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Significance of in-vitro penicillin tolerance in experimental enterococcal endocarditis
21 Infectious Diseases Newsletter 7(3) March 1988 cultures of blood, urine, and peritoneal fluid were reported as negative for bacteria and fungi; the coagulasenegative staphylococcus was found to be susceptible to cefazolin by testing in vitro. Output of urine remained minimal and the creatinine rose to 2.3 mg/dl. Because acute rejection of the transplanted kidney was suspected, treatment with antimicrobics, cyclosporine, and prednisone was discontinued. Pulse therapy with methylprednisolone was begun. Within 6 hours, the patient's symptoms resolved, urine output increased, and the creatinine stabilized. At discharge, his creatinine and urea nitrogen were 2.1 and 24 mg/dl, respectively.
Comment The rejection of a transplanted kidney may be classified clinically as hyperacute, accelerated, acute, and chronic. Hyperacute rejection occurs within minutes to hours after the vascular anastamosis and is usually refactory to immunosuppressive therapy. Allograft nephrectomy is often carried out to avoid secondary microangiopathic hemolytic anemia and disseminated intravascular coagulation. Accelerated rejection occurs from 3 to 7 days after grafting. Fever, leukocytosis or leukopenia, and graft
tenderness are common manifestations. Attempts to reverse accelerated rejection have been disappointing. The manifestations of acute rejection are very similar to those of accelerated rejection except for occurrence after the second week following transplantation. Also, acute rejection is reversible with high doses of immunosuppressive agents. The first sign of chronic rejection is often hypertension. Steady decrease in renal function is manifested by retention of water and increasing proteinuria. As in acute rejection, high doses of glucosteroids and azathioprine are usually very effective in reversing rejection. Despite the availability of a large number of antimicrobics, infection remains the major cause for mortality in patients with renal transplants. Factors of importance to the development of infection include placement of urinary catheters, the surgical transplant procedure, and the immunosuppressive therapy. Bacterial infections involving the urinary tract and surgical wound are the most frequent problems of the immediate post-transplant period, while infection with intraceUular microorganisms are the major concern at later periods. The signs of infection may be minimal, e.g., low-grade fever and myalgia may be the only signs. Un-
fortunately, graft rejection sometimes begins the same way as it did in our patient. Prompt diagnostic workup is crucial to the determination of appropiate therapy and the improvement of the prognosis. Empiric antimicrobic treatment is sometimes required. However, in order to maximize the probability of reversing rejection, aggressive immunosuppression must be applied as soon as infection is ruled out.
Bibliography Berne TV, Gustafson LA, Chatterjee SN: Early severe renal allograft rejection. Arch Surg 111:758-760, 1976. Petersen VP, Olsen TS, Nielsen FK, et al: Late failure of human renal transplants. Medicine 54:45-71, 1975. Peterson PK, Balfour HH Jr, Fryd DS, et al: Fever in renal transplant recipients: Causes, prognostic significance and changing patterns at University of Minnesota Hospital. Am J Med 71:345-351, 1981. Rubin RH, Wolfson JS, Cosimi AB, et al: Infection in the renal transplant recipients. Am J Med 70:405-411, 1981. Washer GF, Schroter GPJ, Starzl TE, et al: Causes of death after kidney transplantation. JAMA 250:49-54, 1983. Joseph K. Koo, MD Division of Infectious & Immunologic Diseases Department of Internal Medicine University of California Davis Medical Center Sacramento, California
C O M M E N T S ON CURRENT PUBLICATIONS Kim KS, Bayer AS: Significance of
in-vitro penicillin tolerance in experimental enterococcal endocarditis. J Antimicrob Chemother 19:475-485, 1987. The significance of tolerance to penicillin in enterococci was examined in vivo in a rabbit model of infective endocarditis. Enterococci were considered tolerant if they exhibited significantly increased ratios of MIC/MLC with penicillin and resis-
tance to penicillin-induced lysis and killing. The results were striking: In animals infected with tolerant enterococci, the bacterial counts in vegetations during 10 days of therapy were significantly higher, and there were lower rates of sterilization than in animals infected with nontolerant strains. The concentrations of penicillin in the serum were not significantly different, but the serum bactericidal titers were significantly lower for the tolerant strains. © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Comment Tolerance to penicillin has been thought to be one explanation for the poor response of enterococcal endocarditis to treatment with penicillin alone. However, documentation in vivo by controlled experiments has been lacking. The work of Kim et al. indicates that tolerance to penicillin is, indeed, a significant determinant of the response of an enterococcal infection to therapy with penicillin and reemphasizes the need to add an
