Gas gangrene and clostridial myonecrosis are interchangeable terms used to describe an infection of muscle tissue by toxin-producing clostridia. In 1861, Louis Pasteur identified the first clostridial species, Clostridium butyricum. In 1892 and later, Welch, Nuttall, and other scientists isolated a gram-positive anaerobic bacillus from gangrenous wounds. This organism, originally known as Bacillus aerogenes capsulatus, was later renamed Bacillus perfringens, and then Clostridium welchii. The organism is now named Clostridium perfringens.
Gas gangrene gained recognition for its wartime incidence, during which only a paucity of civilian cases occurred. During World War I, gas gangrene complicated 6% of open fractures and 1% of all open wounds. These figures steadily decreased to 0.7% during World War II, 0.2% during the Korean War, and 0.002% during the Vietnam War. No cases of gas gangrene were reported during the battle in the Falkland Islands in 1982.[1]
Despite numerous casualties caused by enormous firepower and improvised explosive devices (IEDs), no cases of gas gangrene have been reported among US soldiers during the ongoing operation Iraqi Freedom. The lethality of war wounds has decreased from 24% during operation Desert Storm (1991) to an unprecedented 10% during operation Iraqi Freedom. The US military medicine has credited this to the mobility of the forward surgical teams (FSTs) in keeping up with the fast-moving military units.[2, 3, 4]
The incidence of gas gangrene was 0.96% in a study of 1970 survivors admitted to Sichuan Provincial People’s Hospital after the 2008 Wenchuan earthquake.[5] Another study of 226 patients during the same earthquake showed the importance of rapid and accurate screening, as well as isolation, in the successful treatment of gas gangrene and in helping to prevent nosocomial diffusion. Debridement, amputation, and supportive treatment yielded acceptable therapeutic results.[6]
Gas gangrene is caused by an anaerobic, gram-positive, spore-forming bacillus of the genus Clostridium. C perfringens is the most common etiologic agent that causes gas gangrene. Other common clostridial species that cause gas gangrene include Clostridium bifermentans, Clostridium septicum, Clostridium sporogenes, Clostridium novyi, Clostridium fallax, Clostridium histolyticum, and Clostridium tertium.[7]
These organisms are true saprophytes and are ubiquitous in soil and dust. Clostridia have been isolated from the mucous membranes of humans, including the GI tract and the female genital tract. Clostridia may also colonize the skin, especially around the perineum. Clostridia are obligate anaerobes, but some species are relatively aerotolerant. Bacterial multiplication and the production of soluble proteins called exotoxins require a low oxygen tension.
Other bacteria are also capable of producing gas, and nonclostridial organisms have been isolated in 60-85% cases of gas gangrene. A recent clinical series on gas gangrene demonstrated a predominance (83.3%) of aerobic gram-negative bacilli in wound cultures compared with anaerobic gram-positive bacilli, with Clostridium species accounting for 4.5% of the isolates. The most frequently identified aerobic gram-negative bacteria were Escherichia coli,Proteus species, Pseudomonas aeruginosa, and Klebsiella pneumoniae.[7, 8, 9]
C perfringens produces at least 20 exotoxins. The most important exotoxins and their biologic effects are as follows:
Nu toxin - Lethal,* deoxyribonuclease, hemolytic, necrotizing
*Lethal as tested by injection in mice
Significant variance exists among clostridial species as to the mechanism of action of the alpha toxin. In C septicum, the alpha toxin forms pores and induces necrosis by causing the rapid loss of intracellular potassium and depletion of adenosine triphosphate (ATP). Strains that do not produce alpha-toxin are less virulent, underscoring its importance.[10] In mice models, alpha-toxin–induced lethality was inhibited by the preadministration of erythromycin. Erythromycin resulted in a reduction of the release of cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1, and interleukin 6. Additionally, TNF-alpha–deficient mice were resistant to C perfringens alpha-toxin, suggesting that TNF-alpha is an important contributor to the toxic effects of clostridial proteins.[11]
Genetic regulation of clostridial cytotoxic exotoxin production is under the control of several different regulatory systems, including the global VirR/VirS 2-component signal transduction system, and the RevR. The VirR, a membrane bound external sensor, and the VirS, a gene response regulator, together transmit and receive signals from the environment to the inside of the cell. The VirR/VirS system uses RNA intermediates to control 147 distinct genes and their associated operons.[12]
The phi-toxin is a hemolysin. Although it does not directly suppress myocardial function in vitro, it contributes to myocardial suppression in vivo, possibly by increasing the synthesis of secondary mediators that do suppress myocardial function in vitro. At higher concentrations, the phi-toxin can cause extensive cellular degeneration and direct vascular injury.
