp. | 5 | 7.0% | 1.0–12.0% | 73.06% | <0.001 |
| Escherichia coli | 10 | 6.0% | 2.0–9.0% | 40.46% | <0.001 |
| Citrobacter spp. | 4 | 5.0% | 2.0–8.0% | 0.0% | <0.001 |
| Bacteroides fragilis | 6 | 5.0% | 2.0–8.0% | 0.0% | <0.001 |
| Serratia spp. | 6 | 5.0% | 2.0–8.0% | 0.0% | <0.001 |
| Aeromonas hydrophila | 8 | 5.0% | 2.0–8.0% | 14.80% | <0.001 |
| Pseudomonas aeruginosa | 5 | 4.0% | 2.0–7.0% | 0.0% | <0.001 |
| Klebsiella pneumonia | 6 | 3.0% | 1.0–5.0% | 0.0% | <0.001 |
Bold values represent the significant value of P <0.05.
Subgroup analysis of snakebite infection according to snake families.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 5; 10.4269/ajtmh.23-0278
Prevalence of surgical interventions in snake bite infections.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 5; 10.4269/ajtmh.23-0278
Prevalence of bacteria isolated in snakebite infection.
The prevalence of Gram-positive (assessed in 16 studies), Gram-negative (evaluated in 16 studies), and anaerobic bacteria (assessed in eight studies) was 40.0% (Supplementary Figure 1), 63.0% (Supplementary Figure 2), and 4.0% (Supplementary Figure 3), respectively. Assessment of the prevalence of each isolated bacteria was: M. morganii (32.0%, Supplementary Figure 4), Enterococcus sp. (23.0%, Supplementary Figure 5), Staphylococcus aureus (15.0%, Supplementary Figure 6), Proteus sp. (8.0%, Supplementary Figure 7), Shewanella sp. (7.0%, Supplementary Figure 8), E. coli (6.0%, Supplementary Figure 9), Citrobacter sp. (5.0%, Supplementary Figure 10), Bacteroides fragilis (5.0%, Supplementary Figure 11), Serratia spp. (5.0%, Supplementary Figure 12), Aeromonas hydrophila (5.0%, Supplementary Figure 13), Pseudomonas aeruginosa (4.0%, Supplementary Figure 14), and K. pneumonia (3.0%, Supplementary Figure 15).
DISCUSSION
Snakebite is considered a high-priority neglected tropical condition categorized by the WHO.81,82 Furthermore, snakebite has been identified as a poverty-related illness that necessitates increased awareness and collaboration worldwide to develop measures that effectively reduce the economic burden with high impact in rural tropical areas and also, to a lesser extent, in urban zones,83–85 as well as in travelers from multiple nontropical countries.81,86–88 Although most of their overall assessment has been focused on its clinical consequence, given the acute phase of envenomation, fewer studies have focused on the bite’s infectious consequences. Overall most studies focused on the clinical consequences of snakebite infection in the acute phase of envenomation, with few studies evaluating the infectious consequences of snakebite.89
In the current systematic review, we found a considerable prevalence of infection associated with snakebite (27%, 95% CI: 22–32%), being higher in Asia (32%) than in the Americas (21%). In the case of Africa, there is a lack of studies, limiting the analysis of this region. Nevertheless, some studies, such as that carried out in South Africa in 2017, reported a prevalence of infection by snakebite of 24.39%.9 Another study in Ethiopia described a higher prevalence of 62.8% in a retrospective cohort study that collected data from the medical charts of 250 patients at the University of Gondar Hospital and Metema Hospital between September 2012 and August 2020.53 Environmental aspects and differences in exposure may influence these results, including the growing awareness of the impact of climate change on snakebite.5,90,91
Snakebite infection may require surgical intervention, such as surgical debridement for extensive skin and soft-tissue necrosis,9 as reported in most cases (67%) in the present review. Unfortunately, the studies indicating the need for surgery lack details regarding the specific type of interventions and other related characteristics.21 Also, a limitation of this systematic review is that, regrettably, such secondary infections are often diagnosed due to cellulitis and abscess and, in most cases, not necessarily performing a microbiological culture to identify the causative agent, then being a purely clinical diagnosis. Thus, this review shows only those who collected secretions or biopsied the site to identify the species. Additionally, most studies did not report the antimicrobials used, the time between snakebite and the occurrence of associated infection, or the grade of envenoming of each patient. In addition, a limitation of this systematic review is that such secondary infections are often diagnosed due to the development of cellulitis and abscesses without a microbiological culture to identify the causative agent in most cases, and with the subsequent management based on a purely clinical diagnosis. Thus, this review included only studies in which secretions were collected or the bite site was biopsied to identify the bacterial species. Additionally, most studies did not report the antimicrobials administered, the time between snakebite and the occurrence of associated infection, or the grade of envenomation of each patient.
