In vitro and in vivo studies of streptomycin-resistant, penicillin-susceptible streptococci from patients with infective endocarditis.

The combination of penicillin and streptomycin did not act synergistically in vitro against three streptomycin-resistant strains (MIC, greater than or equal to 1,000 micrograms of streptomycin/ml) of penicillin-susceptible streptococci. Using a model of experimental infective endocarditis, we infected rabbits with a control streptomycin-susceptible strain, with an intermediately streptomycin-resistant strain (MIC, 1,000 micrograms/ml), and with a highly streptomycin-resistant strain (MIC, greater than 32,000 micrograms/ml). Treating animals with a combination of procaine penicillin and streptomycin was more effective (P less than .01) than treating them with procaine penicillin alone only for those animals infected with the control streptomycin-susceptible strain. Treatment with procaine penicillin plus gentamicin was more effective (P less than .01) than treatment with procaine penicillin alone for all three treatment groups and was more effective (P less than .01) than treatment with procaine penicillin and streptomycin for those animals infected with an intermediately or highly streptomycin-resistant strain of streptococci.

In vitro and in vivo activity of ciprofloxacin against enterococci isolated from patients with infective endocarditis.

In vitro activity of ciprofloxacin against 27 strains of enterococci was inoculum dependent. Using inocula of 10(5) to 10(6) or 10(7) to 10(8) CFU of enterococci per ml, the MICs for 50 and 90% of strains tested increased from 1 to greater than or equal to 128 micrograms of ciprofloxacin per ml with the higher inoculum compared with the lower inoculum. The MBC for 50% of strains tested increased from 2 to greater than 128 micrograms/ml and the MBC for 90% of strains tested increased from 8 to greater than 128 micrograms of ciprofloxacin per ml with the lower and higher inocula, respectively. The combination of penicillin-gentamicin was more effective in vitro than the combination of ciprofloxacin-gentamicin against the low or high inoculum of enterococci. Using two strains of enterococci, we studied the efficacy of ciprofloxacin in the treatment of enterococcal experimental endocarditis in rabbits. Ciprofloxacin used alone or combined with gentamicin was significantly less effective (P less than 0.01) than procaine penicillin alone or procaine penicillin combined with gentamicin for the treatment of enterococcal experimental endocarditis. The combination of ciprofloxacin-procaine penicillin was not a more effective therapy than procaine penicillin alone.

Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin.

We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.

Activity of penicillin combined with an aminoglycoside against group B streptococci in vitro and in experimental endocarditis.

Group B streptococci were less susceptible in vitro to penicillin and to aminoglycosides with an inoculum size of 10(7)-10(8) cfu/ml than with an inoculum size of 5.5 X 10(5)-10(6) cfu/ml. With a rabbit model of experimental group B streptococcal endocarditis, after one or three days of therapy with procaine penicillin alone, the mean log10 cfu/g of valve vegetation was significantly lower (P less than 0.01) than that of the control groups. After one day of therapy, procaine penicillin combined with streptomycin was significantly more effective (P less than 0.01) than was treatment with procaine penicillin alone. There was no significant difference (P greater than 0.05) in the results of treatment of animals for one day with procaine penicillin combined with streptomycin compared with those of animals treated for three days with procaine penicillin alone.

Antimicrobial therapy of experimental endocarditis caused by nutritionally variant viridans group streptococci.

Rabbits with nutritionally variant viridans group streptococcal experimental endocarditis were treated three times daily for 3 days with procaine penicillin (1.2 X 10(6) U) alone or together with low-dose streptomycin (2 mg/kg), high-dose streptomycin (8 mg/kg), low-dose gentamicin (0.32 mg/kg), or high-dose gentamicin (1.05 mg/kg). The mean 0.5-h serum concentrations of streptomycin were 5.3 and 22.5 micrograms/ml in the low- and high-dose group, respectively, and the concentrations of gentamicin were 0.7 and 2.5 micrograms in the low- and high-dose groups, respectively. The combination of procaine penicillin with each dose of aminoglycoside was significantly more effective (P less than 0.001) than was procaine penicillin alone. In combination with procaine penicillin, the higher dose of streptomycin was significantly more effective (P less than 0.02) than the lower dose of streptomycin. The higher dose of streptomycin was not significantly more effective than either dose of gentamicin. The results of treatment with the high or low dose of gentamicin were virtually identical.

Treatment of streptococcal infective endocarditis.

Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration for penicillin of 0.1 microgram/ml or less) may be treated successfully with one of the following regimens: aqueous penicillin G administered intravenously for four weeks, intravenous aqueous penicillin G for four weeks combined with streptomycin for the first two weeks of therapy, or parenterally administered penicillin plus streptomycin for two weeks. A cure rate of at least 98 percent may be anticipated with each of these regimens. During a 12-year period among 142 patients treated for two weeks with penicillin and streptomycin, one (0.7 percent) had relapse and four (3 percent) had vestibular toxicity. The major advantage of the two-week regimen is that it is more cost-effective than the four-week regimens. The major disadvantage of the use of streptomycin is the relatively low risk of vestibular toxicity. Patients with enterococcal endocarditis were treated initially for four weeks with aqueous penicillin G together with either streptomycin (streptomycin-susceptible enterococci, 36 patients) or gentamicin (streptomycin-resistant enterococci, 20 patients). Compared with patients who had symptoms for less than three months, patients with symptoms for longer than three months had a higher relapse rate (0 percent versus 44 percent; p less than 0.001) and mortality (2.5 percent versus 25 percent; p less than 0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25 percent) than patients with aortic valve infection (0 percent; p less than 0.01]. Gentamicin-associated nephrotoxicity was more frequent (p less than 0.001) among patients treated with more than 3 mg/kg per day of gentamicin than among those treated with 3 mg/kg per day or less (100 percent versus 20 percent). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for longer than three months or perhaps patients with mitral valve infection should receive at least six weeks of penicillin therapy together with an aminoglycoside; patients without either high-risk factor may be treated successfully for four weeks.

Group B streptococcal infective endocarditis.

From 1970 to 1983, five patients with group B streptococcal endocarditis were treated at the Mayo Clinic, Rochester, Minn. The minimal inhibitory concentration and the minimal bactericidal concentration of penicillin were 0.09 microgram/mL or less and 1.56 micrograms/mL or less, respectively. The in vitro activity of cefazolin against group B streptococci was similar to that of penicillin. In three of the five cases, penicillin and streptomycin acted synergistically in vitro against group B streptococci. Four of the five patients were cured, three by use of an aminoglycoside combined with penicillin, ampicillin, or vancomycin. Three of the five patients had multiple large systemic emboli, and one of the three died of brain-stem infarct. Penicillin alone or in combination with an aminoglycoside is effective therapy for group B streptococcal endocarditis. Patients unable to tolerate penicillin may be treated with cefazolin or vancomycin. Clindamycin therapy should be avoided in patients with endocarditis caused by strains that are tolerant in vitro to clindamycin.

Synergy of imipenem or penicillin G and aminoglycosides against enterococci isolated from patients with infective endocarditis.

We tested the synergistic activity of imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK 0787) (20 micrograms/ml) or penicillin (20 micrograms/ml) in combination with increasing concentrations of either streptomycin (5, 10, and 20 micrograms/ml) against 13 strains of streptomycin-susceptible enterococci or gentamicin (1, 3, and 5 micrograms/ml) against 13 strains of streptomycin-susceptible enterococci and 7 strains of streptomycin-resistant enterococci. At 24 h, penicillin together with each increment in streptomycin concentration resulted in a significant increase (P less than 0.001) in killing of streptomycin-susceptible enterococci compared with imipenem and the corresponding concentration of streptomycin. Similarly, at 24 h, the magnitude of killing of streptomycin-susceptible enterococci by a combination of penicillin plus each increment of gentamicin concentration was significantly greater (P less than 0.001) than that of the combination of imipenem and the corresponding concentration of gentamicin. Against streptomycin-resistant enterococci, penicillin together with each increment of gentamicin concentration killed significantly more enterococci (P less than 0.02) than did the combination of imipenem and the corresponding concentration of gentamicin. When combined with an aminoglycoside, the synergistic activity in vitro against enterococci of imipenem was significantly less than that of penicillin.

Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis.

