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Combination Antimicrobial Therapy
Symposium on Anti-Infective Therapy
Combination Antimicrobial Therapy David M. Shlaes, M.D., Ph.D.,* and Steven N. Bass, M.D.t
The decision to use combination antimicrobial therapy depends upon two factors: (I) the identification and results of antimicrobial susceptibility tests of the infecting organism and (2) the presence of any of a number of clinical indications. The clinical relevance of in vitro susceptibility testing and the determination of antibiotic synergism and antagonism have been the subject of several recent reviews. 28 • 85, 117 An absolute correlation between in vitro results and outcome of therapy does not exist. In vitro data do not take into account the presence of underlying disease, the site of infection, or the requirement for drainage or debridement of infected tissue. Further, differences in technique among different laboratories make extrapolation of published data to specific clinical problems difficult. 43, 12. 76, 11 2 In serious infections such as meningitis, osteomyelitis, or endocarditis, the cerebrospinal fluid or serum bactericidal titer might be a more relevant guide to therapy. 17• 50• 53• 94 • 96 Although there is a rough correlation between the level of antibiotic in the fluid used, the minimum concentration of antibiotic required to kill the organism (MBC), and the bactericidal titer, many patients fall outside these expectations. 38 Thus, for a given patient, the bactericidal titer must be measured. Indications for combination antimicrobial therapy include (a) to prevent emergence of resistance; (b) to achieve broad antimicrobial activity in a patient with serious but undefined infection; (c) to treat mixed infections; (d) to decrease the administered dose of one agent and therefore decrease toxicity; and (e) to achieve a greater effect against the organism(s) involved.85· 107 We will concern ourselves with the latter circumstance as it occurs in infection owing to bacterial pathogens.
ANTIBIOTIC TOLERANCE
Infections due to antibiotic-tolerant organisms may require combination therapy. Antibiotic tolerance is a type of resistance wherein the organ*Chief, Microbiology Unit, Division of Infectious Disease, Veterans Administration Medical Center, Cleveland, Ohio tAssociate Director, Division of Infectious Disease, St. Luke's Hospital, Cleveland Ohio
Pediatric Clinics of North America-Vol. 30, No. 1, February 1983
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ism is inhibited but not killed by a drug that is usually bactericidal. 93· 109 Operationally, this can be defined as a ratio of minimum inhibitory antimicrobial concentration (MIC) to minimum bactericidal antimicrobial concentration (MBC) of 10 or greater. The basic mechanism of tolerance is related to a defect in the production or action of autolysins after exposure to a drug that usually promotes lysis via autolytic action, such as the betalactams.109 Since there are several steps on this pathway that may be defective in a given strain, many variables, such as strain storage conditions, growth conditions, and others, may affect the observation of tolerance. 36, 42. 65, 75 Tolerance has been described in a number of gram-positive and a few gram-negative isolates, but the clinical relevance of this observation is not as yet clear. 21 · 33· 41 · 44 · 73· 93 Patients with endocarditis due to tolerant strains of Staphylococcus aureus have prolonged fever and greater morbidity and mortality than those with nontolerant strains. 21 · 24 · 87 Adequate serum bactercidial titers (2:::1:8) are more difficult to achieve in these patients, and combination therapy is required more frequently. Patients with transient bacteremia and other less severe infections due to tolerant S. aureus appear to fare no differently than those with non tolerant staphylococcal infections. 33 The importance of the tolerance observed occasionally in group B streptococci, and commonly in Streptococcus mutans, sanguis, and bovis, is as yet unclear. 41 · 52 · 73· 109 A prudent approach to patients with microbiologically. documented severe infections would be to adjust therapy according to serum or cerebrospinal fluid bactericidal titers, using a titer of 1:8 at sometime during the dosage interval as a minimum acceptable level. 17
GRAM-POSITIVE INFECTIONS Staphylococci Endocarditis due to S. aureus is one human infection wherein combination therapy has been carefully studied. 1· 98 Combinations of semisynthetic penicillinase-resistant penicillins and aminoglycosides are synergistic in vitro and are beneficial in the treatment of S. aureus endocarditis in the rabbit model. 97 Prospective trials of the combination of nafcillin and gentamicin compared with nafcillin alone in the treatment of endocarditis in intravenous drug abusers and nonaddicts have shown a decrease in number of days of fever and bacteremia in the combined therapy group. However, no overall decrease in mortality could be demonstrated1· 98 (and Sande, M. A., personal communication). The authors of these studies recommend using the combination only for the first several days of therapy and then discontinuing the aminoglycoside. Data from animal models suggest a beneficial effect from combination therapy (oxacillin plus an aminoglycoside or rifampin, for example) of staphylococcal osteomyelitis, but data for the human situation are lacking. 74 S . epidermidis is a common cause of infection in the presence of prosthetic devices. Cerebrospinal fluid shunt infections can often be cured by intraventricular (via the shunt) instillation of antibiotics without systemic therapy or shunt removaU 06 • m For those cases that fail with this approach, surgical removal and systemic and intraventri-
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cular combination therapy may be indicated. In spite of in vitro antagonism observed between penicillins, cephalosporins, or vancomycin and rifampin, combinations including oral rifampin have been successful in increasing cerebrospinal fluid bactericidal titers and clearing infection in the animal model and in human infection. 59· 62· 91 · us, 127 S . epidermidis strains that have multiple-resistance provide the greatest challenge. They are almost always sensitive to vancomycin; if they are also sensitive to aminoglycosides, this combination can be effective. 22· 59 If not aminoglycoside sensitive, the addition of rifampin should be considered.22, 59, 91 In the granulocytopenic host, combination therapy is not necessary to treat a documented staphylococcal infection but may be required to prevent superinfection with other organisms, such as gram-negative bacilli, during the course of treatment. 84, 104 Enterococci
Enterococcal infections of children occur both perinatally and as nosocomial events. s, 10· 103 These organisms are tolerant to both penicillin and vancomycin but are killed by ampicillin. 30• 52 Because of the high recurrence rate after penicillin therapy of enterococcal endocarditis, combination therapy of these infections has been well studied. 61 Aminoglycosides, usually streptomycin or gentamicin, are synergistic in combination with many penicillins and vancomycin both in vitro and in animal models. 30• a1, 35, ua In some areas of the country, enterococcal strains highly resistant to streptomycin are common. 12 These organisms do not show synergy in vitro or in vivo with streptomycin or other aminoglycosides except gentamicin. 12 Of the two species of enterococci studied, Streptococcus faecalis and faecium, faecium is more resistant to the penicillins and is less likely to show synergism between penicillins and aminoglycosides than is faecalis .11 Thus, for streptomycin-susceptible isolates, the choice of aminoglycoside is not critical, but where this is not known, or when the organism is resistant to high levels of streptomycin, gentamicin is preferable. Infections with S. faecium should also be treated with combinations that include gentamicin. Further, higher concentrations of gentamicin (and, therefore, higher dosage) may be required to treat endocarditis due to streptomycin-resistant strains.l4· 64 Finally, since gentamicin-resistant enterococci have been reported, 7 susceptibility testing is important in choosing the antimicrobial regimen for these patients. Other combinations, such as penicillins or vancomycin and rifampin, have been used successfully in the treatment of enterococcal infection, and in vitro studies have suggested synergism with these combinations. 77, 92 Comparative in vitro studies of combinations of semisynthetic penicillinase-resistant penicillins and gentamicin have shown nafcillin to be more active than oxacillin or methicillin against the enterococcus.27· 114 Streptococcus Pneumoniae and Other Streptococci In vitro studies of combinations of penicillins and chloramphenicol against both S. pneumoniae and group B streptococci show antagonism. 85, 116 Meningitis is one human infection in which these in vitro studies appear to have direct relevance. In clinical studies by Lepper and Dowling, pa-