The kappa-toxin produced by C perfringens is a collagenase responsible for destruction of blood vessels and connective tissue. Other toxins include a deoxyribonuclease and hyaluronidase.
Contamination with clostridial spores in posttraumatic or postoperative lesions establishes the initial stage of infection. Local wound conditions are more important than the degree of clostridial contamination in the development of gas gangrene. Disrupted or necrotic tissue provides the necessary enzymes and a low oxidation/reduction potential, allowing for spore germination. Foreign bodies, premature wound closure, and devitalized muscle reduce the spore inoculum necessary to cause infection in laboratory animals.
The typical incubation period for gas gangrene is frequently short (ie, < 24 h), but incubation periods of 1 hour to 6 weeks have been reported. Self-perpetuating destruction of tissue occurs via a rapidly multiplying microbial population and the production of locally and systemically acting exotoxins. Local effects include necrosis of muscle and subcutaneous fat and thrombosis of blood vessels. Marked edema may further compromise blood supply to the region. Fermentation of glucose is probably the main mechanism of gas production in gas gangrene. In C septicum spontaneous gas gangrene, nitrogen is the predominant gas component (74.5%), followed by oxygen (16.1%), hydrogen (5.9%), and carbon dioxide (3.4%). Production of hydrogen sulfide and carbon dioxide gas begins late and dissects along muscle bellies and fascial planes. These local effects create an environment that facilitates rapid spread of the infection.[13]
Systemically, exotoxins may cause severe hemolysis. Hemoglobin levels may drop to very low levels and, when occurring with hypotension, may cause acute tubular necrosis and renal failure. A rapidly progressive infection can quickly result in shock. The mechanism of shock is poorly understood. Unconcentrated filtrate from C perfringens, purified alpha-toxin, and purified phi-toxins cause hypotension, bradycardia, and decreased cardiac output when injected into laboratory animals. Because alpha-toxins and phi-toxins are lipophilic and may remain locally bound to tissue plasma membranes, the toxins may stimulate synthesis of secondary mediators that cause cardiovascular abnormalities.
Clostridia species are ubiquitous and widely distributed in the soil, especially in cultivated land. The density of clostridia in the soil is a contributing factor in the development of trauma-related gas gangrene. Civilian cases of gas gangrene are more common, with approximately 3000 cases per year. Gas gangrene can be classified as posttraumatic, postoperative, or spontaneous. Posttraumatic gas gangrene accounts for 60% of the overall incidence; most cases involve automobile collisions.[14]
From 1998-2002, C septicum was implicated in causing serious infections in recipients of contaminated musculoskeletal-tissue allografts. In addition, 5 pediatric patients who had hemolytic uremic syndrome (HUS) secondary to infection by Escherichia coli O157 were later infected by C septicum with fatal complications.[15] Recently, Clostridium sordellii, an uncommon human pathogen, caused fatal toxic shock syndrome, bacteremia, and extensive endometritis in 4 young women who underwent medical abortion with oral mifepristone and vaginal misoprostol.[16]
In 2018, the FDA issued a warning about Fournier gangrene in numerous patients with type 2 diabetes mellitus who took sodium-glucose cotransporter-2 (SGLT2) inhibitors; they required a new warning concerning this risk to be added to the prescribing information of all SGLT2 inhibitors.[17] SGLT2 inhibitors include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.
