Streptococcus species (Group G and Group C Streptococci, Viridans Group, Nutritionally Variant Streptococci)
Authors: James S. Tan, MD, MACP, Thomas M. File, MD, FACP
"Strep" infections have been commonly associated with skin and throat infections due to Group A streptococcus (S. pyogenes). Non-group A streptococci have also been implicated from mild to serious infections. Group B (S. agalactiae), Group C and G streptococci, and viridans group streptococci (VGS) are known to colonize human respiratory, gastrointestinal, and genitourinary tracts. These bacteria are pathogenic given the right conditions.
MICROBIOLOGY
Traditionally, streptococci are classified by the use of Lancefield group antigens and by hemolysis on blood agar. Lancefield group antigen does not correlate with the species. Classification by hemolysis is imprecise. The molecular taxonomic studies have improved classification. The beta-hemolytic isolates under Lancefield group A, C, F, and G are subdivided into large and small colony forming groups. The large colony groups possess numerous virulence mechanisms, and are labeled "pyogenic". Large colony group C streptococci are usually resistant to bacitracin. This is the method used by many clinical laboratories from Group A Streptococci (GABHS) in many clinical laboratories. However, some Group C Streptococci (GCS) are susceptible to bacitracin and may result in misidentification if Lancefield serologic typing is not performed. Among the Group G streptococci (GGS), Bacitracin susceptibility has been reported to be as high as 67% (87). Trimethoprim/sulfamethoxazole (SXT) disk testing has been added to improve in the identification. Both GCS and GGS are susceptible and GABHS are resistant. For specific identification, a serogrouping reagent is used. The large colony Lancefield GCS are variably classified into some of several possible species, namely, S. dysgalactiae, S. equisimilis, S. zooepidemicus, and S. equi (36). These species can be differentiated by microbiological and biochemical characteristics. All but S.dysgalactiae commonly cause beta-hemolysis in blood agar. S. equisimilis is the most common GCS to cause infection in humans but may also infect domestic animals. The other species primarily infect animals. Most clinical laboratories do not speciate GCS isolates.
The small colony forming groups are classified under Anginosus group that was formerly called "S. milleri" group, or S. intermedius group. Although these "small colony" organisms may possess the Lancefield group A, C, F, G, and ungroupable antigen, they are commensals and are seldom pathogenic by themselves. For example, the Anginosus group organisms with group A antigen can be differentiated fromS. pyogenes by their small colony formers and are resistant to bacitracin. Anginosus or "S. milleri" group belongs to one of the 5 groups of VGS based on 16S rRNA sequences. The other viridans groups classified by this method include Mitis group, Salivarius group, Bovis group, and Mutans group (see Table 1) (39). VGS has been a wastebasket term referring to streptococci that produce partial or no hemolysis on blood agar and were not groupable. VGS is established by exclusion of S. pyogenes, enterococci, pneumococci, S. agalactiae, and large colony groups C and G (16), and has the following characteristics: vancomycin susceptibility, produces leucine aminopeptidase (LAP) enzyme, and does not produce pyrrolidonyl arylamidase (PYR) enzyme (72).
Group B streptococcus (GBS) has only one species, i.e., S. agalactiae, but is subclassified into 7 capsular serotypes, namely: Ia, Ib, II, III, IV, V, and VI. Type III is most commonly associated with neonatal disease while Ia and Ib with adult diseases (25,91). GABS is discussed elsewhere in this textbook.
This chapter discusses the antimicrobial treatment of pyogenic groups C and G, and the VGS. It will not discuss the treatment of infections caused by S. pyogenes. S. agalactiae and S. pneumoniae.
GROUP C AND G STREPTOCOCCI
Clinical Manifestations
Large colony forming GCS and GGS are part of the normal human skin and oral flora (Table l). Human infections due to GCS and GGS are much less common than GABHS and GBS. GCS and GGS have been associated with pharyngitis, although their exact role is uncertain. The clinical manifestations are not clinically different from GABHS. Their association with rheumatic fever has been investigated but not definitely established (32), and their association with glomerulonephritis has been anecdotal (36). Skin infection is second most common. Other infections include puerperal and neonatal infections, bacteremia, endocarditis, meningitis, arthritis, osteomyelitis, pneumonia, toxic shock-like syndrome, and rhabdomyolysis (8, 10, 11, 43, 48, 51, 75, 77, 79, 87, 89, 90). Infections with these organisms are frequently found in patients with underlying conditions such are chronic lung or heart disease, diabetes, malignancy (particularly GGS), alcoholism, and immunosuppressive therapy. GCS are common pathogens in animal and many patients with this infection have a history of animal exposure.
In Vitro Susceptibility
Penicillins, cephalosporins, carbapenems, and vancomycin are the most active antimicrobial agent against Group C and G streptococci (Table 2-Table 4). Most strains are highly sensitive to penicillin G with MIC <0.05 μg/ml. Strains with MIC >0.1 μg/ml are rarely encountered (56). Broad spectrum penicillins are also active. Rolston et al reported MIC90s of 0.03 and 0.06 μg/ml for piperacillin and azlocillin respectively in 44 isolates of GCS and GGS (62).
