Synergistic Antibiotic Combinations Research Articles

Comparison of ampicillin-sulbactam with vancomycin for treatment of experimental endocarditis due to a beta-lactamase-producing, highly gentamicin-resistant isolate of Enterococcus faecalis

Increasing antibiotic resistance in the enterococci, including the capacity for beta-lactamase production and the development of high-level aminoglycoside resistance, has complicated the treatment of serious enterococcal infections, which often require synergistic antibiotic combinations for cure. We utilized the rabbit model of aortic valve endocarditis to investigate the effects of various antibiotics, alone and in combination, against a multiply antibiotic-resistant isolate of Enterococcus faecalis. Female New Zealand White rabbits were infected with either a beta-lactamase-producing, gentamicin-resistant isolate of E. faecalis or a non-beta-lactamase-producing, aminoglycoside-susceptible isolate, and the mean log10 CFU per gram of vegetation were determined. The most active agents were low-dose ampicillin-sulbactam (200 mg/kg of body weight per day), high-dose ampicillin-sulbactam (400 mg/kg of body weight per day), and vancomycin (150 mg/kg of body weight per day), which reduced the titers of bacteria by 2.27, 2.76, and 2.85 log10 (CFU/g, respectively, compared with controls. While ampicillin-sulbactam and vancomycin were equally efficacious in reducing titers of bacteria in vegetations, no animals were cured (defined as < 2 log10 CFU/g of vegetation) by either agent, whether treatment was continued for 3 or 7 days. The addition of gentamicin was not associated with increased killing in rabbits infected with the aminoglycoside-resistant isolate. Both high-dose ampicillin-sulbactam and vancomycin regimens demonstrated significant, continued reduction in bacterial titers with the longer periods of treatment (P < or = 0.05); 7-day treatment with high-dose ampicillin-sulbactam produced a greater reduction in bacterial titers in vegetation than 7-day treatment with vancomycin (P < or = 0.05). We conclude that ampicillin-sulbactam and vancomycin are equally effective in the treatment of experimental endocarditis due to beta-lactamase-producing, highly gentamicin-resistant E. faecalis. The optimum therapy for such infections in humans is not known.

Combination therapy and monotherapy in the treatment of severe infection in the immunocompromised host

Profoundly granulocytopenic patients in whom fever develops are likely to have gram-negative septicemia, which may rapidly be fatal. These patients require early empiric therapy with a synergistic bactericidal combination of antibiotics that should be chosen on the basis of in vitro studies, animal models, and results of volunteer and clinical trials. From in vitro studies, it is apparent that the degree of synergy between an aminoglycoside and a beta-lactam is determined mainly by the aminoglycoside. Amikacin is the most synergistic of the aminoglycosides. A combination of an aminoglycoside such as amikacin plus a beta-lactam active against Pseudomonas is probably still the best empiric therapy available. The newer compounds and beta-lactam combinations still have to be proven effective in the clinical setting of the persistently and profoundly granulocytopenic patient with fever and bacteremia.

Pulmonary Aspergillosis in Immunosuppressed Patients with Haematological Malignancies

Invasive pulmonary aspergillosis as a cause of mortality and morbidity in patients with haematological malignancies is becoming more common. Predisposing factors are powerful immunosuppressive chemotherapy, neutropenia and synergistic combinations of antibiotics of great potency and wide spectrum of activity. Clinical and radiological signs are heterogeneous, sometimes misleading and often absent. Treatment is often empirical on suspicion alone. Amphotericin B is the only effective drug but it has marked toxicity, mainly renal. Infection is usually fatal without adequate treatment. This paper describes eight cases of invasive pulmonary aspergillosis seen in one centre in two years, reviews the literature and assesses associated problems.

The pain of osteoarthritis

To determine whether antimicrobial synergism affects the outcome of gram-negative bacteremia among profoundly (less than 100/microliter) neutropenic cancer patients, the clinical courses of 75 such patients who received empiric therapy with combination, broad-spectrum antibiotics were analyzed. Twenty-nine of 34 (85 percent) patients whose granulocyte count increased to more than 100/microliter during therapy improved, whereas only 12 of 41 (29 percent) patients with no increase in granulocyte count showed improvement (p = 0.0002). The critical group for further analysis was, therefore, those patients with persistent, profound granulocytopenia. Among these 41 patients, synergism was associated with a substantially better response rate: eight of 18 (44 percent) improved compared with none of 13 in whom synergism was not detected (p = 0.005); presence or absence of synergism could not be assessed for the pathogens isolated from the remaining 10 patients because the organisms were exquisitely susceptible to one of the two antibiotics used. Further evaluation of these persistently neutropenic patients indicated that synergism appeared critical even when the pathogen was susceptible to both antibiotics. Thus, seven of 11 (64 percent) showed response when the two drugs were synergistic in activity, compared with none of six when synergism was not present (p = 0.01). These data again demonstrate the importance of granulocyte recovery to patient response and further indicate that synergistic combinations of antibiotics are indicated for cancer patients with gram-negative bacteremia and persistent, profound granulocytopenia.