22 Infectious Diseases Newsletter 7(3) March 1988 aminocyclitol when treating enterococcal endocarditis in order to insure bactericidal activity. CWS
[]
Watanakunakorn C: In-vitro activity of LY 146032, a novel cylic iipopeptide, alone and in combination with gentamicin or tobramycin against enterococci. J Antimicrob Chemother 19:445-448, 1987. A kill-kinetic method was used to examine the bactericidal activity of LY 146032, alone and in combination with gentamicin or tobramycin, against enterococci. Although the MICs and MLCs of LY 146032 were low (/>2 ug/ml) and were either the same or only one dilution different as determined by a broth macrodilution method, the killing activity of LY 146032 concentrations t>4 × MIC was slow with a 2-3 log10 decrease at 24 hours. The combination of LY 146032 and either gentamicin or tobramycin yielded synergy against almost all strains of enterococci, and the bactericidal activity was rapid (~>3 loglo decrease at 6 hours).
Comment Typically, neither ampicillin nor vancomycin is bactericidal against enterococci. Newer agents, such as teicoplanin, are also not bactericidal against enterococci. Accordingly, when bactericidal therapy is essential to cure, as in enterococcal endocarditis, clinicians rely on a combination of an aminocyclitol with either ampicillin or vancomycin. The slow bactericidal activity of LY 146032 against enterococci may be of clinical significance, particularly against strains of enterococci with high resistance to the aminocyclitols.
We have demonstrated similar bactericidal activity of LY 146032 against enterococci (Antimicrob Agents Chemother 31:1014-1016, 1987). Because antimicrobial agents are less active against enterococci when tested in human serum (J Clin Invest 68:639-645, 1986), kill-kinetic studies should be done to determine the bactericidal activity of LY 146032 against enterococci in human serum. Should the drug be bactericidal in human serum, animal studies and clinical trials would be warranted. CWS
[]
agar and broth dilution methods might overestimate the activity of fluoroquinolones against staphylococci. Using a kill-kinetic method, we obtained similar results (Antimicrob Agents Chemother 31" 1210-1215, 1987). Although ciprofloxacin was very active according to broth microdilution M1Cs (0.125-1 ugml), its bactericidal activity was considerably less. We, too, found that ciprofloxacin was notably less active against methicillin-resistant staphylococci than it was against methicillin-susceptible staphylococci. While there are few data on the clinical results of treatment of staphylococcal infections with ciprofloxacin, ciprofloxacin resistance in S. aureus has been reported (Lancet ii:383, 1985). CWS
[] Gahm-Hansen B, Sogaard P, Arpi M:
In vitro activity of ciprofloxacin against methicillin-susceptible and methicillin-resistant staphylococci. Euro J Clin Micro 6:581-584, 1987. A kill-kinetic method was used to examine the in-vitro bactericidal activity of ciprofloxacin against both methicillin-susceptible and methicillinresistant isolates of both Staphylococcus aureus and Staphylococcus epidermidis. Although the MICs of ciprofloxacin, as determined by agar dilution, were 0.25-0.5 ug/ml, the killing activity of ciprofloxacin at concentrations >14 × MIC was low (<3 loglo at 6 hours). Moreover, regrowth of the culture occurred after 24 and 48 hours with a resistant mutant. Finally, the killing rate was lower against methicillin-resistant strains of both S. aureus and S. epidermidis.
Comment The fluoroquinolones have significant activity in vitro against staphylococci when tested by agar or broth dilution methods. The kill-kinetic data of this report suggest that the results of the © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Chandrasekar PH, Crane LR, Bailey ET: Comparison of the activity of
antibiotic combinations in-vitro with clinical outcome and resistance emergence in serious infections by Pseudomonas aeruginosa in nonneutropenic patients. J Antimicrob Chemother 19:321-329, 1987. Techniques for demonstrating synergy in vitro were compared using different combinations of beta-lactams plus aminocyclitols against isolates of Pseudomonas aeruginosa. There was poor agreement in the results from checkerboard and kill-kinetic studies. Comparison of in vitro synergy results with clinical outcome showed that antagonism in the 24-hour kill-kinetic studies was the most reliable prognostic indicator of clinical and bacteriological outcome.
