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Enterococcal Infections
Enterococcal Infections Bertha Ayi Creighton University Medical Center, Omaha, USA ã 2007 Elsevier Inc. All rights reserved.
Introduction Enterococci are bacteria that normally inhabit the gastrointestinal tract of humans and animals. An important cause of endocarditis, they have come to public health attention lately due to acquired vancomycin resistance.
Definition Enterococci are gram-positive cocci that occur in singles, pairs, or chains.
Classification Enterococci were initially classified as group D streptococci because they share morphologic and Lancefield antigenicity. In the late 1980’s, Enterococcus was classified as a genus, with currently more than 17 species. Clinically important species include E. faecium and E. faecalis. The latter comprises approximately 80–90% of the clinically important species.
Consequences Urinary tract infections: This is one of the most common infections caused by enterococci. It accounts for about 12% of all urinary tract infections in the intensive care unit. This is usually nosocomial, being acquired mostly from instrumentation or urinary catheterization. It is rarely a cause of urinary tract infection in nonhospitalized patients. Bacteremia and endocarditis: Only about 1 out of every 50 cases of enterococcal bacteremia results in endocarditisMoellering (2000). About 9% of intensive care unit blood stream infections are due to enterococci. Enterococcal bacteremia may be transient and self-limited. Enterococci mostly cause a subacute endocarditis with an indolent and prolonged clinical course. It accounts for 5–15% of infective endocarditis and is mostly caused by E. faecalis. The other species E. faecium, E. avium, E. casseliflavus, E. durans, E. gallinarum, and E. raffinosus also cause endocarditis. The mitral valve is most often involved. Those affected are most likely to be elderly male patients with underlying valvular abnormalities or prosthetic valves. Intraabdominal sepsis: Intraabdominal sepsis can be ’pure’ or ’mixed’. Pure enterococcal spontaneous peritonitis occurs in patients with nephrotic syndrome or cirrhosis and in those undergoing chronic ambulatory peritoneal hemodialysis. Enterococci may also complicate abdominal surgery or trauma. Enterococci are often found in the drainage from mixed abdominal and pelvic infections where they are presumed to be causing an infection. Wound infections: Enterococci are often found mixed with other organisms in diabetic foot ulcers, surgical wounds, and decubitus ulcers. These wounds can be 1
2
Enterococcal Infections
complicated by bacteremia and culture-positive osteomyelitis, depending on their proximity to bone. Meningitis and infection of cerebrospinal fluid shunts. While very rare, meningitis can be a complication of high-grade enterococcal bacteremia Bayer et al (1976). Most cases are due to trauma or neurosurgery. Lung infections are rarely caused by enterococci. Neonatal sepsis: Enterococci can cause bacteremia and meningitis especially in premature and low birth-weight infants who are tube-fed and/or have intravascular devices.
Associated Disorders Conditions that predispose to enterococcal bacteremia include urinary tract infections, diabetic wounds, and abdominal/pelvic infections caused by these organisms. Patients with gastrointestinal malignancy are at increased risk, presumably due to the break in intestinal mucosa that facilitates entry of these intestinal organisms into the blood. Peritonitis can occur in patients with nephrotic syndrome, cirrhosis, or those undergoing peritoneal dialysis.
Etiology This intestinal organism can gain entry into the blood through gastrointestinal ulcerations. Genital contamination with stool contents may account for the propensity of this organism to cause urinary tract infections.