In 2019, the FDA identified a total of 55 Fournier gangrene cases among patients treated with SGLT2 inhibitors during a six-year span (March 2013 to January 2019). All patients were critically ill and required surgical intervention, three of whom died. Although the causality of Fournier gangrene was not established, prescribers of SGLT2-inhibitors must be aware of this serious complication.[18]
Although rare, 4 cases of C perfringens gas gangrene developed quickly among patients who injected epinephrine with an auto-injector.[19]
International
From April 2000 to June 2000, several users of injection drugs in Scotland, Ireland, and England developed serious clostridial infections (C novyi and C perfringens) complicated by a high mortality rate (97%). Most of these patients reported injecting heroin intramuscularly within the previous two weeks.[20]
With more than 200,000 liposuctions performed in Germany in 2003, several serious complications had been reported. Necrotizing fasciitis and gas gangrene were the most frequent, major and lethal complications observed in a review of 72 cases of complications caused by liposuction performed in Germany between 1998 and 2002.[21]
A tsunami ravaged Indonesia in December 2004 and killed more than 200,000 Indonesians. Soaking in contaminated water, several injured persons later died of tetanus or gas gangrene.
In May 2008, the Sichuan earthquake in China caused more than 70,000 deaths and approximately 400,000 injuries; several injured persons developed gas gangrene and later underwent amputations. Among 2131 survivors admitted to a public hospital in the Sichuan area, at least 19 patients (0.9%) developed gas gangrene.[5]
Mortality/Morbidity
Gas gangrene is undoubtedly an infection that carries a very high mortality rate. The reported mortality rates vary widely, with a rate of 25% in most recent studies. The mortality rate approaches 100% in individuals with spontaneous gas gangrene and in those in whom treatment is delayed.[22, 23]
Sex
Gas gangrene has no reported sexual predilection, and the sex of the individual does not affect the outcome.
Although clostridial species rarely cause gynecological infection, numerous reports in the literature have described clostridial endometritis occurring after amniocentesis, cordocentesis, molar pregnancy, vaginal delivery, cesarean section, medical or spontaneous abortion, endometrial ablation, and cervical procedures.
Five cases of uterine C perfringens infection in middle-aged women were reported between 1970 and 2009. All 5 cases showed abnormal uterine pathology: two with degenerating uterine leiomyoma and three with endometrial adenocarcinoma. Common symptoms included fever, hemolysis, hyperbilirubinemia, hemoglobinemia, hemoglobinuria, and/or hypotension.[24]
Age
Although age is not a prognostic factor in gas gangrene, advanced age and comorbid conditions are associated with a higher likelihood of mortality.
Failure to provide an early diagnose and inadequate surgical intervention are the two most common mistakes in the management of gas gangrene. These factors eventually dictate the outcome.
The prognosis of gas gangrene is better if the incubation period is shorter than 30 hours, if the patient has limb involvement, and if he or she does not have concomitant serious medical conditions or complications (eg, shock, DIC, ARDS, renal failure).
Spontaneous gas gangrene frequently carries a much worse prognosis than other forms of gas gangrene.
A clinical algorithm based on six admission parameters was developed not only to predict the likelihood of unfavorable outcomes of patients with necrotizing soft tissue infections but also to guide appropriate aggressive therapy.[25]
Educate patients with spontaneous gas gangrene about the strong association with occult malignancies, especially malignancies of the GI tract.
Educate intravenous drug users about potential fatal complications of gas gangrene due to injection of contaminated heroin or other chemicals.[26]
Prescribers of SGLT2 inhibitors must educate their patients about the potential complication and seriousness of Fournier gangrene. Patients should seek medical attention immediately if they develop any symptoms of tenderness, redness, disproportional pain, fever, or swelling of the genitals or the area from the genitals to the rectum.[17, 18]
Educate patients with epinephrine auto-injectors about the rare but serious complication of gas gangrene associated with use of the device.[19]
The history in patients with gas gangrene depends on the precipitating factors of the infection. Most patients with posttraumatic gas gangrene have sustained serious injury to the skin or soft tissues or have experienced open fractures. Patients with postoperative gas gangrene have frequently undergone recent surgery of the GI or biliary tract. In contrast, the history is usually unremarkable in patients with occult malignancy–associated spontaneous gas gangrene.
A sudden onset of pain is usually the first symptom of gas gangrene. The pain gradually worsens but spreads only as the underlying infection spreads.
Some patients report a feeling of heaviness in the affected extremity.
A low-grade fever and apathetic mental status may develop.