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tients with pneumococcal meningitis fared better when treated with penicillin alone compared with those treated with a combination of penicillin and tetracycline, an inhibitor of protein synthesis. 55 Although chloramphenicol can be bactericidal against the pneumococcus in vitro, when used in the animal model of pneumococcal meningitis the combination of chloramphenicol and penicillin is less effective than penicillin alone. 86· 96 The studies of Mathies et al. of patients with bacterial meningitis treated with ampicillin alone compared with those treated with the combination of ampicillin, chloramphenicol, and streptomycin demonstrate a similar result. 63 Combinations of a penicillin plus chloramphenicol should be avoided in the treatment of pneumococcal or group B streptococcal meningitis. The classification of "viridans" streptococci has become increasingly important over the last 10 to 15 years. 80 · 102 We now know that some species, sanguis, mutans, and bovis, are more likely to cause endocarditis, 80 and are more likely to be tolerant to penicillin and other cell wall-active antibiotics. 52, 73 · 109 Penicillins, cephalosporins, and vancomycin clearly have a synergistic effect with aminoglycosides both in vitro and in the animal model of endocarditis. 98 Two-week therapy with penicillin plus streptomycin appears to have a relapse rate comparable to four weeks of penicillin alone. 40· 118 In spite of this observation, the increased toxicity of aminoglycoside therapy makes routine combination therapy difficult to recommend.98 By following bactericidal titers and ensuring minimum titers of 1:8 at sometime during the dosage interval throughout the course of treatment, two weeks of intravenous penicillin therapy followed by two weeks of oral therapy should be sufficient. 17 The occasional patient with endocarditis due to B6-dependent streptococci probably should have two weeks of aminoglycoside plus penicillin followed by two more weeks of penicillin alone. 13 Listeria Monocytogenes
Listeria is not an uncommon cause of bacteremia or meningitis in the infant, the elderly, or the immunocompromised adult. 15· 39• 54, 110 Mortality ranges from 30 to 60 per cent with a relapse rate up to 33 per cent. 15• 54 Although both penicillin and ampicillin are effective in vitro and in vivo, ampicillin tends to be more active and is considered the drug of choice. 99 • 54 Some have recommended combination therapy, usually ampicillin plus gentamicin, 6· 99 but this has not achieved wide acceptance, since there is a lack of comparative data in humans. In the animal model of meningitis, this combination is clearly more effective than ampicillin alone. 99 In the same model, as predicted from in vitro data, the addition of rifampin is not synergistic. Retrospective studies of Listeria infection in New York City, where elderly and immunocompromised adults comprised the majority of cases, indicate that the combination of ampicillin and chloramphenicol is deleterious, but no conclusion regarding the combination of penicillin or ampicillin and aminoglycosides could be reached. 15 Thus, ampicillin alone is probably adequate; no firm recommendations regarding the addition of an aminoglycoside can be made at this time. The combination of ampicillin and chloramphenicol should be avoided.
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GRAM-NEGATIVE INFECTIONS Pseudomonas Aeruginosa The in vitro evidence for synergy against Pseudomonas aeruginosa with aminoglycoside-beta-lactam (carbenicillin, ticarcillin) combination is clear.16, 49, ss. 85, 123 This in vitro synergy is not invariably present, is strain dependent, and varies with different aminoglycoside-beta-lactam combinations.32 A number of studies in neutropenic and normal animals with peritonitis have confirmed the in vitro synergy against Pseudomonas .3. 4, 101 Gentamicin-carbenicillin is more effective than gentamicin alone in the rabbit infectious endocarditis model. 5 Neutropenic dogs with Pseudomonas pneumonia, however, have equal ultimate survival when treated with either gentamicin or the combination of gentamicin and carbenicillin. 19 Human studies concerning the therapy of serious Pseudomonas infections have predominantly involved patients with cancer. 125 Poor results with aminoglycoside therapy alone for Pseudomonas infection in neutropenic patients have been reported. 9· 100 Klasters}cy46· 48 reported improved outcome in cancer patients with and without neutropenia when therapy consisted of combination antibiotics with demonstrated in vitro synergy. These studies involved a wide variety of gram-negative bacilli and indicated a beneficial effect of synergistic combinations against these organisms, including Pseudomonas. Prospectively comparing gentamicin, carbenicillin, and the combination in patients with cancer (only a minority with neutropenia), Klastersky found the combination significantly better than single-agent therapy. 45 The predominant organism in this series was Pseudomonas, and the clearest benefit of combination therapy was against this organism. In a retrospective analysis, only infections caused by Pseudomonas benefited from synergistic combination antibiotic therapy. 2 Intact host defense plays an important role in the outcome of gramnegative infections. 67 The benefit of combination antibiotic therapy seems most prominent in patients with impaired host defense. Anderson, 2 in a retrospective review, assessed the response rate to single-drug, nonsynergistic, and synergistic combination therapy related to host factors. Using McCabe's criteria67 for severity of underlying disease, there was no beneficial effect of synergy in patients with ultimately fatal or nonfatal underlying disease. Only in patients with rapidly fatal underlying disease, which included those with neutropenia, was combination therapy beneficial. Moreover, only with combinations demonstrating in vitro synergism was benefit shown. Additionally, when the site of infection was evaluated, only in patients with bacteremia of unknown source was synergy of benefit. Outcome of patients with pneumonia or urinary or biliary tract infection was not improved by synergistic combinations. Therefore, combination therapy that was synergistic in vitro was of benefit only for patients with rapidly fatal underlying disease and with Pseudomonas bacteremia of unknown source. In addition, the only combination that was synergistic in vivo was carbenicillin and an aminoglycoside. Other than patients with cancer, serious Pseudomonas infections occur in heroin drug addicts. Pseudomonas infective endocarditis in the animal model is more effectively treated with combination of gentamicin-carbeni-