Epidemiology Enterococci are mostly isolated from the gastrointestinal tract of humans and other animals. They can also be found in the perineal area, oropharyngeal secretions, and vaginal secretions. They are very hardy organisms and can be found in food, soil, and water. Infections can be acquired inside or outside the hospital setting. It is the third most common cause of nosocomial infection in intensive care patients in the United States. Strains spread between patients, from healthcare workers to patients, or from institution to institution. Resistance strains are spread this way. Vancomycin resistant enterococci (VRE) were first reported in 1986 Leclercq (1988). About 80% of the VRE’s are E. faecium strains. The rates of resistance have increased dramatically worldwide, with a rate of 26.3% in United States intensive care unit isolates as of December 2000 Delisle and Perl (2003). VRE colonized-individuals can carry the organism in their rectums or hands for several years. Once colonized, they are at increased risk of getting a wound infection, urinary tract infection, or pelvic/abdominal abscess. The organism has been isolated from phones, computers, bedrails, doorknobs, and other objects in hospitals. Risk factors for acquiring VRE include oral vancomycin; prolonged antibiotic usage; use of certain antibiotics, such as cephalosporins, metronidazole, clindamycin, and imipenem; prolonged hospitalization; proximity to colonized patients; care by a nurse taking care of colonized patients; long intensive care unit stay; and hospitalization where there is a high VRE colonization rate.
Enterococcal Infections
Pathophysiology The virulence factors of enterococci are not fully understood. They are usually part of a polymicrobial infection with an attributable mortality of 30–37% Delisle and Perl (2003). One major factor that allows them to proliferate is their resistance to antibiotics. This allows them to multiply in patients receiving multiple antibiotics and to cause superinfections. The ability to withstand a low-gastric pH facilitates gastrointestinal colonization. From here, they can translocate from the intestinal lumen into the mesenteric lymph nodes, liver, and spleen. The ability to adhere to renal epithelial cells and heart valves accounts for the ease in causing urinary tract infections and endocarditis. It has been suggested that hemolysins may play a role in human pathogenicity Ike et al (1987).
Signs and Symptoms The clinical presentation depends on the site of infection. Urinary tract infections are characterized by dysuria, frequency, and urgency. Involvement of the upper urinary tract will give flank pain, whereas endocarditis causes fever, weight loss, malaise, and evidence of embolic events. Embolic events include strokes, Roth’s spots, Janeway lesions, and Osler’s nodes. Other findings include splenomegaly and heart murmurs. Wound infections are characterized by increased discharge, increased odor, or presence of new surrounding erythema. Neonates with sepsis present with hypothermia, bradycardia, poor feeding, and reduced muscle tone.
Standard Therapies Ampicillin and penicillin remain the drugs of choice for enterococcal infections. Options for penicillin allergic patients or ampicillin-resistant isolates are vancomycin or teicoplanin. The latter antibiotic is not available in the United States. Nitrofurantoin is useful for mild urinary tract infections. Monotherapy is usual for wound infections, urinary tract infections, or peritonitis. However, dual therapy with penicillin or ampicillin and an aminoglycoside should be used for serious infections such as endocarditis and meningitis. Multi-resistant strains require a combination of several agents. Enterococcus has intrinsic resistance to several antimicrobial agents, including the cephalosporins, antistaphylococcal penicillins, low concentrations of clindamycin, and aminoglycosides and trimethoprim/ sulfamethoxazole, and is able to acquire high-level resistance to several others after exposure. High-level resistance to vancomycin and teicoplanin characterizes VanA resistance. VanB resistance is characterized by highlevel resistance to vancomycin and susceptibility to teicoplanin. Unlike VanA and VanB resistance, which are acquired, Van C resistance is endogenous to certain species, namely E. casselflavus, E. galinarum, and E. flavescenceMurray (2000). The latter three organisms do not yet pose a significant clinical threat. Little is known about the VanD and VanE mechanisms of resistance. Agent Name
Discussion
Ampicillin