Local swelling and a serosanguineous exudate appear soon after the onset of pain. The skin characteristically turns to a bronze color, then progresses to a blue-black color with skin blebs and hemorrhagic bullae. Within hours, the entire region may become markedly edematous. The wound may be nonodorous or may have a sweet mousy odor. Crepitus follows gas production; at times, crepitus may not be detected with palpation owing to brawny edema. Pain and tenderness to palpation disproportionate to wound appearance are common findings.
Tachycardia disproportionate to body temperature is common, and the patient may report a feeling of impending doom.
Late signs of gas gangrene include hypotension, renal failure, and a paradoxical heightening of mental acuity.
In summary, the typical signs and symptoms of gas gangrene include severe pain and tenderness, local swelling to massive edema, skin discoloration with hemorrhagic blebs and bullae, nonodorous or sweet odor, crepitus, fever, relative tachycardia, and altered mental status.
Gas gangrene can be classified as posttraumatic, postoperative, or spontaneous.
Posttraumatic gas gangrene
Posttraumatic gas gangrene accounts for 60% of all gas gangrene cases.
Most of these cases involve automobile collisions.
Other complications of trauma arise from crush injuries, compound fractures, gunshot wounds, thermal or electrical burns, and frostbite.
Farm or industrial injuries contaminated with soil are especially prone to developing gas gangrene.
Intramuscular or subcutaneous injections with insulin, epinephrine, quinine, heroin or cocaine are rare antecedent events leading to gas gangrene.
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A patient developed gas gangrene after injecting cocaine. Clostridium septicum was isolated in both blood and wound cultures.
Postoperative clostridial infections
Postoperative clostridial infections follow cases of colon resection; ruptured appendix; bowel perforation; and biliary or other GI surgery, including laparoscopic cholecystectomy and colonoscopy. It has also been reported following liposuction procedures.[21] Septic back-street abortions are the main cause of uterine gas gangrene.
Spontaneous gas gangrene without external wound or injury
Spontaneous gas gangrene without external wound or injury occurs frequently in patients who have serious underlying conditions.
Colorectal adenocarcinoma is the most prevalent risk factor in this group. Hematologic malignancy is also a major premorbid condition.
In children, neutropenia, either induced by chemotherapy or cyclic in nature, represents the single most important risk factor for spontaneous C septicum infections.
The remaining cases are associated with diabetes or neutropenic colitis. In many cases, no predisposing condition can be found.
Although C perfringens and C septicum infections are commonly reported, C septicum infection predominates. Patients with C septicum infections have overt or occult malignancies approximately 5 times more often than patients with other clostridial infections. In a large series of nontraumatic C septicum myonecrosis, malignant tumors were identified in 92% of patients; of these, 58% had colonic adenocarcinomas.[13, 27]
Rapidly developing hemolytic anemia with an increased lactate dehydrogenase (LDH) level is common in patients with gas gangrene.
Despite serious infection, white blood cell counts may not show leukocytosis. However, in patients with toxic shock syndrome due to C sordellii or C septicum, the CBC count may show hemoconcentration and extreme leukocytosis.
A Gram stain of the exudate or infected tissues reveals "box-car," large gram-positive bacilli without neutrophils. One study reported the usefulness and good sensitivity of Gram stain (86%) in the diagnosis of clostridial gas gangrene in survivors of Wenchuan earthquake.[28]
Less than 1% of blood cultures in patients with gas gangrene grow clostridial species.
The chemistry profile may show significant metabolic abnormalities (metabolic acidosis and renal failure) frequently associated with tissue injuries and hypotension.
Radiography can help delineate the typical feathering pattern of gas in soft tissue; however, gas may not be present in patients with gas gangrene. Conversely, the simple presence of gas in soft tissue does not confirm the diagnosis of gas gangrene. See the images below.
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Gas feathering in the arm soft tissue of a patient with gas gangrene.
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Extension of gas gangrene to the chest wall despite initial debridement.