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cillin therapy than standard-dose gentamicin alone. 5 However, high dose gentamicin is as effective as combination therapy. The beneficial effect of either high dose gentamicin or combination therapy is probably based upon the need for high serum bactericidal activity against organisms growing in the cardiac vegetation, a lesion protected from normal host defense mechanisms. In human studies, high dose gentamicin with carbenicillin is successful in curing most patients with Pseudomonas endocarditis, a disease that previously required valve replacement. 89 Medical failure is associated with combination therapy that is not synergistic. 88 There is marginal penetration of aminoglycosides into bronchial secretions;83, 120 therefore, combination therapy may be beneficial in treating Pseudomonas pneumonia. 18 However, in patients with cystic fibrosis, gentamicin, ticarcillin, and the combination of gentamicin-ticarcillin are equally effective in treating Pseudomonas pulmonary infections. 81 The combination of tobramycin-ticarcillin seems superior to gentamicin-carbenicillin in this situation. 82 Klebsiella Cephalosporin-aminglycoside combination therapy is frequently used for serious Klebsiella infections. 56· 60• 124 There are in vitro data demonstrating synergy with this combination;20· 47.58 however, this is not predictable. 20• 79 Moreover, in the rat peritonitis model, gentamicin as a single agent is extremely active. The addition of a cephalosporin to gentamicin does not improve outcome. 69 Clinical evidence favoring combination therapy is not clear. In patients with cancer, there is no beneficial effect of aminoglycoside-cephalosporin over other combinations in patients with Klebsiella infections.2 In another retrospective analysis the authors suggest that in patients with rapidly fatal disease there is improved outcome with combination therapy against Klebsiella, 126 although specific data substantiating this are not presented. Winston 119 studied amikacin, cefazolin, and amikacin-cefazolin therapy in the neutropenic peritonitis rat model. Although in vitro synergy was demonstrated, amikacin alone was as effective as the combination. Cefazolin alone was no better than control. In addition, combination aminoglycoside-cephalosporin therapy is probably more nephrotoxic than single agent or other combination therapy. 23 Therefqre, despite in vitro data, there is no proven clinical benefit of combination therapy, and there may be associated increased nephrotoxicity. The literature recommends cephalosporin-aminoglycoside therapy for Klebsiella pneumonia, but good clinical studies are lacking. Hemophilus Influenzae Ampicillin-chloramphenicol is frequently employed as initial therapy for meningitis and other serious infections caused by this organism. 25 The beneficial effect in this situation arises from avoiding inadequate therapy of a resistant organism, rather than taking advantage of in vitro synergy. In H. influenzae meningitis, however, the combination may be associated with a higher incidence of hearing impairment when compared with either antibiotic alone, 57 despite the bactericidal activity of chloramphenicol against H. influenzae. 86 Currently, therefore, avoiding the prolonged use
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of ampicillin-chloramphenicol combination therapy when treating H. influenzae meningitis by eliminating either antibiotic when sensitivities are known is advised. For H. injluenzae that produce beta-lactamase, there is in vitro and in vivo evidence for a beneficial effect of ampicillin-nafcillin combination therapy. 121 There is competitive inhibition of beta-lactamase by nafcillin, allowing ampicillin to retain its antibacterial effect. In addition, clavulanic acid, a beta-lactamase inhibitor, appears effective in combination with amoxicillin against ampicillin-resistant H. influenzae. type b in vitro and in the rat bacteremia and meningitis models.I22 Other Gram-Negative Bacilli There are no clinical studies demonstrating the efficacy of combination antibiotic therapy for other gram-negative infections. In vitro synergy has been demonstrated with a number of antibiotic combinations against a variety of gram-negative bacilli.I1· 26, 58• 78· ros The clinical relevance of these data is unclear. In a large retrospective study there was no beneficial effect of combination therapy over single-drug therapy for gram-negative bacteremia, irrespective of underlying disease. 51 With serious infection caused by these organisms, consideration may be given to using potentially synergistic combinations; however, in vitro synergy studies should be performed. Antagonism Potential antagonistic antibiotic combinations against gram-negative organisms include those in which a bacteriostatic drug is used with a bactericidal drug. 85 In vitro data demonstrating this phenomenon have been reported with chloramphenicol in combination with an aminoglycoside against Klebsiella20 and Proteus. 95 In the mouse peritonitis model, Jawetz demonstrated antagonism against Klebsiella using penicillin-chloramphenicol, but only with low-dose penicillin and in a single-dose regimen. 37 In a more recent study, Sande and Overton95 demonstrated in vivo antagonism only in neutropenic mice using chloramphenicol-gentamicin in single-dose and multiple-dose regimens. Clinically significant antagonism against gram-negative bacteria is infrequently documented. In a retrospective review, antagonistic antibiotic combinations were associated with a low success rate in the treatment of urinary tract infections. 66 Chloramphenicol-aminoglycoside combination therapy, however, has been used successfully in severe gram-negative infections.29 The nature of the host may be important for antagonism to become manifest, as in the neutropenic mouse with peritonitis. In addition, the site of infection could determine the significance of potentially antagonistic combinations. 94 In the rabbit meningitis model, the addition of chloramphenicol to an aminoglycoside worsened the outcome of Proteus meningitis, and this combination was found to be antagonistic in vitro.ros In a large retrospective review of Listeria and non-Herrwphilus gram-negative bacillary meningitis, the use of chloramphenicol alone and in combination with bactericidal antibiotics was associated with a poor outcome. 15 Therefore, in granulocytopenic patients or in the treatment of meningitis, antagonistic combinations should be avoided.
Table 1. ORGANISM
INFECTION
Summary of Combination Antimicrobial Therapy SYNERGISTIC COMBINATION
ANTAGONISTIC COMBINATION
COMMENT
Staph. aureus
endocarditis
nafcillin, oxacillin, methicillin or vancomycin + aminoglycoside
Synergistic combination for first 3-5 days only
Staph. epidermidis
endocarditis CSF shunt prosthetic joint
as above
Rifampin may increase serum and CSF bactericidal titer
Enterococcus
endocarditis bacteremia
penicillin, ampicillin or vancomycin+ aminoglycoside
Rifampin may increase bactericidal titer
Strep. pneumoniae Group B streptococci
meningitis
Other Streptococci
endocarditis
Listeria monocytogenes
pencillin + aminoglycoside
meningitis bacteremia carbenicillin or ticarcillin + aminoglycoside
Klebsiella pneumoniae
pneumonia
cephalosporin + aminoglycoside 1
Other gram-negative bacilli
bacteremia meningitis endocarditis
2 weeks of aminoglycoside in addition to penicillin may be beneficial
0
> <
8
penicillins + chloramphenicol
bacteremia of unknown source; pneumonia
meningitis
00
penicillins + chloramphenicol or tetracycline
Pseudomonas aeruginosa
H. injluenzae
......
1::0
~ [JJ
:I: t"
chloramphenicol+ aminoglycosidez
ampicillin+ chloramphenicol
chloramphenicol and aminoglycoside
(l) Based upon in vitro data. No supportive clinical data. (2) Avoid antagonistic combination in meningitis. No evidence for in vitro antagonism. Increased hearing impairment when combination used.
~
"' > z tl
...,
[JJ
t'1
<
t'1
z
z
to
>
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COMBINATION ANTIMICROBIAL THERAPY
129
Aminoglycoside inactivation by beta-lactam antibiotics (carbenicillin, ticarcillin) has been reported. 34• 68 · 90 This appears to occur when the two antibiotics are mixed in the same intravenous bottle but not shown to occur in vivo except in patients with severe renal failure on hemodialysis. 90 The clinical significance of this interaction is unclear. This in vitro phenomenon should not deter the use of this valuable antibiotic combination, although care should be taken to administer these agents separately.
SUMMARY In spite of a large volume of data regarding the in vitro activity of single and combined antimicrobial activity, the clinical relevance of these studies is unclear. Few comparative trials of combined and single antibiotic therapy of human infection have been performed. Synergistic combination therapy has been shown to be beneficial in a few specific circumstances. Antagonistic combinations should be avoided in the treatment of meningitis, endocarditis, and infections of immunocompromised patients. The bactericidal titer of serum or spinal fluid should reflect adequacy of therapy of meningitis, endocarditis, and osteomyelitis, and adjustments can be made accordingly.
Acknowledgments We are grateful to Miss Ruth Kirk for excellent secretarial assistance.