Ampicillin and penicillin inhibit bacterial cell wall synthesis and are the drugs of choice for all enterococcal infections. The MIC’s (minimum inhibitory concentrations) for E. faecalis tend to be lower than E. faecium for both
3
4
Enterococcal Infections drugs. Ampicillin and penicillin MIC’s for E. faecalis are 1 mg/ml and 2 mg/ml respectively, while that for E. faecium are 8 mg/ml and 16 mg/ml. Penicillin Ampicillin and penicillin inhibit bacterial cell wall synthesis and are the drugs of choice for all enterococcal infections. The MIC’s (minimum inhibitory concentrations) for E. faecalis tend to be lower than E. faecium for both drugs. Ampicillin and penicillin MIC’s for E. faecalis are 1 mg/ml and 2 mg/ml respectively, while that for E. faecium are 8 mg/ml and 16 mg/ml. Vancomycin Vancomycin is a glycopeptide that inhibits cell wall synthesis. For vancomycin-sensitive isolates MIC’s for E. faecalis and E. faecium are2mg/ ml and 1mg/ml. It is the preferred agent in penicillin-allergic patients. Vancomycin resistance has occurred with strains having MIC’s between 16–1000mg/ml. Teicoplanin Teicoplanin has a mechanism of action similar to vancomycin. It is the agent of choice for VanB resistant isolates. However, the VanA type of resistance is more common. Besides, resistance has emerged in VanB isolates during treatment. Teicoplanin is not available in the United States. Ampicillin/ This product combines ampicillin with a b-lactamase inhibitor. It is useful for Sulbactam the rare penicillase-producing strains of E. faecalis infections where there is b-lactamase expression by enterococci with resulting resistance to all blactams. E. faecium does not produce penicillase. Penicillase-producing strains are sensitive to b-lactam/b-lactamase inhibitor combinations of amoxicillin, ampicillin, and piperacillin. Gentamicin and Addition of gentamicin to any of the b-lactam agents or glycopeptides other discussed above provides a synergistic bactericidal effect. This is aminoglycosides particularly useful in endocarditis, severe sepsis, and meningitis. In endocarditis, combined therapy should be continued for 4–6 weeks. Streptomycin was the first aminoglycoside used in combination therapy to treat endocarditis. However, high-level resistance (MIC > 2000 mg/ml) developed, eliminating this benefit. Gentamicin has proved useful, although a high level of resistance has also developed to it. Endocarditis caused by isolates that are both gentamicin and streptomycin-resistant may be treated by ampicillin alone or by valve replacement. Moxifloxacin and These agents are DNA gyrase inhibitors. Newer quinolones, such as other quinolones moxifloxacin, sitafloxacin, and gemifloxacin, have greater gram-positive potency than ciprofloxacin, levofloxacin, and ofloxacin. Monotherapy is not advised. They are used in combination with ampicillin. Nitrofurantoin Nitrofurantoin and related antibiotics damage bacterial DN A. They are effective in the treatment of enterococcal urinary tract infection. Fosfomycin Fosfomycin is useful for the treatment of mild urinary tract infections Linezolide An oxazolidinone, linezolide represents a new class of agents that act by blocking the initiation phase of protein synthesis. Specifically, it binds to the 50S ribosome at a site that prevents the formation of the 70S initiation complex. Oral and Intravenous forms make it useful for easy switching when used for infections requiring prolonged antibiotic therapy. There is almost 100% bioavailability. It is ideal for vancomycin-resistant infections or infections in penicillin-allergic patients. It can be used for monotherapy. Quinupristin (with Quinupristin in combination with Dalfopristin inhibits protein synthesis by Dalfopristin) binding to the 50S subunit of the bacterial ribosome. It is a combination of quinupristin, a Streptogramin A, and dalfopristin, a Streptogramin B agent. The combination is ideal forvancomycin-resistant infections or for infections in penicillin-allergic patients. Most isolates of E. faecium, but not E. faecalis, are susceptible to it in vitro. Acquired resistance by E. faecium has been described. Dalfopristin (with Dalfopristin in combination with Quinupristin inhibits protein synthesis by Quinupristin) binding to the 50S subunit of the bacterial ribosome. It is a combination of quinupristin, a Streptogramin A, and dalfopristin, a Streptogramin B agent. The combination is ideal forvancomycin-resistant infections or for infections in penicillin-allergic patients. Most isolates of E. faecium, but not E. faecalis, are susceptible to it in vitro. Acquired resistance by E. faecium has been described.