Potential of imipenem as single-agent empiric antibiotic therapy of febrile neutropenic patients with cancer

Infection remains a major cause of morbidity and mortality for the patient with cancer who experiences episodes of severe granulocytopenia. The search continues for new antimicrobial agents with improved efficacy and lower incidence of toxicity. Imipenem is a new carbapenem antibiotic which possesses a broad antibacterial spectrum with excellent activity against Pseudomonas aeruginosa and the other commonly recovered enteric gram-negative bacilli that infect the granulocytopenic patient with cancer. The combination of imipenem plus an aminoglycoside has shown in vitro synergy against P. aeruginosa and Staphylococcus aureus whereas the combination of imipenem plus piperacillin or the extended spectrum cephalosporins have frequently shown antagonism when tested against P. aeruginosa and Serratia marcescens. The use of a P. aeruginosa-infected neutropenic rat model has provided an in vivo system to evaluate the activity of new antibiotics or antibiotic combinations. Monotherapy with imipenem is as effective in this model as any of the currently available synergistic antibiotic combinations. This degree of activity has not been found with other broad-spectrum antibiotics when used alone. Imipenem provides serum bactericidal activity well above a 1:8 dilution for the four most commonly isolated pathogens: P. aeruginosa, Escherichia coli, Klebsiella species, and S. aureus. In addition, imipenem's post-antibiotic effect against P. aeruginosa may be pertinent. Imipenem is a unique antibiotic, with properties that make it well suited for study as monotherapy for fever and suspected infection in granulocytopenic patients with cancer. A prospective randomized, double-blind study comparing imipenem with a control regimen of piperacillin plus amikacin as empiric antibiotic therapy of febrile granulocytopenic patients with cancer is currently underway at the University of Maryland Cancer Center.

The effect of antibiotic treatment on the in vivo selection of resistant haemolytic Escherichia coli clones in mice

The appearance of resistant haemolytic Escherichia coli clones was studied in mice treated with a synergistic combination of antibiotics. The R plasmid donor and the haemolytic recipient were given orally. Ten animals were treated i.p. with 2.5 mg carbenicillin and 2.5 mg kanamycin pro die for 7 days. Ten control mice were injected with saline. Out of 80 faecal samples of animals receiving antibiotic treatment resistant haemolytic transconjugants were isolated from 13 samples by direct plating, and from 27 samples after selective enrichment. Out of 80 parallel samples of control animals a single one yielded a positive culture — after enrichment.

The effect of antibiotic treatment on the in vivo selection of resistant haemolyticEscherichia coliclones in mice

The appearance of resistant haemolytic Escherichia coli clones was studied in mice treated with a synergistic combination of antibiotics. The R plasmid donor and the haemolytic recipient were given orally. Ten animals were treated i.p. with 2.5 mg carbenicillin and 2.5 mg kanamycin pro die for 7 days. Ten control mice were injected with saline. Out of 80 faecal samples of animals receiving antibiotic treatment resistant haemolytic transconjugants were isolated from 13 samples by direct plating, and from 27 samples after selective enrichment. Out of 80 parallel samples of control animals a single one yielded a positive culture — after enrichment.

Pseudomonas aeruginosa septicemia in childhood cancer patients.

Twenty-three pediatric cancer patients developed Pseudomonas aeruginosa septicemia during an 11-year period. Typically the patients had advanced neoplasia and were receiving immunosuppressive therapy. Severe myelosuppression was almost always present and antibiotic therapy during the prior 2-week period for proven or suspected sepsis was common. Disruption of the skin and mucosa in the anogenital regions was evident in the majority of patients, and the gastrointestinal tract represented the most common portal of entry. Patients who developed sepsis while relapsed had the highest case-fatality rate, and use of synergistic antibiotic combinations did not affect outcome in this group.

Penetration of the outer membrane of Pseudomonas aeruginosa by synergistic combinations of beta-lactam and aminoglycoside antibiotics.

The mechanism of the synergistic action of carbenicillin-gentamicin and moxalactam-tobramycin combinations against Pseudomonas aeruginosa ATCC 9027 was investigated. Disruption of the outer membrane penetration barrier by EDTA treatment enhanced the activity of both combinations against the cells during growth for 100 min in exponential phase. However, there was no loss of the synergistic activity of the antibiotics as a result of this treatment. A procedure involving minimal inhibitory concentration testing in the presence of rifampin did not detect any destabilization of the outer membrane barrier by any of the four drugs over an 18-h period. The combined evidence indicates that beta-lactamaminoglycoside synergy is not mediated by the outer membrane of this organism.

Synergistic combinations of antibiotics in gram-negative bacillary infections.