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AND STEVEN
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34. Holt, H. A., Broughall, J. M., McCarthy, M., et al.: Interactions between aminoglycoside antibiotics and carbenicillin or ticarcillin. Infection, 4:107, 1976. 35. Hook, E. W., Roberts, R. B., and Sande, M. A.: Antimicrobial therapy of experimental enterococcal endocarditis. Antimicrob. Agents Chemother., 8:564, 1975. 36. Horne, D., and Tomasz, A.: pH-dependent penicillin tolerance of group B streptococci. Antimicrob. Agents Chemother., 20:128, 1981. 37. Jawetz, E., Gunnison, J. B., Speck, R. S. et al.: Studies in the antibiotic synergism and antagonism. The interference of chloramphenicol with the action of penicillin. Arch. Intern. Med., 87:349, 1951. 38. Jordan, G. W., and Kawachi, M. M.: Analysis of serum bactericidal activity in endocarditis, osteomyelitis and other bacterial infections. Medicine, 60:49, 1981. 39. Kalis, P., LeFrock, J. L., Smith, W., et al.: Listeriosis. Am. J. Med. Sci., 271:159, 1976. 40. Karchmer, A. W., Moellering, R. C., Maki, D. G., et al.: Single-antibiotic therapy for streptococcal endocarditis. J. Am. Med. Assoc., 241:1801, 1979. 41. Kim, K. S., and Anthony, B. F.: Penicillin tolerance in group B streptococci isolated from infected neonates. J. Infect. Dis., 144:411, 1981. 42. Kim, K. S., Yoshimori, R.N., Imagawa, D. T., et al.: Importance of medium in demonstrating penicillin tolerance by group B streptococci. Antimicrob. Agents Chemother., 16:214, 1979. 43. King, T. C., Schlessinger, D., and Krogstad, D. J.: The assessment of antimicrobial combinations. Rev. Infect. Dis., 3:627, 1981. 44. Kitano, K., and Tomasz, A.: Escherichia coli mutants tolerant to beta-lactam antibiotics. ]. Bacteriol., 140:955, 1979. 45. Klastersky, J., et al.: Therapy with carbenicillin and gentamicin for patients with cancer and severe infections caused by gram-negative rods. Cancer, 31:331, 1973. 46. Klastersky, J., Cappel, R., and Daneau, D.: Clinical significance of in vitro synergism between antibiotics in gram-negative infection. Antimicrob. Agents Chemother., 2:470, 1972. 47. Klastersky, J., Meunier-Carpentier, F., Prevost, J. M., et al.: Synergism between amikacin and cefazolin against KlebsieUa: in vitro studies and effect on the bactericidal activity of serum. J. Infect. Dis., 134:271, 1976. 48. Klastersky, J., Meunier-Carpentier, F., and Prevost, J.: Significance of antimicrobial synergism for the outcome of gram-negative sepsis. Am. J. Med. Sci., 273:157, 1977. 49. Kluge, R. M., Standford, B. A., Talem, F. M., et al.: Comparative activity of tobramycin, amikacin and gentamicin alone and with carbenicillin against Pseudomonas aeruginosa. Antimicrob. Agents Chemother., 6:442, 1974. 50. Kolyvas, E., Ahronheim, G., Marks, M. I. et al.: Oral antibiotic therapy of skeletal infections in children. Pediatrics, 65:867, 1980. 51. Kreger, B. E., et al.: Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am. J. Med., 68:344, 1980. 52. Krogstad, D. J., and Parquette, A. R.: Defective killing of enterococci: A common property of antimicrobial agents acting on the cell wall. Antimicrob. Agents Chemother., 17:965, 1980. 53. Landesman, S. H., Corrado, M. L., Shah, P. M. et al.: Past and current roles for cephalosporin antibiotics in treatment of meningitis. Am. J. Med., 71:693, 1981. 54. Lavetter, A., Leedom, J. M., Mathies, A. W., et al.: Meningitis due to Listeria nwnocytogenes. A review of25 cases. N. Engl. J. Med., 285:598, 1971. 55. Lepper, M. H., and Dowling, H. F.: Treatment of pneumococci meningitis with penicillin compared with penicillin plus aureomycin. Arch. Intern. Med., 88:489, 1951. 56. Lerner, A. M.: The gram-negative bacillary pneumonias. Disease A Month, 27:1, 1980. 57. Lindberg, J., Rosenhall, U., Nylen, 0., et al.: Long-term outcome of Hemophilus injluenzae meningitis related to antibiotic treatment. Pediatrics, 60:1, 1977. 58. Lorian, V., (ed.): Antibiotics in Laboratory Medicine. Baltimore, Williams & Wilkins, 1980, pp. 298-341. 59. Lowy, F. D., Walsh, J. A., Mayers, M. M., et al.: Antibiotic activity in vitro against methicillin-resistant Staphylococcus epidermidis and therapy of an experimental infection. Antimicrob. Agents Chemother., 16:314, 1979. 60. McHenry, M. C.: Klebsiella-Enterobacter-Serratia and Pseudomonas infections. In Kagen, B. K. (ed.): Antimicrobial Therapy. Philadelphia, W.B. Saunders Co., 1980, pp. 231-239.
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61. Mandell, G. L., Kaye, D., Levison, M. E., et al.: Enterococcal endocarditis. An analysis of 38 patients observed at the New York Hospital-Cornell Medical Center. Arch. Intern. Med., 125:258, 1970. 62. Mandell, G. L., and Moorman, D. R.: Treatment of experimental staphylococcal infections: Effect of rifampin alone and in combination on development of rifampin resistance. Antimicrob. Agents Chemother., 17:658, 1980. 63. Mathies, A. W., Leedom, J. M., Ivler, D., eta!.: Antibiotic antagonism in bacterial meningitis. Antimicrob. Agents Chemother., 7:218, 1967. 64. Matsumoto, J. Y., Wilson, W. R., Wright, A. J., et al.: Synergy of penicillin and decreasing concentrations of aminoglycosides against enterococci from patients with infective endocarditis. Antimicrob. Agents Chemother., 18:944, 1980. 65. Mayhall, C. G., and Apollo, E.: Effect of storage and changes in bacterial growth phase and antibiotic concentrations on antimicrobial tolerance in Staphylococcus aureus. Antimicrob. Agents Chemother., 18:784, 1980. 66. McCabe, W., and Jackson, G. G.: Treatment of pyelonephritis. N. Engl. J. Med., 272:1037, 1965. 67. McCabe, W. R., and Jackson, G. G.: Gram-negative bacteremia. II. Clinical laboratory and therapeutic observations. Arch. Intern. Med., 110:856, 1962. 68. McLaughlin, J. E., and Reeves, D. S.: Clinical and laboratory evidence for inactivation of gentamicin by carbenicillin. Lancet, 1:261, 1971. 69. McNeely, D. J., D'Alessandri, R. M., and Kluge, R. M.: In vitro antimicrobial synergy and antagonism against Klebsiella species-What does it all mean? Clin. Res., 24:636A, 1976. 70. Moellering, R. C.: Antimicrobial synergism-An elusive concept. J. Infect. Dis., 140:639641, 1979. 71. Moellering, R. C., Jr., Korzeniowski, 0. M., Sande, M. A., et a!.: Species-specific resistance to antimicrobial synergism in Streptococcus faecium and Streptococcus faecalis. J. Infect. Dis., 140:203, 1979. 72. Murray, P. R., and Jorgensen, J. H.: Quantitative susceptibility test methods in major United States medical centers. Antimicrob. Agents Chemother., 20:66, 1981. 73. Mychajlonka, M., McDowell, T. D., and Shockman, G. D.: Inhibition of ribonucleic acid and protein synthesis in tolerant strains of Streptococcus mutans. Antimicrob. Agents Chemother., 17:572, 1980. 74. Norden, C.: Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin and cephalothin. J. Infect. Dis., 132:493, 1975. 75. Norden, C. W., and Keleti, E.: Antibiotic tolerance in strains of Staphylococcus aureus. J. Antimicrob. Chemother., 7:599, 1981. 76. Norden, C. W., Wentzel, H., and Keleti, E.: Comparison of techniques for measurement of in vitro antibiotic synergism. J. Infect. Dis., 140:629, 1979. 77. Oil!, P. A., Kalmanson, G. M., and Guze, L. B.: Rifampin, ampicillin, streptomycin and their combinations in the treatment of enterococcal pyelonephritis in rats. Antimicrob. Agents Chemother., 20:491, 1981. 78. Ostenson, R. C., Fields, B. T., and Nolan, C. M.: Polymyxin and rifampin: New regimen for multiresistant Serratia marcescens infectious. Antimicrob. Agents Chemother., 12:655, 1977. 79. Panwalker, A. P., Trager, G. M., and Porembski, P. E.: Klebsiella species: Antimicrobial susceptibilities, bactericidal kinetics and in vitro inactivation of beta-lactam agents. Antimicrob. Agents Chemother., 18:877, 1980. 80. Parker, M. T., and Ball, L. C.: Streptococci and aerococci associated with systemic infection in man. J. Med. Microbiol., 9:275, 1976. 81. Parry, M., Neu, H. C., Merlino, M., et al.: Treatment of pulmonary infections in patients with cystic fibrosis: A comparative study of ticarcillin and gentamicin. Pediatrics, 90:144, 1977. 82. Parry, M. F., and Neu, H. C.: A comparative study ofticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli. Am. J. Med., 64:961, 1978. 83. Pennington, J. E., and Reynolds, H. Y.: Concentrations of gentamicin and carbenicillin in bronchial secretions. J. Infect. Dis., 128:63, 1973. 84. Pizzo, P. A., Ladisch, S., and Robichaud, K.: Treatment of gram-positive septicemia in cancer patients. Cancer, 45:206, 1980.