Enterococcal Infections
Experimental Therapies
Agent Name
Discussion
Clinafloxacin
Clinafloxacin is a dihalogenated quinolone with greater potency than other members of this class against gram-positive cocci. In animal studies, combination with penicillin was better than either drug alone. Daptomycin is an inhibitor of lipoteichoic acid (cell wall component) synthesis. It is an experimental gram-positive agent. The glycylcyclines are a new class of semisynthetic tetracycline derivatives. Active against all enterococci, including tetracycline-resistant, vancomycinresistant, and other gram-positive cocci Shonekan et al (1997).
Daptomycin Glycylcyclines
Animal Models There are mouse, rat, and rabbit models of enterococcal peritonitis. Mouse and rat models of enterococcal peritonitis Dupont et al (1998). Rabbit model of endocarditisZaman et al (1996). Disparate findings on the role of virulence factors of Enterococcus faecalis in mouse and rat models of peritonitis. Treatment of experimental endocarditis due to multidrug resistant Enterococcus faecium with clinafloxacin and penicillin.
Other Information – Web Sites This is a website that needs a paid registration. Once in the medicine section, an infectious disease section opens up. It discusses various aspects of enterococcal infections:www. emedicine.com This is also a website that provides information on different management strategies for difficult-to-treat enterococcal infections. It requires paid registration: www.uptodate.com
Journal Citations Delisle, S., Perl, T.M., 2003. Vancomycin-resistant enterococci: A road map on how to prevent the emergence and transmission of antimicrobial resistance. Chest, 123(Suppl 5), 504S–518S. Leclercq, R., Derlot, E., Duval, J., et al. 1988. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N. Eng. J. Med., 319, 157–161. Murray, B.E., 2000. Drug Therapy: Vancomycin-resistant enterococcus infections. N. Eng. J.Med., 342(10), 710–721. Ike, Y., Hashimoto, H., Clewell, D.B., 1987. High incidence of hemolysin production by Enterococcus (streptococcus) faecalis strains associated with human parenteral infections. J. Clin. Microb., 25, 1524–1528. Bayer, A.S., Seidel, J.S., Yoshikawa, T.T., et al. 1976. Group D enterococcal meningitis. Clinical and therapeutic considerations with report of three cases and review of the literature. Arch. int. Med., 136, 883–886. Shonekan, D., Handwerger, S., Mildvan, D., 1997. Comparative in-vitro activities of RP 59500(Quinupristin/ dalfopristin), CL329, 998, CL 331,002, trovafloxacin, clinafloxacin, teicoplanin and vancomycin against gram-positive bacteria. J. Antimicrob. Chemother., 39, 405–409. Dupont, H., Montravers, P., Mohler, J., Carbon, C., 1998. Disparate findings on the role of virulence factors of Enterococcus faecalis in mouse and rat models of peritonitis. Infect. Immun., 66(6), 2570–2575. Zaman, M.M., Landman, D., Burney, S., Quale, J.M., 1996. Treatment of experimental endocarditis due to multidrug resistant Enterococcus faecium with clinafloxacin and penicillin. J. Antimicrob. Chemother., 37 (1), 127–132.
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Enterococcal Infections
Book Citations Moellering, R.C. Jr, 2000. Enterococcus Species, Streptococcus bovis, and Leuconostoc Species. Mandell, G.L., Bennett, J.E., Dolin, R. (Ed.), Mandell, Douglas, and Bennett’s Principles and Practice of infectious diseases, Edition 5, pp. 2147–2156, Churchill Livingstone, Philadelphia, PA.
Further Reading Huycke, M.M., Sahm, D. F. and Gilmore, M.S., Multiple drug resistant enterococci; the nature of the problem and an agenda for the future, Emerg. Infect. Dis., 4 (1998) 239–249. Vergis, E.N., Hayden, M.K., Chow, J.W., et al., Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study, Ann. Int. Med., 135 (2001) 484–492.