CT scanning is also helpful, especially in abdominal cases of gas gangrene. A recent study with the new-generation CT scanners reported 100% sensitivity to detect necrotizing soft tissue infections; however, it excluded patients taken to surgery prior to CT scanning and did not explore surgically all clinically suspected cases .[29]
Studies on MRI to detect necrotizing soft tissue infection have reported lower sensitivity (80-90%) and limited specificity. In addition, MRI is time consuming and not always available.[30]
Ultrasound, although attractive as rapid bedside test, has not been well studied in this clinical scenario. In a cadaveric model of soft tissue gas, it showed excellent sensitivity in detecting gas and its localization.[31]
Rapid detection of alpha-toxin or sialidases (ie, neuraminidases) in infected tissues through enzyme-linked immunosorbent assay (ELISA) is not widely available but represents a potential diagnostic tool. ELISA can provide results in as little as 2 hours when the test is applied to wound exudate, tissue samples, or serum.
Although not widely available for clinical practice, in vitro amplification of the alpha-toxin or DNA by polymerase chain reaction (PCR) has been used to isolate clostridial species.
Surgical exploration confirms the diagnosis of myonecrosis. Affected muscle appears pale and shows no contractile function when incised or electrically stimulated.
Under local anesthesia, bedside biopsy with immediate frozen section can be performed to provide early and accurate diagnosis of gas gangrene. Although advocated by some authors for early diagnosis of necrotizing fascitis,[32] others question bedside biopsy for its practical application and potential delay of appropriate surgical exploration in the operating room.[33]
Because adjunctive diagnostic studies are time consuming and have limited utility for the diagnosis of necrotizing soft tissue infections, it is important to emphasize the invaluable role of the direct examination of the involved tissues in the operating room in making the diagnosis.
Due to the potentially high mortality and morbidity associated with delays in treatment, the threshold for operative exploration should be very low if the diagnosis is under consideration.[33]
Patients with gas gangrene frequently develop massive hemolysis, shock, acute respiratory distress syndrome (ARDS), and renal failure, which often require invasive procedures (eg, right-sided heart catheterization, mechanical ventilation, hemodialysis).
Histopathologic findings in gas gangrene consist of widespread myonecrosis, destruction of other connective tissues, and a paucity of neutrophils in the infected area. Leukocyte aggregates are found in the border regions.
Diagnosing necrotizing fasciitis is notoriously difficult because the early clinical signs are neither sensitive nor specific. Based on routine laboratory tests readily available at most centers, the Laboratory Risk Indicator for Necrotizing Fasciitis Scoring System (LRINEC) was introduced as a screening tool to distinguish necrotizing fasciitis from other soft tissue infections rapidly and accurately (see Table 1).[34]
If the total score exceeds 6, a diagnosis of necrotizing fasciitis should be considered (positive predictive value [PPV], 92% [95% CI, 84.3-96.0]; negative predictive value [NPV], 96% [95% CI, 92.6-97.9]). A score of more than 8 is highly suggestive of necrotizing fasciitis (PPV 93.4% [95% CI, 85.5-97.2]).
Only limited number of retrospective studies (but no prospective studies) have been conducted to validate the role of LRINEC for the early diagnosis of necrotizing fasciitis. Since none of the parameters in LRINEC is specific for necrotizing fasciitis and all can be abnormal in any inflammatory condition or infection, other diagnostic tools (imaging or biopsy) may be necessary in conjunction with the LRINEC score for making an early diagnosis and planning appropriate therapy for necrotizing fasciitis.
Table 1. Laboratory Risk Indicators for Necrotizing Fasciitis
View Table
See Table
A clinical algorithm was designed to categorize necrotizing soft tissue infections (NSTI) to predict the risk of unfavorable outcomes. The clinical score is based on six admission parameters (see Table 2).[25]
Table 2. Clinical Score Predictive of Death for Patients with Necrotizing Soft Tissue Infections
The combination of aggressive surgical debridement and effective antibiotic therapy is the determining factor for successful treatment of gas gangrene.
Antibiotic therapy
In animal models, prompt treatment with antibiotics significantly improves survival rates.
Historically, penicillin G in dosages of 10-24 million U/d was the drug of choice. Currently, a combination of penicillin and clindamycin is widely used.[22]
Recent studies show that protein synthesis inhibitors (eg, clindamycin, chloramphenicol, rifampin, tetracycline) may be more effective because they inhibit the synthesis of clostridial exotoxins and lessen the local and systemic toxic effects of these proteins.[35]
In spite of increasing clindamycin resistance among anaerobes, cases of clindamycin-resistant C perfringens are exceptional.[36, 37]
A combination of clindamycin and metronidazole is a good choice for patients allergic to penicillin.