Cephalothin and cefotaxime are very active with MIC90s of 0.06 and 0.12 μg/ml respectively (62). Kansenshoyaku et al observed that all GGS and 99% of GCS were susceptible to 0.2 μg/ml of cephalothin (37). Other cephalosporins were less active, e.g., MIC90 for cephalexin was 3.13 μg/ml, and MIC90 for both GCS and GGS, and MIC90 for cefaclor was 1.56 and 3.13 μg/ml respectively (37). Vancomycin is active with most isolates and has an MIC90 of <0.5 mg/ml. Rolston et al have reported isolates with MIC of 4.0 μg/ml isolates from cancer patients (69). Imipenem is active against both GCS and GGS, all isolates evaluated by Muro et al were susceptible (47).
Susceptibility of GCS and GGS to clindamycin and the macrolides is variable, and recent studies reported some resistance (37, 43, 47, 62, 65). Kansenshoyaku et al found an MIC90 for erythromycin of 0.1 μg/ml for both GCS and GGS, but 16 of 463 strains of GGS had MIC above 1.0 μg/ml (37). Kataja et al from Finland reported that 95% of 21 macrolide-resistant GCS had mefA or mefE drug efflux gene, and 94% of 32 macrolide-resistant GGS had ermTR methylase gene (38).
Using National Committee for Clinical Laboratory Standards (NCCLS) guidelines, Muro et al reported the in vitro susceptibility of 113 isolates of GCS and 35 isolates of GGS obtained from 1992 to 1995. All were susceptible to penicillin G, ampicillin, amoxicillin/clavulanate, cefotaxime, imipenem, rifampin, and vancomycin (47). For GCS strains, the percentages of strain resistant to other antimicrobial agents were: erythromycin and azithromycin, 9%; clindamycin, 8%; chloramphenicol, 2%; tetracycline, 17%; and trimethoprim/sulfamethoxazole (SXT), 20% (47). For GGS strains, the percentages of resistance to other antimicrobial agents were: erythromycin, 32%; azithromycin, 16%; clindamycin, 19%; chloramphenicol, 0%; tetracycline, 39%; and SXT, 23% (47).
Tolerance, a condition in which bactericidal activity is greater than 32 times that of bacteriostatic activity, has been reported by numerous investigators (50, 56, 63). Zaoutis et al reported vancomycin tolerance in 54% of 32 GCS and GGS isolates (97). The frequency and clinical importance of tolerance have not been established (43,87). This same group of investigators have subsequently evaluated the in vitroactivities of meropenem, linezolid, and quinupristin/dalfopristin against 130 clinical isolates of GCS and GGS (98). The MIC90 for meropenem, linezolid, quinupristin/dalfopristin, vancomycin, and penicllin were 0.06, 2.0, and 0.25, 0.5 and <0.016 ug/ml respectively. Meropenem, linezolid, quinupristin/dalfopristin, and penicillin were all active against the vancomycin-resistant or tolerant strains.
Synergism has been demonstrated when an aminoglycoside is added to penicillin, cefotaxime, and vancomycin. Portnoy et al found that all isolated tested have enhanced killing when penicillin is combined with gentamicin compared to penicillin alone (56). Rolston et al found that penicillin-tolerant GCS isolates were killed following the addition of gentamicin to penicillin or cefotaxime (63). Lam and Bayer compared the in vitro bactericidal interaction of penicillin, cefotaxime, or vancomycin in combination with gentamicin for 20 isolates of GGS. Synergism was demonstrated in each combination between 80 to 90% of the isolates (44).
Antimicrobial Therapy
The response of GCS or GGS infections to specific antimicrobial agents as reported in the literature is difficult to assess. Many patients in individual reports or population-based studies received multiple antibiotics with varying doses, routes of administration, and duration of therapy. There are no controlled antimicrobial efficacy trials. Most patients reported with GCS and GGS infections have received apenicillin or cephalosporin (often with an aminoglycoside). Small numbers of patients have been treated with other antimicrobial agents (vancomycin, erythromycin, clindamycin, or chloramphenicol). On the basis of in vitro data as well as reported clinical experience, penicillin G is the preferred antibiotic (8, 10, 13, 43, 75, 87, 89). Alternative agents with relatively uniform activity include ampicillin, cefotaxime,imipenem, and vancomycin. In vitro testing should be performed if clindamycin or the macrolides are considered for therapy in light of the recent reports of resistance to these agents.
The less serious GCS or GGS infection (pharyngitis, cellulitis) can be treated with similar therapy as for GABHS; however, the in vitro activity of the macrolides or clindamycin is not as consistent. Patients have responded readily to therapy with a β-lactam antibiotic. The in vitro activity of the new fluoroquinolones appear to be excellent for GCS and GGS although the number of strains studied were limited, i.e. 8 GCS, and 22 GGS (5). These new fluoroquinolones with enhanced gram positive activity such as levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin may be considered as an alternative since the MICs are consistently low (<1.0 μg/ml) but clinical data are lacking.