Introduction Enterococci are bacteria that normally inhabit the gastrointestinal tract of humans and animals. An important cause of endocarditis, they have come to public health attention lately due to acquired vancomycin resistance.
Definition Enterococci are gram-positive cocci that occur in singles, pairs, or chains.
Classification Enterococci were initially classified as group D streptococci because they share morphologic and Lancefield antigenicity. In the late 1980’s, Enterococcus was classified as a genus, with currently more than 17 species. Clinically important species include E. faecium and E. faecalis. The latter comprises approximately 80–90% of the clinically important species.
Consequences Urinary tract infections: This is one of the most common infections caused by enterococci. It accounts for about 12% of all urinary tract infections in the intensive care unit. This is usually nosocomial, being acquired mostly from instrumentation or urinary catheterization. It is rarely a cause of urinary tract infection in nonhospitalized patients. Bacteremia and endocarditis: Only about 1 out of every 50 cases of enterococcal bacteremia results in endocarditisMoellering (2000). About 9% of intensive care unit blood stream infections are due to enterococci. Enterococcal bacteremia may be transient and self-limited. Enterococci mostly cause a subacute endocarditis with an indolent and prolonged clinical course. It accounts for 5–15% of infective endocarditis and is mostly caused by E. faecalis. The other species E. faecium, E. avium, E. casseliflavus, E. durans, E. gallinarum, and E. raffinosus also cause endocarditis. The mitral valve is most often involved. Those affected are most likely to be elderly male patients with underlying valvular abnormalities or prosthetic valves. Intraabdominal sepsis: Intraabdominal sepsis can be ’pure’ or ’mixed’. Pure enterococcal spontaneous peritonitis occurs in patients with nephrotic syndrome or cirrhosis and in those undergoing chronic ambulatory peritoneal hemodialysis. Enterococci may also complicate abdominal surgery or trauma. Enterococci are often found in the drainage from mixed abdominal and pelvic infections where they are presumed to be causing an infection. Wound infections: Enterococci are often found mixed with other organisms in diabetic foot ulcers, surgical wounds, and decubitus ulcers. These wounds can be 1
2
Enterococcal Infections
complicated by bacteremia and culture-positive osteomyelitis, depending on their proximity to bone. Meningitis and infection of cerebrospinal fluid shunts. While very rare, meningitis can be a complication of high-grade enterococcal bacteremia Bayer et al (1976). Most cases are due to trauma or neurosurgery. Lung infections are rarely caused by enterococci. Neonatal sepsis: Enterococci can cause bacteremia and meningitis especially in premature and low birth-weight infants who are tube-fed and/or have intravascular devices.
Associated Disorders Conditions that predispose to enterococcal bacteremia include urinary tract infections, diabetic wounds, and abdominal/pelvic infections caused by these organisms. Patients with gastrointestinal malignancy are at increased risk, presumably due to the break in intestinal mucosa that facilitates entry of these intestinal organisms into the blood. Peritonitis can occur in patients with nephrotic syndrome, cirrhosis, or those undergoing peritoneal dialysis.
Etiology This intestinal organism can gain entry into the blood through gastrointestinal ulcerations. Genital contamination with stool contents may account for the propensity of this organism to cause urinary tract infections.