A combination of penicillin and metronidazole may be antagonistic and is not recommended. Because other nonclostridial bacteria are frequently found in gas gangrene tissue cultures, additional antimicrobial coverage is indicated.
Although approved for treating complicated skin and soft-tissue infections, newer antibiotics such as daptomycin, linezolid, and tigecycline have not been studied in patients with gas gangrene; therefore, they should not be used as primary antibiotics for treating this condition.
Intensive care
Patients with gas gangrene frequently have end-organ failure and other concomitant serious medical conditions that require intensive supportive care.
Serum calcium monitoring
Monitoring serum calcium may need special attention when large areas of necrotic fat may lead to its deposition.[33]
Adjuvant therapy
Recombinant human activated protein C (drotrecogin alfa activated) has been used as an adjuvant therapy for patients with severe sepsis who scored 25 or more on the Acute Physiology and Chronic Health Evaluation (APACHE II). However, the mortality rate was higher in patients who had single-organ dysfunction and had undergone surgery within 30 days prior to treatment with drotrecogin alfa activated than in control groups (subset analyses of the PROWESS and ADDRESS studies).[38, 39] In addition, aside from the serious bleeding that may be associated with drotrecogin alfa activated, repeated surgical debridement in patients with gas gangrene requires frequent interruption of the continuous infusion of this product. Therefore, the authors do not recommend this adjuvant therapy in the treatment of gas gangrene.
Hyperbaric oxygen (HBO) therapy
Since the 1960s, HBO therapy has been used in the United States for the treatment of gas gangrene; however, its use remains controversial.
Controlled prospective studies on human subjects have not evaluated the impact of this treatment on survival. One reason for this is the low number of patients with gas gangrene. In addition, the therapeutic effect of HBO is difficult to reliably assess because of a lack of well-designed comparative studies.[40]
Many retrospective studies report increased survival in patients when HBO therapy is added to treatment with surgery and antibiotics. However, HBO therapy failed to show a survival advantage in 2 retrospective multicenter studies of the treatment of major necrotizing infections,[41, 42] although a more recent (2014) study reported that HBO therapy increased survival rates in necrotizing soft-tissue infections.[43]
Studies of animal models show conflicting reports about enhanced survival associated with HBO therapy. Studies indicate that HBO therapy has a direct bactericidal effect on most clostridial species, inhibits alpha-toxin production, and can enhance the demarcation of viable and nonviable tissue prior to surgery. For these reasons, some authors recommend the use of HBO therapy before the initial debridement, if possible.
The most common regimen for HBO therapy involves administration of 100% oxygen at 2.5-3 absolute atmospheres for 90-120 minutes 3 times a day for 48 hours, then twice a day as needed.
In view of the frequent catastrophic outcomes in patients with gas gangrene, HBO therapy is an important adjunct to surgery and antimicrobial therapy, despite the lack of convincing clinical efficacy.
Potential risks in patients undergoing HBO therapy include pressure-related trauma (eg, barotraumatic otitis, pneumothorax) and oxygen toxicity (eg, myopia, seizures). Other common adverse effects include claustrophobia. Most adverse effects are self-limiting and resolve after termination of HBO therapy.[44]
Fasciotomy for compartment syndrome may be necessary and should not be delayed in patients with extremity involvement.
Copious irrigation should be performed with sterile normal saline solutions and/or 3% liquid hydrogen peroxide.
Debridement of all wounds should be performed as soon as possible, with removal of badly damaged, contaminated, and necrotic tissue, especially in patients who tmight have been contaminated by soil, farm land, or dirty water.
If the wounds were treated elsewhere and closed, it is safest to reopen them, clean them, and leave them open with negative-pressure wound dressing therapy (if available) or just a sterile dressing.
Perform daily debridement as needed to remove all necrotic tissue until the wound has clean and healthy granulation tissue.
Amputation of the extremity may be necessary and life saving.
Abdominal involvement requires excision of the body wall musculature.
If faced with limited resources and extreme conditions caused by natural disasters such as an earthquake and/or tsunami, surgical care with the above-described principles also can be performed with the patient under local and/or regional analgesia.