Because of the theoretical concern of tolerance and probability of synergy, many authorities have recommended combination therapy using penicillin plus gentamicin for serious infections such as sepsis and endocarditis (56, 75, 87). Such recommendations, however, have not been substantiated by controlled studies. Watanakunakorn has reported a relatively high mortality (40%) for patients with endocarditis in spite of penicillin susceptibility (90). This may in part be due to high association with comorbid conditions of these patients. For serious infections such as endocarditis, bacteremia, and any septic condition penicillin 20 million units intravenously per day is recommended. Alternatives include cefotaxime 8 g intravenously in divided doses. Vancomycin 2 g intravenously per day may be used for patients who are unable to receive beta-lactam agents. Alternatively, Linezolid or quinupristin/dalfopristin could be used in beta-lactam intolerant patients but clinical data is lacking. The duration of therapy for endocarditis is 28 days, and for bacteremia or sepsis 14 days of therapy should be adequate. There is currently no consensus on the value of adding gentamicin. However, it is reasonable to consider gentamicin initially for therapy of patients with severe infections until the results of in vitro susceptibility. If the Penicillin MIC is >0.1 μg/ml, combination therapy should be used for the full course of therapy.
VIRIDANS GROUPS OF STREPTOCOCCI
Clinical Manifestations
Viridans groups of streptococci (VGS) have been considered to be of low virulence. Transient bacteremias may occur following dental manipulation and frequently are of no consequence in patients without predisposing conditions. It has been estimated that only 21% of the positive blood cultures for VGS are clinically significant (81). VGS is the most common cause of native valve endocarditis and late onset prosthetic valve endocarditis ( 78, 83, 90). They have also been associated with serious pyogenic infections, bacteremias in neutropenic patients, neonatal sepsis, and septicemia/shock syndrome (also known as "α strep shock syndrome")(4, 9, 24, 36).
The sites of colonization and infections of VGS in humans are listed in Table 1. Certain VGS produce dextran that is associated with plaque formation and is highly associated with infective endocarditis when cultured from the blood (78). Dextran production results in glycocalyx deposition that promotes adherence and serves as an adherence factor. For example, S. mutans, S. sanguis (the proposed nomenclature isS. sanguinis (39,73), we will use S. sanguis in this chapter because of another recent proposal to conserve the original name (42)), dextran-positive S. mitis (also known as S. mitior, S. mitis will be used in this chapter), and S. bovis are mouth organisms are associated with dental disease and endocarditis. In their review of 229 cases with blood cultures positive for VGS, Dwyer et al reported that S. mitis, when isolated, should be considered a clinically significant pathogen (23).
S. bovis is a common gastrointestinal commensal and has been reported to cause bacteremia, endocarditis, and meningitis (58,72). S. bovis biotype I bacteremia has been shown to be highly associated with gastrointestinal malignancies while biotype II and S. salivarius are less likely to be associated (74).
Anginosus group (also known as S. milleri or S. intermedius group) isolates have been associated with purulent infections in oral, thoracic, abdominal, and central nervous system sites (31). S. anginosushas been found mostly in genitourinary tract and gastrointestinal tract, S. constellatus from the chest, and S. intermedius from the central nervous system, head and neck, and abdomen (35,92). Singh et al review 186 cases of S. anginosus infections and found 110 patients had at least one abscess identified. Among their 33 cases of bacteremia due to "S. milleri", Salavert et al observed that approximately 60% were intraabdominal in origin (76). Because of the frequent association of abscess formation, a routine workup in Anginosus group bacteremia should include a search for abscess.
In Vitro Susceptibility
VGS are presumed to be uniformly susceptible to penicillin. However, Pfaller et al reported 9.2% of VGS isolates from the SCOPE Hospital Study Group were penicillin resistant (53). In the 1995 American Heart Association guidelines for treatment of endocarditis divided VGS into penicillin susceptible, intermediate resistance, and high level of resistance. Penicillin was recommended for penicillin susceptible VGS (94). Increasing percentage of penicillin resistance has been reported even in serious infections and this resistance is believed to be due to the alteration of penicillin binding protein ( 2, 29, 31, 57,59, 93). Alcaide, et al from Barcelona, Spain found that 33.6% of 410 isolates were resistant to penicillin (41.5% of S. mitis, 41.7% of S. sanguis, 28.1% of S. salivarius, and 14% of S. anginosus) (2). They divided the beta-lactam agents tested against the penicillin-resistant strains into three groups. In the first group, imipenem, ceftriaxone, cefotaxime showed similar or higher activity to that of penicillin. The antibiotics in the second group showed lower activities than that of penicillin: ampicillin, amoxicillin/clavulanate, piperacillin, cefuroxime, and cefpodoxime. The third group showed poor in vitro activities: it includes the first generation cephalosporins, ceftazidime, cefixime, cefaclor, ceftibuten, and oxacillin. Traub et al from Germany reported his collection of 116 VGS isolates from patients and 162 isolates from healthy adults (85): all isolates were susceptible to vancomycin and teicoplanin; none had high level resistance to gentamicin; all were resistant to fusidic acid. The susceptibility to non-beta-lactam antibiotics was not consistent, e.g. ciprofloxacin was 59.7%; ofloxacin, 89.2%; doxycycline, 65.8%; tetracycline, 56.8%; clindamycin 87.8%; erythromycin, 59%; clarithromycin, 74.9%; and SXT, rifampin, and chloramphenicol were over 97%. All 12 S. mitis isolates were from patients and were penicillin resistant. The susceptibility of the VGS to penicillin G was 79.1%; ampicillin, 66.9%; piperacillin, 98.2%; cefoxitin, 76.6%; cefuroxime 96.8%; cefotaxime, 98.6%; ceftriaxone, 98.6%; cefepime, 98.6%; imipenem 98.2%. Potgieter, et al from South Africa studied 211 isolates from blood cultures showed that all were consistently susceptible to cefotaxime, ceftriaxone, and imipenem (57). It appears from the above reports that imipenem, cefotaxime, and ceftriaxone are acceptable alternatives in serious infections caused by penicillin resistant strains, but further clinical studies are needed. When intermediate resistance (MIC = 0.25 to 2 μg/ml of penicillin) or high level resistance (MIC of 4 μg/ml or greater) is encountered, synergism with aminoglycoside can still be achieved (15). Synergistic combination should be considered after in vitro synergism has been confirmed. High percentage of SXT, erythromycin and tetracycline resistance has been reported (22,57). In contrast to its group D counterpart, the enterococcus, S. bovis is highly susceptible to penicillin.