Epidemiology Enterococci are mostly isolated from the gastrointestinal tract of humans and other animals. They can also be found in the perineal area, oropharyngeal secretions, and vaginal secretions. They are very hardy organisms and can be found in food, soil, and water. Infections can be acquired inside or outside the hospital setting. It is the third most common cause of nosocomial infection in intensive care patients in the United States. Strains spread between patients, from healthcare workers to patients, or from institution to institution. Resistance strains are spread this way. Vancomycin resistant enterococci (VRE) were first reported in 1986 Leclercq (1988). About 80% of the VRE’s are E. faecium strains. The rates of resistance have increased dramatically worldwide, with a rate of 26.3% in United States intensive care unit isolates as of December 2000 Delisle and Perl (2003). VRE colonized-individuals can carry the organism in their rectums or hands for several years. Once colonized, they are at increased risk of getting a wound infection, urinary tract infection, or pelvic/abdominal abscess. The organism has been isolated from phones, computers, bedrails, doorknobs, and other objects in hospitals. Risk factors for acquiring VRE include oral vancomycin; prolonged antibiotic usage; use of certain antibiotics, such as cephalosporins, metronidazole, clindamycin, and imipenem; prolonged hospitalization; proximity to colonized patients; care by a nurse taking care of colonized patients; long intensive care unit stay; and hospitalization where there is a high VRE colonization rate.
Enterococcal Infections
Pathophysiology The virulence factors of enterococci are not fully understood. They are usually part of a polymicrobial infection with an attributable mortality of 30–37% Delisle and Perl (2003). One major factor that allows them to proliferate is their resistance to antibiotics. This allows them to multiply in patients receiving multiple antibiotics and to cause superinfections. The ability to withstand a low-gastric pH facilitates gastrointestinal colonization. From here, they can translocate from the intestinal lumen into the mesenteric lymph nodes, liver, and spleen. The ability to adhere to renal epithelial cells and heart valves accounts for the ease in causing urinary tract infections and endocarditis. It has been suggested that hemolysins may play a role in human pathogenicity Ike et al (1987).
Signs and Symptoms The clinical presentation depends on the site of infection. Urinary tract infections are characterized by dysuria, frequency, and urgency. Involvement of the upper urinary tract will give flank pain, whereas endocarditis causes fever, weight loss, malaise, and evidence of embolic events. Embolic events include strokes, Roth’s spots, Janeway lesions, and Osler’s nodes. Other findings include splenomegaly and heart murmurs. Wound infections are characterized by increased discharge, increased odor, or presence of new surrounding erythema. Neonates with sepsis present with hypothermia, bradycardia, poor feeding, and reduced muscle tone.
Standard Therapies Ampicillin and penicillin remain the drugs of choice for enterococcal infections. Options for penicillin allergic patients or ampicillin-resistant isolates are vancomycin or teicoplanin. The latter antibiotic is not available in the United States. Nitrofurantoin is useful for mild urinary tract infections. Monotherapy is usual for wound infections, urinary tract infections, or peritonitis. However, dual therapy with penicillin or ampicillin and an aminoglycoside should be used for serious infections such as endocarditis and meningitis. Multi-resistant strains require a combination of several agents. Enterococcus has intrinsic resistance to several antimicrobial agents, including the cephalosporins, antistaphylococcal penicillins, low concentrations of clindamycin, and aminoglycosides and trimethoprim/ sulfamethoxazole, and is able to acquire high-level resistance to several others after exposure. High-level resistance to vancomycin and teicoplanin characterizes VanA resistance. VanB resistance is characterized by highlevel resistance to vancomycin and susceptibility to teicoplanin. Unlike VanA and VanB resistance, which are acquired, Van C resistance is endogenous to certain species, namely E. casselflavus, E. galinarum, and E. flavescenceMurray (2000). The latter three organisms do not yet pose a significant clinical threat. Little is known about the VanD and VanE mechanisms of resistance. Agent Name
Discussion
Ampicillin