Comment Because only 14 patients were evalu-
Comment The rejection of a transplanted kidney may be classified clinically as hyperacute, accelerated, acute, and chronic. Hyperacute rejection occurs within minutes to hours after the vascular anastamosis and is usually refactory to immunosuppressive therapy. Allograft nephrectomy is often carried out to avoid secondary microangiopathic hemolytic anemia and disseminated intravascular coagulation. Accelerated rejection occurs from 3 to 7 days after grafting. Fever, leukocytosis or leukopenia, and graft
tenderness are common manifestations. Attempts to reverse accelerated rejection have been disappointing. The manifestations of acute rejection are very similar to those of accelerated rejection except for occurrence after the second week following transplantation. Also, acute rejection is reversible with high doses of immunosuppressive agents. The first sign of chronic rejection is often hypertension. Steady decrease in renal function is manifested by retention of water and increasing proteinuria. As in acute rejection, high doses of glucosteroids and azathioprine are usually very effective in reversing rejection. Despite the availability of a large number of antimicrobics, infection remains the major cause for mortality in patients with renal transplants. Factors of importance to the development of infection include placement of urinary catheters, the surgical transplant procedure, and the immunosuppressive therapy. Bacterial infections involving the urinary tract and surgical wound are the most frequent problems of the immediate post-transplant period, while infection with intraceUular microorganisms are the major concern at later periods. The signs of infection may be minimal, e.g., low-grade fever and myalgia may be the only signs. Un-
fortunately, graft rejection sometimes begins the same way as it did in our patient. Prompt diagnostic workup is crucial to the determination of appropiate therapy and the improvement of the prognosis. Empiric antimicrobic treatment is sometimes required. However, in order to maximize the probability of reversing rejection, aggressive immunosuppression must be applied as soon as infection is ruled out.
Bibliography Berne TV, Gustafson LA, Chatterjee SN: Early severe renal allograft rejection. Arch Surg 111:758-760, 1976. Petersen VP, Olsen TS, Nielsen FK, et al: Late failure of human renal transplants. Medicine 54:45-71, 1975. Peterson PK, Balfour HH Jr, Fryd DS, et al: Fever in renal transplant recipients: Causes, prognostic significance and changing patterns at University of Minnesota Hospital. Am J Med 71:345-351, 1981. Rubin RH, Wolfson JS, Cosimi AB, et al: Infection in the renal transplant recipients. Am J Med 70:405-411, 1981. Washer GF, Schroter GPJ, Starzl TE, et al: Causes of death after kidney transplantation. JAMA 250:49-54, 1983. Joseph K. Koo, MD Division of Infectious & Immunologic Diseases Department of Internal Medicine University of California Davis Medical Center Sacramento, California
C O M M E N T S ON CURRENT PUBLICATIONS Kim KS, Bayer AS: Significance of
in-vitro penicillin tolerance in experimental enterococcal endocarditis. J Antimicrob Chemother 19:475-485, 1987. The significance of tolerance to penicillin in enterococci was examined in vivo in a rabbit model of infective endocarditis. Enterococci were considered tolerant if they exhibited significantly increased ratios of MIC/MLC with penicillin and resis-
tance to penicillin-induced lysis and killing. The results were striking: In animals infected with tolerant enterococci, the bacterial counts in vegetations during 10 days of therapy were significantly higher, and there were lower rates of sterilization than in animals infected with nontolerant strains. The concentrations of penicillin in the serum were not significantly different, but the serum bactericidal titers were significantly lower for the tolerant strains. © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Comment Tolerance to penicillin has been thought to be one explanation for the poor response of enterococcal endocarditis to treatment with penicillin alone. However, documentation in vivo by controlled experiments has been lacking. The work of Kim et al. indicates that tolerance to penicillin is, indeed, a significant determinant of the response of an enterococcal infection to therapy with penicillin and reemphasizes the need to add an
22 Infectious Diseases Newsletter 7(3) March 1988 aminocyclitol when treating enterococcal endocarditis in order to insure bactericidal activity. CWS
[]
Watanakunakorn C: In-vitro activity of LY 146032, a novel cylic iipopeptide, alone and in combination with gentamicin or tobramycin against enterococci. J Antimicrob Chemother 19:445-448, 1987. A kill-kinetic method was used to examine the bactericidal activity of LY 146032, alone and in combination with gentamicin or tobramycin, against enterococci. Although the MICs and MLCs of LY 146032 were low (/>2 ug/ml) and were either the same or only one dilution different as determined by a broth macrodilution method, the killing activity of LY 146032 concentrations t>4 × MIC was slow with a 2-3 log10 decrease at 24 hours. The combination of LY 146032 and either gentamicin or tobramycin yielded synergy against almost all strains of enterococci, and the bactericidal activity was rapid (~>3 loglo decrease at 6 hours).