Fifty-six patients with enterococcal endocarditis received 4 weeks of antimicrobial therapy with penicillin G and streptomycin (36 patients) or, if infections were streptomycin resistant, penicillin and gentamicin (20 patients). Compared with patients who had symptoms for less than 3 months, patients with symptoms for more than 3 months had a higher relapse rate (0% versus 44%; p less than 0.001) and mortality (2.5% versus 25%; p less than 0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25%) than patients with aortic valve infections (0%) (p less than 0.01). Gentamicin-associated nephrotoxicity was more frequent (p less than 0.001) among patients treated with greater than 3 mg/kg d of gentamicin than among those treated with 3 mg or less (100% versus 20%). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for more than 3 months or patients with mitral valve infection should receive at least 6 weeks of antimicrobial therapy, but patients without these high-risk factors can be treated for 4 weeks.

Empiric therapy with moxalactam alone in patients with bacteremia.

Moxalactam was administered (20 mg/kg intravenously every 8 hours) as single-drug empiric antimicrobial therapy to 63 patients with bacteremia who were neither neutropenic nor immunosuppressed. Six patients (10%) had microorganisms that were susceptible to moxalactam and resistant to all other antimicrobial agents tested; two patients (3%) had microorganisms that were resistant to moxalactam and other agents tested. Of these 63 patients, 47 (75%) were cured with moxalactam therapy. Nine patients (14%) had breakthrough bacteremia while receiving other antimicrobial therapy and were cured subsequently with moxalactam therapy alone. The two major risk factors for failure of moxalactam therapy were polymicrobial bacteremia and an extrahepatic intra-abdominal source of infection; these two conditions frequently coexisted. Six of nine patients with polymicrobial bacteremia died. Superinfection (one pseudomonal, five enterococcal) was responsible for 6 of the 16 treatment failures. Enterococcal superinfection occurred exclusively among patients who had received relatively prolonged therapy with moxalactam for extrahepatic intra-abdominal infection, especially intraabdominal abscess. These five patients died, and postmortem examination showed that enterococcal superinfection was the major cause of death in all. Mild, reversible adverse reactions associated with use of moxalactam occurred in 14 of the 63 patients (22%). None had clinically overt bleeding. The use of moxalactam alone seems to be safe and effective and a cost-effective alternative empiric antimicrobial therapy for most patients with bacteremia who are not immunosuppressed or neutropenic and who are not at high risk of having Pseudomonas or polymicrobial bacteremia.

Cardiac valve replacement in patients with active infective endocarditis.

Since the introduction of effective antimicrobial therapy, the leading cause of death in patients with infective endocarditis is no longer sepsis but, rather, congestive heart failure. The mortality is higher in patients with severe heart failure due to infective endocarditis who are treated with medical therapy only than in those who additionally undergo cardiac valve replacement. The mortality is also higher in patients with severe heart failure due to aortic infective endocarditis (40 to 93%) than in those with heart failure due to mitral infective endocarditis (17 to 66%). In patients with and in those without infective endocarditis, surgical intervention can be carried out with comparable mortality not only for aortic valve replacement (9 vs 8.4%) but also overall for valve replacement (10 vs 12%). In patients with class IV heart failure, overall mortality of valve replacement was higher (17%) than in patients with class II (8%) or class III heart failure (7%) and, similarly, comparable with that of matched groups of patients without infective endocarditis. In patients with class IV disability, the mortality of valve replacement was higher in those with active infective endocarditis (19%) than in those with inactive infective endocarditis, possibly due to a higher incidence of sudden onset of severe aortic regurgitation and myocardial abscess. No patient with valve replacement for inactive infective endocarditis developed prosthetic valve endocarditis; a single case of prosthetic valve endocarditis occurred in a patient with active infective endocarditis. In general, early surgical intervention is preferable to procrastination in the management of patients with progressive or severe heart failure due to infective endocarditis. Although, in at least 70% of patients, blood cultures may be rendered sterile within one week of initiation of appropriate antimicrobial therapy, patients with infective endocarditis due to staphylococci, multiply-resistant gram-negative bacilli, fungi, Q-fever or those with myocardial abscess or multiple relapses may require surgical intervention. While the overall incidence of clinically apparent emboli has been reported to be as high as 30%, in a ten-year observation period at the Mayo Clinic, the rate was 5.6%. Patients with echocardiographic evidence of large or mobile vegetations and those with infective endocarditis cause by microorganisms associated with a high risk of embolization such as slow-growing fastidious gram-negative bacilli, fungi (especially Aspergillus) and nutritionally-variant viridans streptococci should be considered candidates for surgery irrespective of a history of emboli.(ABSTRACT TRUNCATED AT 400 WORDS)

Vancomycin.