Doern et al, reported their experience with 352 VGS from 43 U.S. medical centers (Figure 1) (22). They found that 13.4% had high level of resistance (MIC >4 μg/mL), 42.9% had intermediate resistance (MIC = 0.25-2.0 μg/mL). Among the cephalosporins tested, ceftriaxone appears to be the most active. Using the breakpoint of 8 μg/mL for ofloxacin, less than 1% was encountered, and using a breakpoint of 2 μg/mL less than 5% resistance was observed. In another U.S. study, blood cultures from 47 neutropenic patients who were on ciprofloxacin prophylaxis yielded VGS (majority were S. mitis and S. sanguis). Penicillin resistance was found in 38%, ceftazidime resistance in 54%, and ciprofloxacin and ofloxacin reistance in 95% (46). Because of this observed increased quinolone resistance, the use of quinolone especially those with poor gram positive coccal activities for prophylaxis in neutropenic cancer patients should be carefully evaluated. Kennedy et al reported the isolation of VGS with increased MICs to beta-lactams from blood in 61 pediatric patients with malignancy despite prior courses of empiric antibiotic therapy that was either ceftazidime plus amikacin or piperacillin/tazobactam plus amikacin (40). Poor susceptibility to macrolide antibiotics was demonstrated in 66 blood culture isolates from neutropenic cancer patients (1). Resistance of VGS to beta-lactams, SXT, clindamycin and macrolides continues to rise even among the non-neutropenic patients (1, 3, 20, 41, 52, 53, 76, 86, 96). In a study from United Kingdom, resistance to beta-lactam and macrolides were mainly found in S. mitis and higher rates of ciprofloxacin resistance were found in isolates identified as S. bovis, S. mitis, and S. mutans (41). The increasing antimicrobial resistance of VGS suggests that the use of beta-lactams and macrolides as prophylactic agents for dental procedures, and the empiric or prophylactic use in granulocytopenic patients should be revisited (20, 53, 60, 95). Similarly, the choice of flouoroquinolones for prophylaxis and treatment should be individualized.
Penicillin resistance in the Anginosus group is rare (34, 76, 85). However, Potgieter et al reported an overall 29% penicillin resistance in the VGS including Anginosus group (57). VGS are still susceptible to vancomycin and certain cephalosporins, but increasing resistance to clindamycin, erythromycin, tetracycline, sulfamethoxazole and aminoglycosides has been reported (30, 31, 33, 55, 96). Synergy can usually be demonstrated with penicillin and aminoglycosides.
Antimicrobial Therapy
Endocarditis
Since the introduction of penicillin, the cure rate of VGS has exceeded 95%. Reasons for failure include bacterial tolerance (when MBC is 32 times higher than MIC), inadequate antimicrobial level in the vegetation (most likely due to inadequate dosing or poor drug penetration), and heart failure. In addition to the maintenance of pump function, the major objective is the eradication of the infecting VGS. The AHA guidelines (Table 5) for the treatment of native valve infection by penicillin susceptible VGS (MIC <0.1 μg/mL) including S. bovis consists of four-week therapy with a single beta-lactam agent or two-week therapy with a combination of a beta-lactam agent plus aminoglycoside. Francioli et al have recently reported successful treatment of VGS endocarditis using a 2-week course of ceftriaxone 2g plus netilmicin at dose of 4 mg/kg (27). Although the guidelines recommended four-week single beta-lactam agent for the elderly, we prefer to treat with combination therapy except in the patient with impaired renal function or in the presence of high level aminoglycoside resistance (MIC >500 μg/mL). Gavalda et al reported that in experimental endocarditis study, once a day intramuscular dosing of gentamicin is as effective as multiple dosing as long as the total daily dose is 3 mg/kg (28). The overall bacteriologic failure rate is extremely low (78). In patients who have been ill for longer than 3 months before therapy, relapse rate is higher and a longer duration of therapy is recommended (54).