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85. Rahal, J. J., Jr.: Antibiotic combinations: The clinical relevance of synergy and antagonism. Medicine, 57:179, 1978. 86. Rahal, J. J., Jr., and Simberkoff, M. S.: Bactericidal and bacteriostatic action of chloramphenicol against meningeal pathogens. Antimicrob. Agents Chemother., 16:13, 1979. 87. Rajasherkaraiah, K. R., Rice, T., Rao, V. A., et al.: Clinical significance of tolerant strains of Staphywcoccus aureus in patients with endocarditis. Ann. Intern. Med., 93:796, 1980. 88. Reyes, M., El-Khatib, M. R., Brown, W. J., eta!.: Synergy between carbenicillin and an aminoglycoside (gentamicin or tobramycin) against Pseudomonas aeruginosa isolated from patients with endocarditis and sensitivity of isolates to human serum. J. Infect. Dis., 140:192, 1979. 89. Reyes, M. P., Palutke, W. A., Wylin, R. E., et a!.: Treatment of patients with Pseudomonas endocarditis with high dose aminoglycoside and carbenicillin. Medicine, 57:57, 1978. 90. Riff, L. J., Jackson, G. G.: Laboratory and clinical conditions for gentamicin inactivation by carbenicillin. Arch. Intern. Med., 130:887, 1972. 91. Ring, J. C., Cates, K. L., Belani, K. K., et al.: Rifampin for CSF shunt infections caused by coagulase-negative staphylococci. J. Pediatr., 95:317, 1979. 92. Ryan, J. L., Pachner, A., Andriole, V. T., eta!.: Enterococcal meningitis: Combined vancomycin and rifampin therapy. Am. J. Med., 68:449, 1980. 93. Sabath, L. D., Laverdiere, M., Wheeler, N., eta!.: A new type of penicillin resistance of Staphylococcus aureus. Lancet, 1:443, 1977. 94. Sande, M.: Antibiotic therapy of bacterial meningitis: Lessons we've learned. Am. J. Med., 71:507, 1981. 95. Sande, M., and Overton, J. W.: In vivo antagonism between gentamicin and chloramphenicol in neutropenic mice. J. Infect. Dis., 128:247, 1973. 96. Sande, M. A.: Antibiotic synergism and antagonism in experimental models in infection. In Williams, J. D. (ed.): Antibiotic Interactions. London, Academic Press, 1979, p. 137. 97. Sande, M. A., and Courtney, K. B.: Nafcillin-gentamicin synergism in experimental staphylococcal endocarditis. J. Lab. Clin. Med., 88:118, 1976. 98. Sande, M. A., and Scheid, W. M.: Combination antibiotic therapy of bacterial endocarditis. Ann. Intern. Med., 92:390, 1980. 99. Scheid, W. M., Fletcher, D. D., Fink, F. N., eta!.: Response to therapy in an experimental rabbit model of meningitis due to Listeria monocytogenes. J. Infect. Dis., 140:287, 1979. 100. Schimpff, S., Satterlee, W., Young, V. M., et al.: Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and neutropenia. N. Engl. J. Med., 284:1061, 1971. 101. Scott, R. E., and Robson, H. G.: Synergistic activity of carbenicillin and gentamicin in experimental Pseudomonas bacteremia in neutropenic rats. Antimicrob. Agents Chemother., 10:646, 1976. 102. Shlaes, D. M., Lerner, P. 1., Gopalakrishna, K. V., et al.: Infections due to Lancefield group F and related Streptococci (S. milleri and S. anginosus). Medicine, 60:197, 1981. 103. Shlaes, D. M., Levy, J., and Wolinsky, E.: Enterococcal bacteremia without endocarditis. Arch. Intern. Med., 147:578, 1981. 104. Sotman, S. B., Schimpff, S. C., and Young, V. M.: Staphylococcus aureus bacteremia in patients with acute leukemia. Am. J. Med., 69:814, 1980. 105. Strausbaugh, L. J., and Sande, M. A.: Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits. J. Infect. Dis., 137:251, 1978. 106. Sutherland, G. E., Palitang, E. G., Marr, J. J., eta!.: Sterilization ofOmmaya reservoir by instillation of vancomycin. Am. J. Med., 71:1068, 1981. 107. Tennebaum, M. J., and Kaplan, M. H.: Antibiotic combinations. Med. Clin. North Am., 66:17, 1982. 108. Thomas, F. E., Leonard, J. M., and Alford, R. H.: Sulfamethoxazole-trimethoprim-polymyxin therapy of serious multiply drug resistant Serratia infections. Antimicrob. Agents Chemother., 9:201, 1976. 109. Tomasz, A.: From penicillin-binding protein to the lysis and death of bacteria: A 1979 view. Rev. Infect. Dis., 1:434, 1979.
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UO. Visinstine, A. M., Oleske, J. M., and Nahmias, A. J.: Listeria monocytogenes infection in infants and children. Am. J. Dis. Child., 131:393, 1977. lll. Wald, S. L., and McLaurin, R. L.: Cerebrospinal fluid antibiotic levels during treatment of shunt infections. J. Neurosurg., 52:41, 1980. ll2. Washington, J. A.: Infectious diseases 197~Antimicrobial susceptibility tests, J. Infect. Dis., 140:261, 1979. ll3. Watanakunakorn, C., and Bakie, C.: Synergism of vancomycin-gentamicin and vancomycin-streptomycin against enterococci. Antimicrob. Agents Chemother., 4:120, 1973. ll4. Watanakunakorn, C., and Glotzbecker, C.: Comparative in vitro activity of nafcillin, oxacillin and methicillin in combination with gentamicin and tobramycin against enterococci. Antimicrob. Agents Chemother., 11:88, 1977. ll5. Watanakunakorn, C., and Guerriero, J. C.: Interaction between vancomycin and rifampin against Staphylococcus aureus. Antimicrob. Agents Chemother., 19:1089, 1981. ll6. Weeks, J. L., Mason, E. 0., Jr., and Baker, C. J.: Antagonism of ampicillin and chloramphenicol for meningeal isolates of group B streptococci. Antimicrob. Agents Chemother., 20:281, 1981. ll7. Williams, J.D., and Drasar, F. A.: Clinical relevance of antibiotic synergy. In Williams, J. D. (ed.): Antibiotic Interactions, London, Academic Press, 1979, p. 13. ll8. Wilson, W. R., Thompson, R. L., Wilkowske, C. J., eta!.: Short-term therapy for streptococcal infective endocarditis. J. Am. Med. Assoc., 245:360, 1981. ll9. Winston, D. J., Sidell, J., Hairston, J., et al.: Antimicrobial therapy of septicemia due to Klebsiella pneumoniae in neutropenic rats. J. Infect. Dis., 139:377, 1979. 120. Wong, G. A., Peirce, T. H., Goldstein, E., eta!.: Penetration of antimicrobial agents into bronchial secretions. Am. J. Med., 59:219, 1975. 121. Yogev, R., and Kabat, W. J.: Synergistic action ofnafcillin and ampicillin against ampicillin-resistant H. injluenzae type b bacteremia and meningitis in infant rats. Antimicrob. Agents Chemother., 18:122, 1980. 122. Yogev, R., Melick, C., and Kabat, W.: In vitro and in vivo synergism between amoxicillin and clavulanic acid against ampicillin-resistant Haemophilus influenzae Type b. Antimicrob. Agents Chemother., 19:993, 1981. 123. Yoshikawa, T. T., and Shibata, S. A.: In vitro antibacterial activity of amikacin and ticarcillin, alone and in combination, against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. ," 13:997, 1978. 124. Young, L. S.: Gram-negative sepsis. In Mandell, G. L., Douglas, R. D., and Bennett, J. E., (eds.): Principles and Practices of Infectious Diseases. New York, Wiley, 1979, pp. 571-608. 125. Young, L. S.: Combination or single drug therapy for gram-negative sepsis. In Remington, J. S., and Swartz, M. N., (Eds.): Current Clinical Topics In Infectious Diseases. New York, McGraw-Hill, 1982, pp. 177-205. 126. Young, L. S., Martin, W. J., Meyer, R. D., eta!.: Gram-negative bacteremia: Microbiologic, immunologic, and therapeutic considerations. Ann. Intern. Med., 86:456, 1977. 127. Zinner, S. H., Lagast, H., and Klastersky, J.: Antistaphylococcal activity or rifampin with other antibiotics. J. Infect. Dis., 144:365, 1981.