Uterine gas gangrene following septic abortion usually necessitates hysterectomy.
Urgent surgical interventions such as hysterectomy can be life-saving in obstetric-gynecological necrotizing infections; however, an obstetrician/gynecologist may be reluctant to consider hysterectomy in young nulliparous patients with these life-threatening infections.[45]
Patients with obstetric/gynecological necrotizing infections must be monitored closely in the ICU and under the care of a multidisciplinary team including an obstetrician/gynecologist, an intensivist, an infectious disease specialist, and a general surgeon. Broad-spectrum antibiotics should be initiated immediately after collection of body fluid from multiple sources, including blood, cervical and vaginal swabs, urine, and uterine aspirate (postpartum or postabortion), for aerobic and anaerobic cultures. Surgical intervention, which is often crucial to preserve the patient’s life, should be performed within the first 24 hours in cases of failing aggressive medical therapy, worsening laboratory results, or clinical signs of worsening sepsis despite appropriate antibiotic therapy. The indications for surgical intervention in serious obstetric/gynecological infections are discussed below.[45]
Major indications for hysterectomy include the following:
Failure to respond to antimicrobial therapy alone in the first 24 hours
Rapid deterioration of clinical status despite medical therapy intervention
Evidence of necrotizing soft tissue infection
Evidence of intraabdominal or pelvic fluid collection suggestive of abscess collection
Evidence of gas within the uterine myometrial tissue suggestive of necrotizing soft tissue infection with clostridial species
The following circumstances suggest the source to be the uterus:
Postpartum (cesarean or vaginal delivery)
Postabortal or septic abortion
The following are worsening laboratory signs suggestive of toxic shock syndrome and/or tissue necrosis despite medical therapy:
WBC counts are generally more than 25,000/µL or less than 4,000/µL
Marked bandemia (>10%) independent of the total WBC count
Hemolysis: Hemoglobin level < 11 mg/dL
Massive hemoconcentration (hematocrit >45%) due to fluid pouring into necrotic areas, resulting in third-spacing and edema and an intravascular fluid depletion
Thrombocytopenia due to disseminated intravascular coagulopathy (DIC)
Serum sodium level less than 135 mEq/L
Creatinine level more than 1.6 mg/dL
Glucose level more than 180 mg/dL
Anion gap metabolic acidosis
Bicarbonate level less than 15 mg/dL
Lactic acid level more than 2.2 mmol/L
Systemic signs of severe sepsis include the following:
Avoid suturing wounds due to a crush injury or open fractures with devitalized muscle and soil contamination.
Provide warnings and instructions of wound care to rescuers and health care workers about clostridial infections, including tetanus and gas gangrene, in injured victims of natural disasters such as earthquake or tsunami.
Gas gangrene is one of the most devastating infections. Patients who survive the infection often sustain extremity amputation or massive loss of muscles, skin, and soft tissues, requiring extensive reconstructive surgery and physical rehabilitation.
Patients with spontaneous gas gangrene may have occult malignancies of the GI tract. Carefully instruct these patients and monitor their cases appropriately.
Aggressive surgical debridement and intensive medical therapy are the mainstays of treatment in gas gangrene; however, HBO therapy has become an important adjunctive therapy, especially in patients with truncal involvement.
Patients transferred for HBO therapy must be in stable condition. If compartment syndrome develops, do not delay fasciotomy to perform HBO therapy.
In 2014, the Infectious Diseases Society of America (IDSA) issued an update of the Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections[47] and had the following recommendations for the evaluation and management of necrotizing fasciitis, including Fournier gangrene:
Prompt/urgent surgical consultation is necessary for patients with aggressive infections associated with signs of systemic toxicity or suspicion of necrotizing fasciitis or gas gangrene.
Empiric antibiotic treatment should be broad-spectrum (eg, vancomycin or linezolid plus [1] piperacillin-tazobactam or a carbapenem or [2] ceftriaxone and metronidazole).
Penicillin plus clindamycin is recommended for treatment of documented clostridial gas gangrene or group A streptococcal necrotizing fasciitis.