Vancomycin is a narrow-spectrum bactericidal antistaphylococcal antibiotic that was introduced in 1956 because of its efficacy against resistant penicillinase-producing staphylococci. It was effective for serious staphylococcal infections for which no satisfactory alternative to penicillin G was available at the time. When methicillin and the other semisynthetic penicillins and the cephalosporins were introduced, the role of vancomycin was relegated to the alternative therapy of choice when the penicillins and the cephalosporins could not be used. In the future, vancomycin may be used more frequently in (1) methicillin-resistant Staphylococcus aureus infections, (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant to penicillin or ampicillin, (3) infections associated with prosthetic devices caused by organisms with multiple antibiotic resistance, and (4) antibiotic-induced enterocolitis associated with Clostridium difficile.

Antibiotic treatment of infective endocarditis.

At least 85% of patients with infective endocarditis can be cured with effective therapy. Streptococci or staphylococci cause 75% of cases of endocarditis. Patients with penicillin-sensitive viridans or nonenterococcal group D streptococcal endocarditis may be treated successfully with aqueous penicillin G alone for four weeks or with combined penicillin and streptomycin for two weeks. Enterococcal endocarditis should be treated for four to six weeks with a combination of aqueous penicillin G together with either streptomycin or gentamicin. Patients with endocarditis caused by Staphylococcus aureus should receive antimicrobial therapy for four to six weeks with a semisynthetic penicillin (nafcillin or oxacillin) or a cephalosporin such as cephalothin or cefazolin. In urgent cases where empiric antimicrobial therapy is necessary before the causative organism is identified, a combination of aqueous penicillin G, nafcillin, and gentamicin is effective therapy.

Infective endocarditis--a 25 year overview of diagnosis and therapy.

Diagnosis and management of infective endocarditis have significantly changed in the past 25 years. Improved bacteriologic techniques have allowed detection of cases of infective endocarditis caused by unusual organisms. Bactericidal therapy has become available for patients with gram-negative endocarditis and antimicrobial therapy has improved. Echocardiography has become an important diagnostic and management aid, and cardiac valve replacement has dramatically improved the outlook for many patients.

Influence of gentamicin dose size on the efficacies of combinations of gentamicin and penicillin in experimental streptomycin-resistant enterococcal endocarditis.

We have evaluated the benefits of low versus high doses of gentamicin combined with procaine penicillin (1.2 X 10(6) U three times daily) in the treatment of streptomycin-resistant experimental enterococcal endocarditis in rabbits. The mean peak serum gentamicin concentration in animals treated with low-dose gentamicin (0.75 mg/kg three times daily) was 3.06 micrograms/ml (range, 2.1 to 4.2 micrograms/ml), and it was 8.05 micrograms/ml (range, 4.5 to 16.1 micrograms/ml) in animals treated with high-dose gentamicin (2 mg/kg three times daily). The mean log10 colony-forming units of enterococci per gram of cardiac valve vegetation in animals treated with procaine penicillin combined with low- or high-dose gentamicin were 2.4 +/- 1.2 and 1.4 +/- 1.3, respectively (P = not significant) after 3 days of treatment and 1.7 +/- 1.2 and 1.7 +/- 1.5, respectively (P = not significant), after 5 days of therapy. The median peak serum bactericidal titer was 1:8 in animals treated with low- or high-dose gentamicin. We detected no significant difference between low- or high-dose gentamicin combined with procaine penicillin in the efficacy of treatment of streptomycin-resistant experimental enterococcal endocarditis.

Lack of in vivo and in vitro bactericidal activity of N-formimidoyl thienamycin against enterococci.

The minimal bactericidal concentrations of N-formimidoyl thienamycin (N-f-thienamycin) against 21 strains of enterococci isolated from patients with infective endocarditis were determined by macro- and microdilution methods. By a macrodilution technique with the minimal bactericidal concentration defined as greater than or equal to 99.9% killing of an initial inoculum, all 21 strains of enterococci were found to have minimal bactericidal concentration/minimal inhibitory concentration ratios of greater than or equal to 32. The mean minimal inhibitory concentration was 1.5 micrograms/ml (range, 0.5 to 4 micrograms/ml), and the minimal bactericidal concentration was greater than or equal to 128 micrograms/ml. The disparity between the results of our study and those published elsewhere, which reported that N-f-thienamycin is bactericidal in vitro against enterococci, may represent the relative insensitivity of the microdilution method in determining greater than or equal to 99.9% killing. The lack of in vitro bactericidal activity of N-f-thienamycin against enterococci was confirmed in vivo in the rabbit model of experimental endocarditis. N-f-Thienamycin was no more effective than penicillin alone in the treatment of experimental enterococcal endocarditis and was less effective than the combination of penicillin and gentamicin. The results indicate that N-f-thienamycin should not be used alone in the treatment of enterococcal endocarditis.