Successful oral penicillin plus intramuscular aminoglycoside therapy for penicillin susceptible VGS has been reported (82). This form of therapy should only be tried in a setting where blood levels can be monitored, and patient compliance can be assured. For patients who have allergy to beta-lactam agents, vancomycin may be used. In younger patients, vancomycin clearance may be faster, therefore it may be prudent to know the vancomycin half-life and adjust the dosing interval.
For patients with native valve endocarditis due to strains with MIC between 0.1 and 0.5 μg/mL, AHA (Table 5) recommends combining 4 weeks treatment with penicillin plus 2 weeks of aminoglycoside therapy. If high level resistance to aminoglycoside is present or synergism with aminoglycoside cannot be demonstrated, vancomycin should be used. Based on the study by Alcaide et al, another option is to check for the susceptibility to cefotaxime, ceftriaxone, and imipenem. If the MIC is low, any of these agents may be considered. If the MIC is high, vancomycin should be used. However, no official recommendation is available for the treatment of these highly beta-lactam resistant organisms. Experimental studies using vancomycin plus gentamicin have shown that this combination is effective against strains that are penicillin resistant (45). Patients infected with Anginosus group streptococci are at a higher risk for complications, therefore a higher dose of penicillin is recommended.
Table 6 shows the 1997 American Heart Association recommendation for antimicrobial regimens for patients undergoing dental, oral, respiratory tract or esophageal procedures to prevent infective endocarditis (17).
Non-cardiac Sites of Infection
Clinically, infections caused by Anginosus group have responded well to penicillin and cephalosporins. With penicillin resistance on the rise, it is prudent to treat serious infection with a combination of penicillin and aminoglycoside. Vancomycin or clindamycin may be used penicillin allergic patients. Since the Anginosus group is frequently associated with abscess, effort should be made to rule out this possibility. When abscess is present, drainage should strongly be considered. Treatment failures have been observed in patients with polymicrobial abscess and who were treated with metronidazoleand anti-gram negative rod antimicrobial agents. Because of the lack of antistreptococcal activity in the above combination, Anginosus group streptococci has been isolated as the sole microbe in liver abscess (55).
Special attention should be made on the neutropenic patients with VGS bacteremia. Although it is not as common as gram negative and staphylococcal bacteremia, this problem has been increasing because of routine use of antibiotic prophylaxis with fluoroquinolones, damage to the oral mucosa caused by chemotherapy, and the presence of neutropenia (6, 14, 61). The oral cavity is the most likely portal of entry especially in those with oral mucosa damage. Complications from VGS bacteremia include pulmonary infiltrates, adult respiratory distress syndrome, hypotension, and endocarditis (6). A related problem is septicemia and shock syndrome due to VGS which has an associated a mortality rate of 11% (24). Alternatives to high dose penicillin include vancomycin. If another beta-lactam drug is used, imipenem,ceftriaxone, and cefotaxime have better activity than most other cephalosporins including ceftazidime (2,57,88).
Meningitis
VGS rarely infect the meningitis. In a report from a 1000 bed hospital in Barcelona, Cabellos et al reported 29 cases of Streptococcal meningitis between 1977 to 1997 (12). Twenty of the 20 cases were VGS and increasing MIC of penicillin was observed. Experience on treatment of meningitis due these organisms is limited. The antibiotic of choice should be one that has better penetration to the cerebrospinal fluid. Ceftriaxone, cefotaxime or high dose penicillin should be effective. Vancomycin may be used for penicillin allergic patients. Cerebrospinal fluid levels should be monitored to ensure adequate levels.
Mixed Infections
When VGS infection is suspected to be part of the overall mixed infection, therapy should be directed against the mixed infection. The physician should make sure that an antimicrobial agent that is effective against VGS is part of the therapy.
NUTRITIONALLY VARIANT STREPTOCOCCI
(Abiotrophia defectivus and A. adjacens)
"Nutritionally variant streptococci" are no longer classified under VGS (73). These streptococcus looking organisms were previously grouped with VGS because of some similarities to S. mitis, but recent the classification has moved them out of the genus of Streptococcus to Abiotrophia (73). Unlike VGS, NVS require pyridoxal or thiol supplement for growth. Two species, namely, A. defectivus and A. adjacens are included in this group. Similar to VGS, these bacteria are found normally in the oropharynx, and have been associated with bacteremia, endocarditis, and eye infections including conjunctivitis, keratitis, endophthalmitis, and infectious crystalline keratopathy (71).
Susceptibility In Vitro
In vitro susceptibility test for this group is difficult to perform, and the results do not correlate well with clinical outcome. Moreover, infections due to these organisms are known to respond poorly to antibiotics (80). Nutritionally variant streptococci, as a rule are less susceptible to penicillin than most other streptococci, but many strains exhibit tolerance (36,71). Most strains have been reported to be susceptible to rifampin, clindamycin, erythromycin, chloramphenicol, and vancomycin (71) . Susceptibility to tetracyclines, aminoglycosides and cephalosporins is variable (36). Time killed curve studies have shown that vancomycin and rifampin are synergistic (71).