Division of Infectious Disease Veterans Administration Medical Center 10701 East Boulevard Cleveland, Ohio 44106
Combination Antimicrobial Therapy David M. Shlaes, M.D., Ph.D.,* and Steven N. Bass, M.D.t
The decision to use combination antimicrobial therapy depends upon two factors: (I) the identification and results of antimicrobial susceptibility tests of the infecting organism and (2) the presence of any of a number of clinical indications. The clinical relevance of in vitro susceptibility testing and the determination of antibiotic synergism and antagonism have been the subject of several recent reviews. 28 • 85, 117 An absolute correlation between in vitro results and outcome of therapy does not exist. In vitro data do not take into account the presence of underlying disease, the site of infection, or the requirement for drainage or debridement of infected tissue. Further, differences in technique among different laboratories make extrapolation of published data to specific clinical problems difficult. 43, 12. 76, 11 2 In serious infections such as meningitis, osteomyelitis, or endocarditis, the cerebrospinal fluid or serum bactericidal titer might be a more relevant guide to therapy. 17• 50• 53• 94 • 96 Although there is a rough correlation between the level of antibiotic in the fluid used, the minimum concentration of antibiotic required to kill the organism (MBC), and the bactericidal titer, many patients fall outside these expectations. 38 Thus, for a given patient, the bactericidal titer must be measured. Indications for combination antimicrobial therapy include (a) to prevent emergence of resistance; (b) to achieve broad antimicrobial activity in a patient with serious but undefined infection; (c) to treat mixed infections; (d) to decrease the administered dose of one agent and therefore decrease toxicity; and (e) to achieve a greater effect against the organism(s) involved.85· 107 We will concern ourselves with the latter circumstance as it occurs in infection owing to bacterial pathogens.
ANTIBIOTIC TOLERANCE
Infections due to antibiotic-tolerant organisms may require combination therapy. Antibiotic tolerance is a type of resistance wherein the organ*Chief, Microbiology Unit, Division of Infectious Disease, Veterans Administration Medical Center, Cleveland, Ohio tAssociate Director, Division of Infectious Disease, St. Luke's Hospital, Cleveland Ohio
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ism is inhibited but not killed by a drug that is usually bactericidal. 93· 109 Operationally, this can be defined as a ratio of minimum inhibitory antimicrobial concentration (MIC) to minimum bactericidal antimicrobial concentration (MBC) of 10 or greater. The basic mechanism of tolerance is related to a defect in the production or action of autolysins after exposure to a drug that usually promotes lysis via autolytic action, such as the betalactams.109 Since there are several steps on this pathway that may be defective in a given strain, many variables, such as strain storage conditions, growth conditions, and others, may affect the observation of tolerance. 36, 42. 65, 75 Tolerance has been described in a number of gram-positive and a few gram-negative isolates, but the clinical relevance of this observation is not as yet clear. 21 · 33· 41 · 44 · 73· 93 Patients with endocarditis due to tolerant strains of Staphylococcus aureus have prolonged fever and greater morbidity and mortality than those with nontolerant strains. 21 · 24 · 87 Adequate serum bactercidial titers (2:::1:8) are more difficult to achieve in these patients, and combination therapy is required more frequently. Patients with transient bacteremia and other less severe infections due to tolerant S. aureus appear to fare no differently than those with non tolerant staphylococcal infections. 33 The importance of the tolerance observed occasionally in group B streptococci, and commonly in Streptococcus mutans, sanguis, and bovis, is as yet unclear. 41 · 52 · 73· 109 A prudent approach to patients with microbiologically. documented severe infections would be to adjust therapy according to serum or cerebrospinal fluid bactericidal titers, using a titer of 1:8 at sometime during the dosage interval as a minimum acceptable level. 17
GRAM-POSITIVE INFECTIONS Staphylococci Endocarditis due to S. aureus is one human infection wherein combination therapy has been carefully studied. 1· 98 Combinations of semisynthetic penicillinase-resistant penicillins and aminoglycosides are synergistic in vitro and are beneficial in the treatment of S. aureus endocarditis in the rabbit model. 97 Prospective trials of the combination of nafcillin and gentamicin compared with nafcillin alone in the treatment of endocarditis in intravenous drug abusers and nonaddicts have shown a decrease in number of days of fever and bacteremia in the combined therapy group. However, no overall decrease in mortality could be demonstrated1· 98 (and Sande, M. A., personal communication). The authors of these studies recommend using the combination only for the first several days of therapy and then discontinuing the aminoglycoside. Data from animal models suggest a beneficial effect from combination therapy (oxacillin plus an aminoglycoside or rifampin, for example) of staphylococcal osteomyelitis, but data for the human situation are lacking. 74 S . epidermidis is a common cause of infection in the presence of prosthetic devices. Cerebrospinal fluid shunt infections can often be cured by intraventricular (via the shunt) instillation of antibiotics without systemic therapy or shunt removaU 06 • m For those cases that fail with this approach, surgical removal and systemic and intraventri-
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cular combination therapy may be indicated. In spite of in vitro antagonism observed between penicillins, cephalosporins, or vancomycin and rifampin, combinations including oral rifampin have been successful in increasing cerebrospinal fluid bactericidal titers and clearing infection in the animal model and in human infection. 59· 62· 91 · us, 127 S . epidermidis strains that have multiple-resistance provide the greatest challenge. They are almost always sensitive to vancomycin; if they are also sensitive to aminoglycosides, this combination can be effective. 22· 59 If not aminoglycoside sensitive, the addition of rifampin should be considered.22, 59, 91 In the granulocytopenic host, combination therapy is not necessary to treat a documented staphylococcal infection but may be required to prevent superinfection with other organisms, such as gram-negative bacilli, during the course of treatment. 84, 104 Enterococci
Enterococcal infections of children occur both perinatally and as nosocomial events. s, 10· 103 These organisms are tolerant to both penicillin and vancomycin but are killed by ampicillin. 30• 52 Because of the high recurrence rate after penicillin therapy of enterococcal endocarditis, combination therapy of these infections has been well studied. 61 Aminoglycosides, usually streptomycin or gentamicin, are synergistic in combination with many penicillins and vancomycin both in vitro and in animal models. 30• a1, 35, ua In some areas of the country, enterococcal strains highly resistant to streptomycin are common. 12 These organisms do not show synergy in vitro or in vivo with streptomycin or other aminoglycosides except gentamicin. 12 Of the two species of enterococci studied, Streptococcus faecalis and faecium, faecium is more resistant to the penicillins and is less likely to show synergism between penicillins and aminoglycosides than is faecalis .11 Thus, for streptomycin-susceptible isolates, the choice of aminoglycoside is not critical, but where this is not known, or when the organism is resistant to high levels of streptomycin, gentamicin is preferable. Infections with S. faecium should also be treated with combinations that include gentamicin. Further, higher concentrations of gentamicin (and, therefore, higher dosage) may be required to treat endocarditis due to streptomycin-resistant strains.l4· 64 Finally, since gentamicin-resistant enterococci have been reported, 7 susceptibility testing is important in choosing the antimicrobial regimen for these patients. Other combinations, such as penicillins or vancomycin and rifampin, have been used successfully in the treatment of enterococcal infection, and in vitro studies have suggested synergism with these combinations. 77, 92 Comparative in vitro studies of combinations of semisynthetic penicillinase-resistant penicillins and gentamicin have shown nafcillin to be more active than oxacillin or methicillin against the enterococcus.27· 114 Streptococcus Pneumoniae and Other Streptococci In vitro studies of combinations of penicillins and chloramphenicol against both S. pneumoniae and group B streptococci show antagonism. 85, 116 Meningitis is one human infection in which these in vitro studies appear to have direct relevance. In clinical studies by Lepper and Dowling, pa-
