Secondary infection profile after snakebite treated at a tertiary referral center in the Brazilian Amazon

ABSTRACT Background: Bothrops envenomations can often lead to complications, such as secondary infections. Methods: This cross-sectional study analyzed the medical records of all patients diagnosed with snakebite. Results: A total of 127 patients were included. Clindamycin was the most commonly prescribed antibiotic, with 105 patients (82.7%) receiving it as the primary antibiotic regimen. In 31 (24.4%) individuals, the first-choice antibiotic did not cease the infection. Conclusions: Secondary infection is an important complication resulting from snakebites, and evidence-based management of this complication can contribute to better clinical outcomes.

secondary bacterial infection 2,7 . Leukocytosis and elevation of transaminases and C-reactive protein levels are laboratory findings that help in the diagnosis of secondary infections from snakebites 2 .
Antibiotics with a large antibacterial spectrum, such as third-generation cephalosporins, piperacillin-tazobactam, and ciprofloxacin, are active antibiotics for treating secondary infections caused by snakebites 7,8 . However, as yet, there is no recommendation to use of an antibiotic for the prevention of these infections after a snakebite. Although amoxicillin clavulanate can be used for animal bites 8 , it has not been shown to be effective for snake bites 2 . Thus, this study aimed to characterize local secondary infections from snakebites and treat them at a referral center in the Brazilian Amazon.
A cross-sectional study was conducted at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Secondary infection after a Bothrops snakebite was defined as the presence of cellulitis and/or abscesses 8 up to 48 h after admission. Cellulitis was defined as the presence of local signs of inflammation (erythema, edema, heat, and pain) associated with fever, leukocytosis, lymphangitis, and/or lymphadenitis, and the abscess was characterized by the presence of an individualized, floating lesion with purulent or seropurulent discharge 2 .
In five (3.9%) patients, culture examination was performed, and only one presented with bacterial growth (Proteus mirabilis). Clindamycin was the first-choice drug in 105 (82.7%) patients and only 18 (17.1%) required another second-choice antibiotic. Treatment with clindamycin resulted in fewer therapeutic failures than other antimicrobial regimens (odds ratio, 9.059; confidence interval, 3.239-24.92; p<0.001). In 31 (24.4%) individuals, the firstchoice antimicrobial treatment was not effective, and a second therapeutic regimen was used. In this second treatment regimen, clindamycin was also the most commonly used drug (nine patients; 29.0%) ( Table 2). Most patients required abscess drainage (76.5%). Among the laboratory tests performed on admission, leukocyte and alanine aminotransferase and aspartate aminotransferase levels were elevated ( Table 3).
In this study, secondary bacterial infection was observed in 127 (23.3%) cases analyzed, which was slightly lower than the frequency found in previous studies in the region. It is known that infection is also related to the oral microbiota of snakes, which comprises a wide variety of aerobic and anaerobic microorganisms, including Enterobacteriaceae, principally Morganella spp., Escherichia coli, Streptococcus, Aeromonas spp., Staphylococcus aureus, and Clostridium spp. 9 .   9 .
The difference between the pathogenic microorganisms found in the oral microbiota of snakes may have contributed to the difference in the frequency of infections found in this study, since a correlation between the oral microbiota of venomous snakes (especially those of the genus Bothrops) and bacteria found in secondary infections and abscesses has been suggested 9,10 . However, there is evidence that the infection may not necessarily be associated with the oral microbiota of the snake on its own 2 .
In the Amazon region, the distance to medical facilities is a major obstacle because of the geographical peculiarities of the region; thus, patients are more prone to develop complications 11 . Moreover, 31.6% of patients were treated ≥ 7 h after the bite, and previous studies have revealed that this factor may contribute to the incidence of secondary bacterial infection, since the longer the time elapsed between the snakebite and treatment, the greater the risks of these complications 11,12 . This results in impaired access to health services for the provision of antivenom treatment and often leads to the use of traditional medicine as a treatment option 13 . The use of traditional medicine often includes the use of a tourniquet and traditional practices, such as the use of roots, fruits, leaves, tree bark, seeds, and other foods and local manipulation in the form of incisions and suction, which may also contribute to the development of secondary infections 2,11,13 .
In this study, only a few patients underwent culture examination, and only one patient presented with bacterial growth (Proteus mirabilis). P. mirabilis is an aerobic gram-negative bacterium that is found in material collected from wounds caused by a snakebite and in the oral cavity of snakes 6,7,14 . The fact that cases of secondary infection have cellulitis as the most frequent clinical manifestation (86.5%) 2 makes it difficult to collect secretions to perform a local culture.
The observed results showed that clindamycin was the antibiotic of the first and second choice that was most often used for the treatment of secondary bacterial infections caused by snakebite. Therapeutic recommendations for antibiotic therapy include antimicrobials with activity against gram-negative, grampositive, and anaerobic bacilli, such as chloramphenicol and amoxicillin clavulanate 8 . Patients with other bacterial soft tissue infections, such as erysipelas, should be treated with penicillin, and the dose and route of administration should be decided according to the severity of the case 8 . Data on bacterial diversity derived from abscesses and the effectiveness of the use of gentamicin or penicillin G for possible control have already been described 14 . In another study, high sensitivity of bacteria to amikacin, gentamicin, chloramphenicol, and sulfamethoxazole-trimethoprim has been identified 10 . However, in the protocols of the Infectious Diseases Society of America 8 , chloramphenicol is recommended for use in the treatment of secondary infections, which corroborates the results of other studies that demonstrate an extremely variable sensitivity of microorganisms to different antibiotics 9,10,14,15 .
The evolution of secondary bacterial infections in the skin can manifest itself through the presence of cellulitis and abscess, and drainage and debridement are recommended according to the needs of each case. These were, in fact, the most commonly used surgical techniques in the patients analyzed in this study.
This study presented some limitations, since when performing an analysis using medical records, there is always the risk of lack of important information from clinical and laboratory evaluations. Another limitation was the lack of identification of the bacteria involved in the secondary infection, since, in most cases, the treatment was conducted empirically.
Snakebites that evolved into secondary infection were more common in the lower limbs, and most envenomations occurred in rural areas and were classified as moderate. The majority of patients received Bothrops antivenom therapy. Blisters were the elementary lesions presented by the majority of patients, with purulent exudate and necrotic tissue. The most commonly used antibiotic was clindamycin, which presented less therapeutic failures, and abscess drainage and debridement were the most commonly used surgical techniques.
The results of this study demonstrate the importance of implementing specific guidelines aimed at standardizing the clinical management of these victims and considering randomized clinical trials that compare different antimicrobial treatments based on the profile for infections caused by snakebites.