Comment Typically, neither ampicillin nor vancomycin is bactericidal against enterococci. Newer agents, such as teicoplanin, are also not bactericidal against enterococci. Accordingly, when bactericidal therapy is essential to cure, as in enterococcal endocarditis, clinicians rely on a combination of an aminocyclitol with either ampicillin or vancomycin. The slow bactericidal activity of LY 146032 against enterococci may be of clinical significance, particularly against strains of enterococci with high resistance to the aminocyclitols.
We have demonstrated similar bactericidal activity of LY 146032 against enterococci (Antimicrob Agents Chemother 31:1014-1016, 1987). Because antimicrobial agents are less active against enterococci when tested in human serum (J Clin Invest 68:639-645, 1986), kill-kinetic studies should be done to determine the bactericidal activity of LY 146032 against enterococci in human serum. Should the drug be bactericidal in human serum, animal studies and clinical trials would be warranted. CWS
[]
agar and broth dilution methods might overestimate the activity of fluoroquinolones against staphylococci. Using a kill-kinetic method, we obtained similar results (Antimicrob Agents Chemother 31" 1210-1215, 1987). Although ciprofloxacin was very active according to broth microdilution M1Cs (0.125-1 ugml), its bactericidal activity was considerably less. We, too, found that ciprofloxacin was notably less active against methicillin-resistant staphylococci than it was against methicillin-susceptible staphylococci. While there are few data on the clinical results of treatment of staphylococcal infections with ciprofloxacin, ciprofloxacin resistance in S. aureus has been reported (Lancet ii:383, 1985). CWS
[] Gahm-Hansen B, Sogaard P, Arpi M:
In vitro activity of ciprofloxacin against methicillin-susceptible and methicillin-resistant staphylococci. Euro J Clin Micro 6:581-584, 1987. A kill-kinetic method was used to examine the in-vitro bactericidal activity of ciprofloxacin against both methicillin-susceptible and methicillinresistant isolates of both Staphylococcus aureus and Staphylococcus epidermidis. Although the MICs of ciprofloxacin, as determined by agar dilution, were 0.25-0.5 ug/ml, the killing activity of ciprofloxacin at concentrations >14 × MIC was low (<3 loglo at 6 hours). Moreover, regrowth of the culture occurred after 24 and 48 hours with a resistant mutant. Finally, the killing rate was lower against methicillin-resistant strains of both S. aureus and S. epidermidis.
Comment The fluoroquinolones have significant activity in vitro against staphylococci when tested by agar or broth dilution methods. The kill-kinetic data of this report suggest that the results of the © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Chandrasekar PH, Crane LR, Bailey ET: Comparison of the activity of
antibiotic combinations in-vitro with clinical outcome and resistance emergence in serious infections by Pseudomonas aeruginosa in nonneutropenic patients. J Antimicrob Chemother 19:321-329, 1987. Techniques for demonstrating synergy in vitro were compared using different combinations of beta-lactams plus aminocyclitols against isolates of Pseudomonas aeruginosa. There was poor agreement in the results from checkerboard and kill-kinetic studies. Comparison of in vitro synergy results with clinical outcome showed that antagonism in the 24-hour kill-kinetic studies was the most reliable prognostic indicator of clinical and bacteriological outcome.
Comment Because only 14 patients were evalu-