Historically, penicillin G in dosages of 10-24 million U/d was the DOC. Recent studies show that protein synthesis inhibitors (eg, clindamycin, chloramphenicol, tetracycline) may be more effective by inhibiting the synthesis of clostridial exotoxins and lessening the local and systemic toxic effects of these proteins.
Clinical Context:
May be used for treatment of skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clinical Context:
Beta-lactam antibiotic that interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Clinical Context:
Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except Clostridium difficile enterocolitis).
Clinical Context:
Semisynthetic antibacterial agent derived from Streptomyces cultures. Treats gram-positive and gram-negative organisms and mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunit(s).
Clinical Context:
Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.
Clinical Context:
Vancomycin is active against Staphylococcus epidermidis. To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dose in a sample drawn 0.5 hours before the next dose. Dose adjustment is possible in patients with renal impairment; the adjustment should be based on creatinine clearance.
Clinical Context:
Linezolid is used as an alternative drug in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci. It is also effective against MRSA and penicillin-susceptible S pneumoniae infections.
This agent is an oxazolidinone antibiotic that prevents formation of the functional 70S initiation complex, which is essential for bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.
Clinical Context:
Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem. It is less likely to cause seizures and achieves superior penetration of the blood-brain barrier compared to imipenem.
Clinical Context:
Imipenem-cilastatin is a carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. It is used for treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to their potential for toxicity.
Clinical Context:
Bactericidal activity results from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. Stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. Hydrolyzed by metallo-beta-lactamases.
Clinical Context:
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell wall synthesis by binding to 1 or more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria, while cell wall assembly is arrested.
Clinical Context:
Cefotaxime is a third-generation cephalosporin that inhibits bacterial cell-wall synthesis. Like other beta-lactam antibiotics, cefotaxime inhibits bacterial growth by arresting bacterial cell wall synthesis. This agent is an alternative drug to ceftriaxone in patients requiring parenteral therapy.
Clinical Context:
Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Cross-resistance has only been shown with other rifamycins.
These agents inhibit bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Hoi Ho, MD, Associate Dean for Faculty Affairs and Development, Professor, Department of Internal Medicine, Director, Center for Advanced Teaching and Assessment in Clinical Simulation (ATACS), Paul L Foster School of Medicine, Texas Tech University Health Sciences Center; Consulting Physician, University Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Phuc Minh Nguyen, MD, MS (GenSurg), Lecturer, General Surgery Department, University of Medicine and Pharmacy of Ho Chi Minh City; Surgeon, Gastrointestinal Surgery Ward, Binh Dan Hospital; Endoscopist, Endoscopy Department, University Medical Center of UMP, Vietnam
Disclosure: Nothing to disclose.
Uyen Vinh Pham Huynh, MD, Lecturer, Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Nhan Dan Gia Dinh Hospital, Vietnam
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Disclosure: Received royalty from Baxter International for other.
Chief Editor
Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Disclosure: Nothing to disclose.
Additional Contributors
David G Maxfield, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine
Disclosure: Nothing to disclose.
Enes Kanlic, MD, Professor, Department of Orthopedic Surgery, Texas Tech University Health Science Center
Disclosure: Nothing to disclose.
Juan B Figueroa-Casas, MD, Associate Professor, Division of Pulmonary and Critical Care Medicine, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine
Disclosure: Nothing to disclose.
Lorenzo B Aragon, MD, Associate Professor, Department of Family Medicine, Paul L Foster Texas Tech University Health Sciences Center; Medical Director, Ambrosio Guillen Texas State Veterans Home
Disclosure: Nothing to disclose.
Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthors Jeffrey P Nelson, MD; Miguel Angel Pena-Ruiz, MD; and Karl C Bentley, MS, to the development and writing of this article.
FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes. August -29-2018; Accessed: July- 25 -2019.
Bryant CS, Perry L, Shah JP, Kumar S, Deppe G. Life-Threatening Clostridial Sepsis in a Postmenopausal Patient with Degenerating Uterine Leiomyoma. Hindawi-Case Reports in Medicine. Available at http://dx.doi.org/10.1155/2010/541959. 2010; Accessed: 2017.
Manning-Giest B, Rimawi BH. Severe Infections in Obstetrics and Gynecology: How Early Surgical Intervention Save Lives. J Clin Gynecol Obstet. 2016 Mar. 5:1-16.
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