Antimicrobial Therapy
There are two groups of streptococci that are more difficult to treat, "tolerant" organisms and nutritionally variant organisms. The NVS organisms are also "tolerant". "Tolerance" is defined as having the MBC 32 times higher than MIC. In other words, the bacterial growth can be inhibited but not killed until the antibiotic concentration is increased by 32-fold or more. Stein, et al reviewed 30 cases of NVS endocarditis and found that the relapse rate, bacteriologic failure, and mortality rate is higher than viridans group. They believe that the slow rate of growth and the production of glycocalyx may have contribute to the lack of success (80). In addition, "tolerance" has been observed with penicillin and vancomycin (71). The current AHA recommendation is to treat nutritionally variant streptococcus endocarditis similar to enterococcal infection (see Table 5). However, even with 6 weeks of combination therapy with penicillin and gentamicin, failure rate is high (21).
Experimental models of endocarditis demonstrated that vancomycin or vancomycin-gentamicin combination may be used as an alternative drug in patients when penicillin-aminoglycoside combination is ineffective or contraindicated (7). Clinical experience is still lacking.
CAVEATS AND COMMENTS
Recent changes in the susceptibility of streptococci have changed to attitude of the clinicians towards this group of bacteria. Certain penicillins and cephalosporins previously considered to be exquisitely active are no longer consistently effective. Beta-lactam antibiotics either alone or in combination are suitable for most endocarditis patients infected with VGS, S. bovis, but alternative regimens are necessary for special situations. Groups C, and G streptococci respond best to the combination of a penicillin and an aminoglycoside (26). The clinician should be aware of these new developments and be ready to use MIC of antimicrobial agents and synergism tests in serious infections caused by streptococci.
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Tables
Table 1. Sites of Colonization and Infections in Humans, Non-Group A and Non-Group B Streptococcal Pathogens
Streptococcus |
Normal residence |
Infection |
|---|---|---|
Group C and G (pyogenes-like or large colony forming organisms) GGS (S. equi, S. equisimillis, S. zooepidemicus) |
oropharyngeal flora, vagina rectum skin S. canis is a zoonotic agent |
pharyngitis skin infection bacteremia endocarditis meningitis osteomyelitis septic arthritis respiratory tract infection puerperal infection neonatal sepsis toxic shock-like syndrome rhabdomyolysis |
Viridans groups of streptococci39 |
oropharynx, gastrointestinal tract, and genital tract |
endocarditis infections in neutropenic patients |
Mitis group S. mitis S. gordonii S. oralis S. sanguis S. parasanguis (S. pneumoniae)* |
dental plaques, oropharynx and gastrointestinal tract |
Bacteremia, endocarditis, meningitis ARDS
|
Anginosus or "S. mlleri" group S. anginosus S. constellatus S. intermedius |
oropharynx, gastrointestinal tract, and vaginal flora, skin |
pyogenic infections, brain, liver, and appendiceal abscesses Associated with polymicrobial infection Endocarditis |
Salivarius group S. salivarius S. thermophilus S. vestibularis |
tongue and gastrointestinal tract |
A frequent contaminant and rarely cause infection, such as bacteremia, meningitis |
Bovis group S. bovis S. equinus S. alactolyticus |
oropharynx, gastrointestinal, genital tract |
bacteremia and endocarditis in patients with malignancies of gastrointestinal tract especially with biotype I meningitis |
Mutans group S. mutans S. rattus S. cricetus S. downei S. sobrinus S. macacae |
dental plaques and tooth surfaces |
dental caries endocarditis |
"Nutritionally variant streptococci" renamed Abiotrophia A. adjacensA. defectivus |
oropharynx |
endocarditis, sepsis pancreatic abscess otitis media eye infections (conjunctivitis, and crystalline keratopathy) |
*Taxonomically, S. pneumoniae is a member of VGS but it is not considered a VGS organism.
Table 2. Susceptibility of Group C Streptococci from Various Reports
| Antibiotic | No. of Strains | MIC90 mg/mL | MIC Range | Reference |
|---|---|---|---|---|
| Penicillin G | 17 | 0.15 | 0.04-0.15 | 56 |
| 125 | 0.05 | <0.006-0.05 | 37 | |
| Amoxicillin | 125 | 0.05 | <0.006-0.1 | 37 |
| Ampicillin | 125 | 0.1 | <0.006-0.2 | 37 |
| Cephalothin | 125 | 0.2 | 0.05-0.39 | 37 |
| Cephalexin | 125 | 3.13 | 0.39-6.25 | 37 |
| Cefaclor | 125 | 1.56 | 0.39-6.25 | 37 |
| Meropenem | 48 | 0.06 | <0.016-0.12 | 98 |
| Erythromycin | 125 | 0.1 | 0.0125-0.39 | 37 |
| Ciprofloxacin | 8 | 1 | 0.5-1 | 5 |
| Clinafloxacin | 8 | 0.5 | 0.13-0.5 | 5 |
| Gatifloxacin | 8 | 0.25 | 0.13-0.25 | 5 |
| Levofloxacin | 8 | 1 | 0.5-1 | 5 |
| Moxifloxacin | 8 | 0.13 | 0.06-0.13 | 5 |
| Trovafloxacin | 8 | 0.25 | 0.13-0.25 | 5 |
| Vancomycin | 48 | 0.5 | 0.06-1.0 | 98 |
| Linezolid | 48 | 2.0 | 0.5-2.0 | 98 |
| Quinupristin-dalfopristin | 48 | .25 | 0.06-0.25 | 98 |
Table 3. Susceptibility of Group G Streptococci from Various reports.