Ampicillin and penicillin inhibit bacterial cell wall synthesis and are the drugs of choice for all enterococcal infections. The MIC’s (minimum inhibitory concentrations) for E. faecalis tend to be lower than E. faecium for both
3
4
Enterococcal Infections drugs. Ampicillin and penicillin MIC’s for E. faecalis are 1 mg/ml and 2 mg/ml respectively, while that for E. faecium are 8 mg/ml and 16 mg/ml. Penicillin Ampicillin and penicillin inhibit bacterial cell wall synthesis and are the drugs of choice for all enterococcal infections. The MIC’s (minimum inhibitory concentrations) for E. faecalis tend to be lower than E. faecium for both drugs. Ampicillin and penicillin MIC’s for E. faecalis are 1 mg/ml and 2 mg/ml respectively, while that for E. faecium are 8 mg/ml and 16 mg/ml. Vancomycin Vancomycin is a glycopeptide that inhibits cell wall synthesis. For vancomycin-sensitive isolates MIC’s for E. faecalis and E. faecium are2mg/ ml and 1mg/ml. It is the preferred agent in penicillin-allergic patients. Vancomycin resistance has occurred with strains having MIC’s between 16–1000mg/ml. Teicoplanin Teicoplanin has a mechanism of action similar to vancomycin. It is the agent of choice for VanB resistant isolates. However, the VanA type of resistance is more common. Besides, resistance has emerged in VanB isolates during treatment. Teicoplanin is not available in the United States. Ampicillin/ This product combines ampicillin with a b-lactamase inhibitor. It is useful for Sulbactam the rare penicillase-producing strains of E. faecalis infections where there is b-lactamase expression by enterococci with resulting resistance to all blactams. E. faecium does not produce penicillase. Penicillase-producing strains are sensitive to b-lactam/b-lactamase inhibitor combinations of amoxicillin, ampicillin, and piperacillin. Gentamicin and Addition of gentamicin to any of the b-lactam agents or glycopeptides other discussed above provides a synergistic bactericidal effect. This is aminoglycosides particularly useful in endocarditis, severe sepsis, and meningitis. In endocarditis, combined therapy should be continued for 4–6 weeks. Streptomycin was the first aminoglycoside used in combination therapy to treat endocarditis. However, high-level resistance (MIC > 2000 mg/ml) developed, eliminating this benefit. Gentamicin has proved useful, although a high level of resistance has also developed to it. Endocarditis caused by isolates that are both gentamicin and streptomycin-resistant may be treated by ampicillin alone or by valve replacement. Moxifloxacin and These agents are DNA gyrase inhibitors. Newer quinolones, such as other quinolones moxifloxacin, sitafloxacin, and gemifloxacin, have greater gram-positive potency than ciprofloxacin, levofloxacin, and ofloxacin. Monotherapy is not advised. They are used in combination with ampicillin. Nitrofurantoin Nitrofurantoin and related antibiotics damage bacterial DN A. They are effective in the treatment of enterococcal urinary tract infection. Fosfomycin Fosfomycin is useful for the treatment of mild urinary tract infections Linezolide An oxazolidinone, linezolide represents a new class of agents that act by blocking the initiation phase of protein synthesis. Specifically, it binds to the 50S ribosome at a site that prevents the formation of the 70S initiation complex. Oral and Intravenous forms make it useful for easy switching when used for infections requiring prolonged antibiotic therapy. There is almost 100% bioavailability. It is ideal for vancomycin-resistant infections or infections in penicillin-allergic patients. It can be used for monotherapy. Quinupristin (with Quinupristin in combination with Dalfopristin inhibits protein synthesis by Dalfopristin) binding to the 50S subunit of the bacterial ribosome. It is a combination of quinupristin, a Streptogramin A, and dalfopristin, a Streptogramin B agent. The combination is ideal forvancomycin-resistant infections or for infections in penicillin-allergic patients. Most isolates of E. faecium, but not E. faecalis, are susceptible to it in vitro. Acquired resistance by E. faecium has been described. Dalfopristin (with Dalfopristin in combination with Quinupristin inhibits protein synthesis by Quinupristin) binding to the 50S subunit of the bacterial ribosome. It is a combination of quinupristin, a Streptogramin A, and dalfopristin, a Streptogramin B agent. The combination is ideal forvancomycin-resistant infections or for infections in penicillin-allergic patients. Most isolates of E. faecium, but not E. faecalis, are susceptible to it in vitro. Acquired resistance by E. faecium has been described.