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tients with pneumococcal meningitis fared better when treated with penicillin alone compared with those treated with a combination of penicillin and tetracycline, an inhibitor of protein synthesis. 55 Although chloramphenicol can be bactericidal against the pneumococcus in vitro, when used in the animal model of pneumococcal meningitis the combination of chloramphenicol and penicillin is less effective than penicillin alone. 86· 96 The studies of Mathies et al. of patients with bacterial meningitis treated with ampicillin alone compared with those treated with the combination of ampicillin, chloramphenicol, and streptomycin demonstrate a similar result. 63 Combinations of a penicillin plus chloramphenicol should be avoided in the treatment of pneumococcal or group B streptococcal meningitis. The classification of "viridans" streptococci has become increasingly important over the last 10 to 15 years. 80 · 102 We now know that some species, sanguis, mutans, and bovis, are more likely to cause endocarditis, 80 and are more likely to be tolerant to penicillin and other cell wall-active antibiotics. 52, 73 · 109 Penicillins, cephalosporins, and vancomycin clearly have a synergistic effect with aminoglycosides both in vitro and in the animal model of endocarditis. 98 Two-week therapy with penicillin plus streptomycin appears to have a relapse rate comparable to four weeks of penicillin alone. 40· 118 In spite of this observation, the increased toxicity of aminoglycoside therapy makes routine combination therapy difficult to recommend.98 By following bactericidal titers and ensuring minimum titers of 1:8 at sometime during the dosage interval throughout the course of treatment, two weeks of intravenous penicillin therapy followed by two weeks of oral therapy should be sufficient. 17 The occasional patient with endocarditis due to B6-dependent streptococci probably should have two weeks of aminoglycoside plus penicillin followed by two more weeks of penicillin alone. 13 Listeria Monocytogenes
Listeria is not an uncommon cause of bacteremia or meningitis in the infant, the elderly, or the immunocompromised adult. 15· 39• 54, 110 Mortality ranges from 30 to 60 per cent with a relapse rate up to 33 per cent. 15• 54 Although both penicillin and ampicillin are effective in vitro and in vivo, ampicillin tends to be more active and is considered the drug of choice. 99 • 54 Some have recommended combination therapy, usually ampicillin plus gentamicin, 6· 99 but this has not achieved wide acceptance, since there is a lack of comparative data in humans. In the animal model of meningitis, this combination is clearly more effective than ampicillin alone. 99 In the same model, as predicted from in vitro data, the addition of rifampin is not synergistic. Retrospective studies of Listeria infection in New York City, where elderly and immunocompromised adults comprised the majority of cases, indicate that the combination of ampicillin and chloramphenicol is deleterious, but no conclusion regarding the combination of penicillin or ampicillin and aminoglycosides could be reached. 15 Thus, ampicillin alone is probably adequate; no firm recommendations regarding the addition of an aminoglycoside can be made at this time. The combination of ampicillin and chloramphenicol should be avoided.
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GRAM-NEGATIVE INFECTIONS Pseudomonas Aeruginosa The in vitro evidence for synergy against Pseudomonas aeruginosa with aminoglycoside-beta-lactam (carbenicillin, ticarcillin) combination is clear.16, 49, ss. 85, 123 This in vitro synergy is not invariably present, is strain dependent, and varies with different aminoglycoside-beta-lactam combinations.32 A number of studies in neutropenic and normal animals with peritonitis have confirmed the in vitro synergy against Pseudomonas .3. 4, 101 Gentamicin-carbenicillin is more effective than gentamicin alone in the rabbit infectious endocarditis model. 5 Neutropenic dogs with Pseudomonas pneumonia, however, have equal ultimate survival when treated with either gentamicin or the combination of gentamicin and carbenicillin. 19 Human studies concerning the therapy of serious Pseudomonas infections have predominantly involved patients with cancer. 125 Poor results with aminoglycoside therapy alone for Pseudomonas infection in neutropenic patients have been reported. 9· 100 Klasters}cy46· 48 reported improved outcome in cancer patients with and without neutropenia when therapy consisted of combination antibiotics with demonstrated in vitro synergy. These studies involved a wide variety of gram-negative bacilli and indicated a beneficial effect of synergistic combinations against these organisms, including Pseudomonas. Prospectively comparing gentamicin, carbenicillin, and the combination in patients with cancer (only a minority with neutropenia), Klastersky found the combination significantly better than single-agent therapy. 45 The predominant organism in this series was Pseudomonas, and the clearest benefit of combination therapy was against this organism. In a retrospective analysis, only infections caused by Pseudomonas benefited from synergistic combination antibiotic therapy. 2 Intact host defense plays an important role in the outcome of gramnegative infections. 67 The benefit of combination antibiotic therapy seems most prominent in patients with impaired host defense. Anderson, 2 in a retrospective review, assessed the response rate to single-drug, nonsynergistic, and synergistic combination therapy related to host factors. Using McCabe's criteria67 for severity of underlying disease, there was no beneficial effect of synergy in patients with ultimately fatal or nonfatal underlying disease. Only in patients with rapidly fatal underlying disease, which included those with neutropenia, was combination therapy beneficial. Moreover, only with combinations demonstrating in vitro synergism was benefit shown. Additionally, when the site of infection was evaluated, only in patients with bacteremia of unknown source was synergy of benefit. Outcome of patients with pneumonia or urinary or biliary tract infection was not improved by synergistic combinations. Therefore, combination therapy that was synergistic in vitro was of benefit only for patients with rapidly fatal underlying disease and with Pseudomonas bacteremia of unknown source. In addition, the only combination that was synergistic in vivo was carbenicillin and an aminoglycoside. Other than patients with cancer, serious Pseudomonas infections occur in heroin drug addicts. Pseudomonas infective endocarditis in the animal model is more effectively treated with combination of gentamicin-carbeni-