The leading group of pathogens identified corresponded to Gram-negative bacteria (63%), particularly M. morganii (32%), and also Gram-positive cocci (40%), especially Enterococcus sp. (23%) and S. aureus (15%). However, multiple other pathogens, also including anaerobes, were found. The pathogens were related to the type of snake mouth microbiota. For example, in some studies, A. hydrophila (5% in this systematic review), M. morganii, K. pneumoniae (3%), Bacillus sp., and Enterococcus sp. were isolated from the oral cavity of Bothrops sp.92 M. morganii is a Gram-negative bacillus usually present in the environment and the intestinal tracts of humans, mammals, and reptiles as microbiota. Despite its wide distribution, it is an uncommon cause of community-acquired infection and is most often encountered in the postoperative setting and as the cause of healthcare-associated infections.93,94 M. morganii is considered an opportunistic secondary invader that was originally thought to be the cause of summer diarrhea.94 However, this pathogen may also cause bacteremia, sepsis, brain abscesses, pyomyositis, meningitis, and pericarditis,94 among other infections,33–43 including the etiology of snakebite infections. Most studies did not indicate when coinfections or polymicrobial infections occurred. Although the prevalence of anaerobic infection secondary to snakebite was low, some pathogens should be taken into account, such as Shewanella, the most frequent anaerobic bacteria in this study (7%). For instance, a case series including 10 Asian patients bitten by cobras reported that all the patients were infected with Shewanella, with most presenting moderate to severe local envenomation and polymicrobial infection. However, all patients had favorable outcomes after administration of antibiotic treatment according to the antimicrobial susceptibility pattern,95 which is of paramount importance for the selection of adequate antimicrobial treatment.
Although we could not assess it given the lack of studies, evaluating the antimicrobial susceptibility profile of the bacterial isolates from snakebite infections would be interesting and is necessary. Because many pathogens would be associated with severe infections, it is a matter of concern, including isolating potentially antimicrobial-resistant pathogens. Although the lack of studies did not allow evaluation of the antimicrobial susceptibility profiles of the bacterial isolates from snakebite infections, it would have been of interest, especially in relation to the potential isolated of antimicrobial-resistant pathogens. Rational use of antimicrobials should be recommended. The isolation and identification of possible bacteria in snakebite wounds should be recommended in all cases to confirm or rule out an associated infection.
On the other hand, this study did not assess which snakes were more prone to cause infections, which would be helpful in clinical practice. Interestingly, a retrospective study found that cobra bites were the most frequent among patients from Taiwan.21 Studying which snakes are most likely to cause snakebite infections is essential for targeting therapy in low-income settings where microbiological testing is scarce.
As has been reported,94 the limitations of many studies include a lack of established or inconsistent criteria for an infected bite wound and the failure to use optimization techniques for pathogen isolation, especially for anaerobic organisms, which may explain the low prevalence of anaerobic infection in the present systematic review (4%). That also implies, for empirical therapy, the need to consider not only Gram-positive pathogens from human skin but also the Gram-negative and anaerobes from the snakes’ oral mouth, which may also vary according to the serpent species. For empirical therapy, this also implies the need to consider not only Gram-positive pathogens from human skin but also Gram-negative bacteria and anaerobes from the mouth of the snake, which may also vary according to the snake species. In addition, no studies from countries in Oceania were included. Nevertheless, local effects in Australian and Neo-Guinean snakebites are rare.94 There is also a lack of understanding of the pathogenic significance of all cultured organisms; although most of them are pathogens, their role in infection is not fully understood in all cases and clinical scenarios, and some not necessarily pathogenic bacteria may be occasionally isolated and identified. There is also a lack of understanding of the pathogenic significance of all the organisms cultured. Although most are pathogens, their role in infection is not fully understood in all cases and clinical scenarios, and some not necessarily pathogenic bacteria may occasionally be isolated and identified. Another interesting aspect would be to assess the differences in the clinical impact of snakebite infections according to the immune status of the host, including significant comorbidities, such as diabetes (e.g., Pseudomonas has been identified in snakebite infections), obesity, and autoimmune diseases, among others. Gathering information and conducting research more systematically and methodically through an organized research network, including zoos, veterinary practices, and rural clinics and hospitals, is needed to establish a better definition of the microbiology of animal-bite wound infections in humans, including snakebites.94 Because no previous systematic review has been published, the value of the current results is even higher. It is essential to highlight a clear need to develop evidence-based guidelines that include the detailed management of such associated infections.
CONCLUSION
The prevalence of snakebite-associated infections is high, primarily due to M. morganii, and should be taken into account when selecting the most adequate empirical therapy. Most patients presenting with snakebite infection require surgical intervention. Rational use of antimicrobials is recommended and should guide initial empirical treatment. In light of the present results, snakebites warrant further microbiological study for the isolation and identification of bacteria in all cases to confirm or rule out an associated infection. Finally, the importance of monitoring infection in snake-bitten patients is of note.96
Supplemental Materials
ACKNOWLEDGMENTS
We thank the Universidad Científica del Sur, Lima, Peru, for their support in the publication of this research and article, as well as the English revision of the manuscript.
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