Management of complications of infective endocarditis.

Complications of infective endocarditis may be considered as those that involve the heart and adjacent structures or those that are extracardiac. Congestive heart failure is the most common serious complication of infective endocarditis and is the leading cause of death among patients with this infection. In patients with severe heart failure unresponsive to medical therapy after 24 to 48 hours, prompt cardiac valve replacement should be considered, irrespective of the duration of preoperative antimicrobial therapy. We believe that all patients with bacterial infective endocarditis who are stable hemodynamically and who have not had multiple large emboli should receive at least one course of antimicrobial therapy in an attempt to sterilize the infected valve before cardiac valve replacement is considered. Most patients with multiple major embolic events should undergo cardiac valve replacement or debridement of the infected valve. The technical limitations and the experience with two-dimensional echocardiography in patients with infective endocarditis who have valve vegetations demonstrated by echocardiography are not yet sufficient to justify cardiac valve replacement solely on the basis of echocardiographic findings. The highest frequency of major embolic events occurs in association with infections that produce large mobile valve vegetations, such as those caused by Haemophilus parainfluenzae and other slow-growing fastidious gram-negative bacilli, fungi (especially Aspergillus), and nutritionally variant viridans streptococci.

Symposium on infective endocarditis. III. Endocarditis due to gram-negative bacteria. Report of 56 cases.

At the Mayo Clinic, 56 patients with infective endocarditis caused by gram-negative bacteria were seen from 1958 through 1979, 35 of whom were seen from 1970 through 1979. The patients were categorized into two divisions: those with medical, naturally acquired valve infections (40 [71%]) and those with infective endocarditis after cardiac operation (16 [29%]). The overall cure rate was 82% (46 of 56 patients); 35 of 40 patients (88%) were cured in the medical group, and 11 of 16 patients (69%) were cured in the surgical group. The patients were further classified on the basis of organism: group 1 (33 patients)--infections caused by Haemophilus (18), Actinobacillus actinomycetemcomitans (4), Cardiobacterium hominis (6), Eikenella corrodens (2), Kingella kingii (2), and Bordetella bronchiseptica (1); 32 of these 33 patients (97%) were cured, and 6 of these infections were on prosthetic valves; group 2 (21 patients)--infections caused by enteric aerobic bacilli; 13 of the 21 patients (62%) were cured; group 3 (1 patient)--infection caused by anaerobes (Bacteroides fragilis); this patient died; and group 4 (1 patient)--infection caused by Neisseria gonorrhoeae; this patient was cured. The gram-negative bacteria in the survivors and nonsurvivors and the curative antibiotic regimens were tabulated. Among the 35 survivors in the medical group, a combined antibiotic regimen cured 21 patients (60%) and a single antibiotic agent cured 14 (40%). Among the 11 survivors in the surgical group, combined therapy was given to 8 (73%), a single drug was used once, and operation alone achieved a cure in 2 patients. Compared with past data, the current study indicates an increasing incidence of gram-negative bacterial endocarditis (approximately 10%) and an improving cure rate 82%).

Prosthetic valve endocarditis.

Prosthetic valve endocarditis is an infrequent but serious complication of cardiac valve replacement. The overall frequency of prosthetic valve endocarditis is approximately 2%. The frequency of early-onset and late-onset infections is 0.78% and 1.1%, respectively. Staphylococci are the most common isolate from patients with early-onset infection, accounting for 47.5% of the total number of isolates. Staphylococcus epidermidis causes 27% of these staphylococcal infections. Among patients with late-onset infection, streptococci are the predominant microorganism, constituting 42% of the total number of isolates from patients in this group. The overall mortality among patients with prosthetic valve endocarditis is high--59%; the mortality among patients with early- or late-onset infections is 77% and 46%, respectively. Most patients with staphylococcal prosthetic valve endocarditis should undergo cardiac valve replacement in addition to antimicrobial therapy. Closely monitored anticoagulant therapy should be cautiously continued in patients with prosthetic valve endocarditis.