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cillin therapy than standard-dose gentamicin alone. 5 However, high dose gentamicin is as effective as combination therapy. The beneficial effect of either high dose gentamicin or combination therapy is probably based upon the need for high serum bactericidal activity against organisms growing in the cardiac vegetation, a lesion protected from normal host defense mechanisms. In human studies, high dose gentamicin with carbenicillin is successful in curing most patients with Pseudomonas endocarditis, a disease that previously required valve replacement. 89 Medical failure is associated with combination therapy that is not synergistic. 88 There is marginal penetration of aminoglycosides into bronchial secretions;83, 120 therefore, combination therapy may be beneficial in treating Pseudomonas pneumonia. 18 However, in patients with cystic fibrosis, gentamicin, ticarcillin, and the combination of gentamicin-ticarcillin are equally effective in treating Pseudomonas pulmonary infections. 81 The combination of tobramycin-ticarcillin seems superior to gentamicin-carbenicillin in this situation. 82 Klebsiella Cephalosporin-aminglycoside combination therapy is frequently used for serious Klebsiella infections. 56· 60• 124 There are in vitro data demonstrating synergy with this combination;20· 47.58 however, this is not predictable. 20• 79 Moreover, in the rat peritonitis model, gentamicin as a single agent is extremely active. The addition of a cephalosporin to gentamicin does not improve outcome. 69 Clinical evidence favoring combination therapy is not clear. In patients with cancer, there is no beneficial effect of aminoglycoside-cephalosporin over other combinations in patients with Klebsiella infections.2 In another retrospective analysis the authors suggest that in patients with rapidly fatal disease there is improved outcome with combination therapy against Klebsiella, 126 although specific data substantiating this are not presented. Winston 119 studied amikacin, cefazolin, and amikacin-cefazolin therapy in the neutropenic peritonitis rat model. Although in vitro synergy was demonstrated, amikacin alone was as effective as the combination. Cefazolin alone was no better than control. In addition, combination aminoglycoside-cephalosporin therapy is probably more nephrotoxic than single agent or other combination therapy. 23 Therefqre, despite in vitro data, there is no proven clinical benefit of combination therapy, and there may be associated increased nephrotoxicity. The literature recommends cephalosporin-aminoglycoside therapy for Klebsiella pneumonia, but good clinical studies are lacking. Hemophilus Influenzae Ampicillin-chloramphenicol is frequently employed as initial therapy for meningitis and other serious infections caused by this organism. 25 The beneficial effect in this situation arises from avoiding inadequate therapy of a resistant organism, rather than taking advantage of in vitro synergy. In H. influenzae meningitis, however, the combination may be associated with a higher incidence of hearing impairment when compared with either antibiotic alone, 57 despite the bactericidal activity of chloramphenicol against H. influenzae. 86 Currently, therefore, avoiding the prolonged use
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127
of ampicillin-chloramphenicol combination therapy when treating H. influenzae meningitis by eliminating either antibiotic when sensitivities are known is advised. For H. injluenzae that produce beta-lactamase, there is in vitro and in vivo evidence for a beneficial effect of ampicillin-nafcillin combination therapy. 121 There is competitive inhibition of beta-lactamase by nafcillin, allowing ampicillin to retain its antibacterial effect. In addition, clavulanic acid, a beta-lactamase inhibitor, appears effective in combination with amoxicillin against ampicillin-resistant H. influenzae. type b in vitro and in the rat bacteremia and meningitis models.I22 Other Gram-Negative Bacilli There are no clinical studies demonstrating the efficacy of combination antibiotic therapy for other gram-negative infections. In vitro synergy has been demonstrated with a number of antibiotic combinations against a variety of gram-negative bacilli.I1· 26, 58• 78· ros The clinical relevance of these data is unclear. In a large retrospective study there was no beneficial effect of combination therapy over single-drug therapy for gram-negative bacteremia, irrespective of underlying disease. 51 With serious infection caused by these organisms, consideration may be given to using potentially synergistic combinations; however, in vitro synergy studies should be performed. Antagonism Potential antagonistic antibiotic combinations against gram-negative organisms include those in which a bacteriostatic drug is used with a bactericidal drug. 85 In vitro data demonstrating this phenomenon have been reported with chloramphenicol in combination with an aminoglycoside against Klebsiella20 and Proteus. 95 In the mouse peritonitis model, Jawetz demonstrated antagonism against Klebsiella using penicillin-chloramphenicol, but only with low-dose penicillin and in a single-dose regimen. 37 In a more recent study, Sande and Overton95 demonstrated in vivo antagonism only in neutropenic mice using chloramphenicol-gentamicin in single-dose and multiple-dose regimens. Clinically significant antagonism against gram-negative bacteria is infrequently documented. In a retrospective review, antagonistic antibiotic combinations were associated with a low success rate in the treatment of urinary tract infections. 66 Chloramphenicol-aminoglycoside combination therapy, however, has been used successfully in severe gram-negative infections.29 The nature of the host may be important for antagonism to become manifest, as in the neutropenic mouse with peritonitis. In addition, the site of infection could determine the significance of potentially antagonistic combinations. 94 In the rabbit meningitis model, the addition of chloramphenicol to an aminoglycoside worsened the outcome of Proteus meningitis, and this combination was found to be antagonistic in vitro.ros In a large retrospective review of Listeria and non-Herrwphilus gram-negative bacillary meningitis, the use of chloramphenicol alone and in combination with bactericidal antibiotics was associated with a poor outcome. 15 Therefore, in granulocytopenic patients or in the treatment of meningitis, antagonistic combinations should be avoided.
Table 1. ORGANISM
INFECTION
Summary of Combination Antimicrobial Therapy SYNERGISTIC COMBINATION
ANTAGONISTIC COMBINATION
COMMENT
Staph. aureus
endocarditis
nafcillin, oxacillin, methicillin or vancomycin + aminoglycoside
Synergistic combination for first 3-5 days only
Staph. epidermidis
endocarditis CSF shunt prosthetic joint
as above
Rifampin may increase serum and CSF bactericidal titer
Enterococcus
endocarditis bacteremia
penicillin, ampicillin or vancomycin+ aminoglycoside
Rifampin may increase bactericidal titer
Strep. pneumoniae Group B streptococci
meningitis
Other Streptococci
endocarditis
Listeria monocytogenes
pencillin + aminoglycoside
meningitis bacteremia carbenicillin or ticarcillin + aminoglycoside
Klebsiella pneumoniae
pneumonia
cephalosporin + aminoglycoside 1
Other gram-negative bacilli
bacteremia meningitis endocarditis
2 weeks of aminoglycoside in addition to penicillin may be beneficial
0
> <
8
penicillins + chloramphenicol
bacteremia of unknown source; pneumonia
meningitis
00
penicillins + chloramphenicol or tetracycline
Pseudomonas aeruginosa
H. injluenzae
......
1::0
~ [JJ
:I: t"
chloramphenicol+ aminoglycosidez
ampicillin+ chloramphenicol
chloramphenicol and aminoglycoside
(l) Based upon in vitro data. No supportive clinical data. (2) Avoid antagonistic combination in meningitis. No evidence for in vitro antagonism. Increased hearing impairment when combination used.
~
"' > z tl
...,
[JJ
t'1
<
t'1
z
z
to
>
"'"'
COMBINATION ANTIMICROBIAL THERAPY
129
Aminoglycoside inactivation by beta-lactam antibiotics (carbenicillin, ticarcillin) has been reported. 34• 68 · 90 This appears to occur when the two antibiotics are mixed in the same intravenous bottle but not shown to occur in vivo except in patients with severe renal failure on hemodialysis. 90 The clinical significance of this interaction is unclear. This in vitro phenomenon should not deter the use of this valuable antibiotic combination, although care should be taken to administer these agents separately.
SUMMARY In spite of a large volume of data regarding the in vitro activity of single and combined antimicrobial activity, the clinical relevance of these studies is unclear. Few comparative trials of combined and single antibiotic therapy of human infection have been performed. Synergistic combination therapy has been shown to be beneficial in a few specific circumstances. Antagonistic combinations should be avoided in the treatment of meningitis, endocarditis, and infections of immunocompromised patients. The bactericidal titer of serum or spinal fluid should reflect adequacy of therapy of meningitis, endocarditis, and osteomyelitis, and adjustments can be made accordingly.
Acknowledgments We are grateful to Miss Ruth Kirk for excellent secretarial assistance.
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