| Antibiotic | MIC90 mg/mL | MIC Range | Reference |
|---|---|---|---|
| Penicillin | 0.017 | .0025-.04 | 43 |
| 0.05 | <.0063-0.1 | 37 | |
| Amoxicillin | 0.05 | <.0063-0.2 | 37 |
| Ampicillin | 0.1 | <.0063-0.2 | 37 |
| 0.022 | .01-0.04 | 43 | |
| Oxacillin | 0.12 | 0.06-0.12 | 64 |
| Piperacillin | 0.06 | 0.03-1.0 | 19 |
| Cephalothin | 0.2 | 0.025-0.2 | 37 |
| 0.09 | 0.04-0.156 | 43 | |
| Cefotaxime | 0.027 | 0. 005-0.04 | 43 |
| 0.022 | 0.01-0.04 | 43 | |
| Ceftazidime | 0.5 | 0.03-32.0 | 19 |
| Cefoxitin | 0.27 | 0.156-0.312 | 43 |
| Cephalexin | 3.13 | 0.1-6.25 | 37 |
| Cefaclor | 3.13 | 0.1-6.25 | 37 |
| Cefpodoxime | 0.12 | not reported | 68 |
| Meropenem | 0.06 | <0.016-0.06 | 98 |
| Vancomycin | 1.13 | 0.312-2.5 | 44 |
| 0.64 | 0.312-1.25 | 43 | |
| .25 | .25-0.5 | 64 | |
| 2.0 | 0.25-4.0 | 69 | |
| 0.5 | 0.12-0.5 | 98 | |
| Teicoplanin | .06 | <0.03-0.5 | 66 |
| 0.25 | 0.25-0.5 | 69 | |
| Linezolid | 2.0 | 0.12-2.0 | 98 |
| Quinupristin-dalfopristin | 0.25 | 0.125-0.25 | 98 |
| Erythromycin | 0.06 | <0.03-0.12 | 16 |
| 1.94 | 0.037-2.5 | 9 | |
| Clarithromycin | .06 | <0.03-0.12 | 16 |
| Clindamycin | 0.5 | <0.03-0.5 | 16 |
| 1.1 | 0.06-2 | 9 | |
| Trimethoprim/sulfamethoxazole | 0.12 | 0.25 | 15 |
| Chloramphenicol | 5.5 | 0.3-10 | 9 |
| Ciprofloxacin | 1.0 | 0.5-2.0 | 18 |
| 2.0 | 0.25-2.0 | 15 | |
| 0.5 | 0.25-0.50 | 15 | |
| 1.0 | 0.25-1 | 22 | |
| 1.0 | 0.15-2.0 | 17 | |
| 1.0 | 0.5-2.0 | 15 | |
| Levofloxacin | 0.5 | 0.25-1.0 | 15 |
| 1.0 | 0.25-1 | 22 | |
| 1.0 | 0.25-4.0 | 17 | |
| Sparfloxacin | 1.0 | 0.25-1.0 | 15 |
| 0.5 | 0.12-2.0 | 17 | |
| Clinafloxacin | 0.06 | <0.03-0.12 | 15 |
| 0.25 | 0.06-0.25 | 22 | |
| Gatifloxacin | 0.25 | 0.13-0.25 | 22 |
| 0.25 | 0.12-0.5 | 17 | |
| Moxifloxacin | 0.13 | 0.06-0.13 | 22 |
| Trovafloxacin | 0.13 | 0.06-0.25 | 22 |
*Isolates from cancer patients
Table 4. Susceptibility of Group C and Group G Streptococci (49,62,84)
| Antibiotic | No. of Strains | MIC90 mg/mL | MIC Range | Reference | |
|---|---|---|---|---|---|
| Penicillin G | 44 | 0.03 | 0.03-0.06 | 62 | |
| Cephalothin | 44 | 0.06 | 0.03-0.5 | 62 | |
| Cefotaxime | 44 | 0.12 | 0.03-0.25 | 62 | |
| Piperacillin | 44 | 0.03 | 0.03-0.5 | 62 | |
| Azlocillin | 44 | 0.06 | 0.03-0.25 | 62 | |
| Vancomycin | 44 | 0.12 | 0.03-0.5 | 62 | |
| Erythromycin | 44 | 1.0 | 0.03-1.0 | 62 | |
| 20 | 0.5 | 0.12-1.0 | 49 | ||
| Clarithromycin | 20 | 0.25 | 0.06-1.0 | 49 | |
| Azithromycin | 20 | 0.5 | 0.12-1.0 | 49 | |
| Quinupristin/dalfopristin | 20 | 0.5 | 0.06-1.0 | 49 | |
| Gatifloxacin | 10 | 0.125 | 0.125 | 84 | |
| Clinafloxacin | 10 | 0.25 | 0.125-0.25 | 84 | |
| Ofloxacin | 10 | 2 | 0.5-2.0 | 84 | |
| Levofloxacin | 10 | 1 | 0.5-1.0 | 84 | |
| Ciprofloxaxin | 10 | 0.5 | 0.5 | 84 | |
| Sparfloxacin | 10 | 2 | 0.125-2 | 84 | |
| Trovafloxacin | 10 | 0.25 | 0.125-0.25 | 84 | |
Table 5. Recommended Therapy for VGS Infections
Endocarditis due to penicillin susceptible viridans streptococci and Streptococcus bovis (Minimum Inhibitory Concentration <0.1 mg/mL).