Enterococcal Infections
Experimental Therapies
Agent Name
Discussion
Clinafloxacin
Clinafloxacin is a dihalogenated quinolone with greater potency than other members of this class against gram-positive cocci. In animal studies, combination with penicillin was better than either drug alone. Daptomycin is an inhibitor of lipoteichoic acid (cell wall component) synthesis. It is an experimental gram-positive agent. The glycylcyclines are a new class of semisynthetic tetracycline derivatives. Active against all enterococci, including tetracycline-resistant, vancomycinresistant, and other gram-positive cocci Shonekan et al (1997).
Daptomycin Glycylcyclines
Animal Models There are mouse, rat, and rabbit models of enterococcal peritonitis. Mouse and rat models of enterococcal peritonitis Dupont et al (1998). Rabbit model of endocarditisZaman et al (1996). Disparate findings on the role of virulence factors of Enterococcus faecalis in mouse and rat models of peritonitis. Treatment of experimental endocarditis due to multidrug resistant Enterococcus faecium with clinafloxacin and penicillin.
Other Information – Web Sites This is a website that needs a paid registration. Once in the medicine section, an infectious disease section opens up. It discusses various aspects of enterococcal infections:www. emedicine.com This is also a website that provides information on different management strategies for difficult-to-treat enterococcal infections. It requires paid registration: www.uptodate.com
Journal Citations Delisle, S., Perl, T.M., 2003. Vancomycin-resistant enterococci: A road map on how to prevent the emergence and transmission of antimicrobial resistance. Chest, 123(Suppl 5), 504S–518S. Leclercq, R., Derlot, E., Duval, J., et al. 1988. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N. Eng. J. Med., 319, 157–161. Murray, B.E., 2000. Drug Therapy: Vancomycin-resistant enterococcus infections. N. Eng. J.Med., 342(10), 710–721. Ike, Y., Hashimoto, H., Clewell, D.B., 1987. High incidence of hemolysin production by Enterococcus (streptococcus) faecalis strains associated with human parenteral infections. J. Clin. Microb., 25, 1524–1528. Bayer, A.S., Seidel, J.S., Yoshikawa, T.T., et al. 1976. Group D enterococcal meningitis. Clinical and therapeutic considerations with report of three cases and review of the literature. Arch. int. Med., 136, 883–886. Shonekan, D., Handwerger, S., Mildvan, D., 1997. Comparative in-vitro activities of RP 59500(Quinupristin/ dalfopristin), CL329, 998, CL 331,002, trovafloxacin, clinafloxacin, teicoplanin and vancomycin against gram-positive bacteria. J. Antimicrob. Chemother., 39, 405–409. Dupont, H., Montravers, P., Mohler, J., Carbon, C., 1998. Disparate findings on the role of virulence factors of Enterococcus faecalis in mouse and rat models of peritonitis. Infect. Immun., 66(6), 2570–2575. Zaman, M.M., Landman, D., Burney, S., Quale, J.M., 1996. Treatment of experimental endocarditis due to multidrug resistant Enterococcus faecium with clinafloxacin and penicillin. J. Antimicrob. Chemother., 37 (1), 127–132.
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6
Enterococcal Infections
Book Citations Moellering, R.C. Jr, 2000. Enterococcus Species, Streptococcus bovis, and Leuconostoc Species. Mandell, G.L., Bennett, J.E., Dolin, R. (Ed.), Mandell, Douglas, and Bennett’s Principles and Practice of infectious diseases, Edition 5, pp. 2147–2156, Churchill Livingstone, Philadelphia, PA.
Further Reading Huycke, M.M., Sahm, D. F. and Gilmore, M.S., Multiple drug resistant enterococci; the nature of the problem and an agenda for the future, Emerg. Infect. Dis., 4 (1998) 239–249. Vergis, E.N., Hayden, M.K., Chow, J.W., et al., Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study, Ann. Int. Med., 135 (2001) 484–492.