Native valve infection: Use any of the following:
- Penicillin G 12-18 million units per day in continuous drip or 6 divided dose plus gentamicin 3 mg/kg IV as single dose or 3 divided doses for 2 weeks.
- Penicillin G 12-18 million units per day in continuous drip or 6 divided dose for 4 weeks.
- Ceftriaxone 2 g IV or IM daily for 4 weeks.
- Vancomycin 30 mg/kg not to exceed 2 g IV in 2 divided doses for 4 weeks.
Prosthetic valve infection.
Penicillin or vancomycin as 2 and 3 for 6 weeks plus gentamicin at the same dose as above for at least 2 weeks.
Endocarditis due to viridans streptococci and Streptococcus bovis relatively resistant to penicillin G (Minimum Inhibitory Concentration >0.1 mg/ml and <0.5 mg/ml)*
- 18 million U/24 h IV either continuously or in six equally divided doses for 4 weeks plus gentamicin 3 mg/kg IV as single dose or 3 divided doses for 2 weeks.
- Vancomycin 30 mg/kg not to exceed 2 g IV in 2 divided doses for 4 weeks.
Endocarditis due to viridans streptococci with (MIC >0.5 mg/ml) or nutritionally variant streptococci
- Aqueous crystalline penicillin G sodium, 18-30 million U/24 h IV either continuously or in six equally divided doses or, ampicillin sodium 12 g/24 h IV either continuously or in six divided doses plus gentamicin sulfate 1 mg/kg IM or IV every 8 h for 4-6 weeks*
- Vancomycin** hydrochloride 30 mg/kg per 24 h IV in two equally divided doses, to exceed 2g/24 h unless serum levels are monitored plus gentamicin sulfate (similar dose as above) for 4-6 weeks*
For patients with prosthetic valve endocarditis due to streptococcus
Treat as resistant streptococcus (MIC >0.5 mg/ml) for 6-8 weeks
For patients with bacteremia without endocarditis due to viridans group of streptococcus and NVS.
- Penicillin G 12-18 million units IV continuously or in 6 divided doses for 2 weeks.
- Ceftriaxone 2 g IV or IM daily for 2 weeks
- Clindamycin 300 mg IV or PO q8h for weeks***
- Vancomycin 30 mg/kg not to exceed 2 g IV in 2 divided doses for 2 weeks.
For patients with meningitis due to viridans group of streptococcus or NVS
- Ceftriaxone 2 g IV or IM daily or cefotaxime 2 g IV q6h for 2 weeks
- Penicillin 18-30 million units IV in 6 divided doses for 2 weeks
- Vancomycin 30 mg/kg not to exceed 2 g IV in 2 divided doses for 2 weeks
For patients with mixed infection where viridans group of streptococcus or NVS is found
- Beta-lactam/beta-lactamase inhibitor combinations at the recommended dose
- Imipenem 500-750 mg every 6-8 hours IV.
- Above agents or clindamycin plus gentamicin.
*4-week therapy recommended for patients with symptoms <3 months in duration; 6-week therapy recommended for patients with symptoms greater than 3 months in duration plus
**Vancomycin therapy is recommended for patients allergic to beta-lactams; cephalosporins is not acceptable unless shown to be effective by susceptibility testing
***Clindamycin susceptibility should be checked.
Table 6. Prophylactic Regimens for Dental, Oral, Respiratory Tract or Esophageal Procedures (From Recommendations Of The American Heart Association, 1997) ( 17 )
Situation |
Agent |
Regimen* |
|---|---|---|
Standard general prophylaxis |
Amoxicillin |
Adults: 2.0 g; children 50 mg/kg orally 1 h before procedure |
Unable to take oral medications |
Ampicillin |
Adults: 2.0 g IM or IV; children: 50 mg/kg IM or IV within 30 minutes before procedure |
Allergic to penicillin |
Clindamycin, or Cephalexin** or cefadroxil** or Azithromycin or clarithromycin
|
Adults: 600 mg; children: 20 mg/kg orally 1 h before procedure Adults: 2.0 g; children: 50 mg/kg orally 1 h before procedure
Adults: 500 mg; children: 15 mg/kg orally 1 h before procedure |
Allergic to penicillin and unable to take oral medications |
Clindamycin or Cefazolin |
Adults: 600 mg; children: 20 mg/kg orally 1 h before procedure Adults: 1.0 g; children: 25 mg/kg IM or IV within 30 min before procedure |
*Total children’s dose should not exceed adult dose
**Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins
Figure 1. In Vitro Activities of Selected Antimicrobial Agents Versus 4 Streptococcal Species Streptococcal Isolates From 43 U.S. Medical Centers From 1993-4. (Modified from Doern et al (22))
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Musher DM. The Naming of Strep, with Apologies to T.S. Eliot. Clin Infect Dis 2009;49:1959-1960.