In vitro synergy (or at least an additive effect between antibiotics in vitro) is likely to have clinical significance. Data in the literature strongly suggest that, in patients who lack the natural mechanisms of defense against infection, better clinical results can be achieved by treatment with two drugs to which the pathogenic organism is sensitive rather than only one. Moreover, there is some evidence that the use of antibiotic combinations found to be synergistic in vitro is associated with a better clinical outcome in patients with decreased mechanisms of defense against infection, especially neutropenia. The use of synergistic drug combinations should be continued as empirical therapy in severely neutropenic or otherwise compromised patients, especially in those with malignant tumors.

Morphological expressions of antibiotic synergism against Pseudomonas aeruginosa as observed by scanning electron microscopy.

Antibiotic-induced changes in Pseudomonas aeruginosa were observed by means of a scanning electron microscope. Seven frequent and five less frequent morphological changes were noted. The frequent changes were: (i) elongation; (ii) chain formation; (iii) nub formation; (iv) spheroplasts; (v) surface holes or pits; (vi) super-elongation; and (vii) increased filamentation. The less frequent changes were: (i) rounded ends; (ii) streptococcal forms; (ii) stalked nubs; (iv) surface bulges; and (v) convoluted surfaces. A morphological equivalent of antibiotic synergism was found in which changes were noted due to synergistic combinations of antibiotics that were not observed when the antibiotics were used alone or when a nonsynergistic combination of antibiotics was used.

Combinations of antibiotics for therapy of severe infections in cancer patients

When severe sepsis is suspected, initial therapy should provide adequate coverage against all the likely pathogens. In neutropenic patients, infections caused by gram-negative bacilli are common; however, gram-positive infections occur as well, and usually they cannot be distinguished from the former on clinical grounds alone. Early antimicrobial therapy with a potentially synergistic combination of antibiotics should be instituted in an empiric manner in febrile, granulocytopenic patients. In most instances, carbenicillin plus gentamicin will prove to be effective. Therapy should be discontinued after four days in patients in whom no infection can be documented microbiologically or clinically. In the other patients without microbiologically proven infection who respond to antimicrobial therapy although remaining neutropenic, antibiotics should be continued for at least seven to ten days. In those patients who do not respond to antimicrobial agents, early empiric therapy with amphotericin B and granulocyte transfusions should be considered especially if the bone marrow depression is profound and if several courses of antimicrobial agents have been given recently. © 1980 MMW Medizin Verlag.

Serratia endocarditis. A follow-up report

Seventeen new cases of Serratia marcescens endocarditis observed in the San Francisco Bay Area since June 1974 are presented. Fifteen patients had a history of illicit intravenous drug use and four patients had prosthetic heart valves. Seven patients with infection of right-sided heart valves did well, although surgery was required in two for persistent fever or recurrent pulmonary emboli. Only three of ten patients with left-sided infection survived despite synergistic antibiotic combinations and high serum bactericidal titers. Fifteen isolates of Serratia from patients with endocarditis were serotyped, and none of these serotypes corresponded to the pigmented strain aerosolized by the US Army in the Bay Area in 1951. The isolation of the same Serratia strain from two patients and their shared injection paraphernalia provided insight into the pathogenesis of endocarditis in the intravenous drug user. A revised therapeutic approach to this difficult infection is presented.

The Effects and Significance of Subminimal Inhibitory Concentrations of Antibiotics*

Subminimal inhibitory concentrations of antibiotics cause structural alterations in gram-positive and gram-negative bacteria and, in certain instances, reduce growth of bacteria, enhance phagocytosis, increase the bactericidal activity of human serum, and induce production of beta-lactamase from gram-negative bacilli. Extrapolation of these in vitro effects to infection in humans is difficult but appears to be most appropriate in patients who receive synergistic combinations of antibiotics.

Synergism of Ampicillin and Gentamicin against Obstructive Pyelonephritis Due to Escherichia coli in Rats

Rats with obstructive pyelonephritis due to Escherichia coli were treated for different intervals with ampicillin and gentamicin either alone or in combination. The combination of ampicillin and gentamicin was synergistic in vitro and significantly more effective in vivo than was either drug alone. After treatment for 10 days, the combination of ampicillin and gentamicin was the only regimen that sterilized all of the pyelonephritic kidneys. The importance of achieving sterility was illustrated by the observation that severe infection and acute pyelonephritis recurred after religation of the ureter in 12 (71%) of 17 ampicillin-treated animals that had harbored as few as 46 organisms per kidney before ligation. A synergistic combination of antibiotics rapidly sterilizes obstructed pyelonephritic kidneys. In view of the particular risk of renal infection in the presence of urinary obstruction in humans, synergistic antibiotic combinations may be useful in the treatment of obstructive pyelonephritis in humans.

Pseudomonas maltophilia Causing Heroin-Associated Infective Endocarditis

The association of Pseudomonas maltophilia endocarditis in three patients with recent history of intravenous drug abuse is reported. All three patients had abnormal heart valves (two prosthetic and one rheumatic). A prominent characteristic of this uncommon pathogen is its in vitro resistance to the commonly used antimicrobials. Cure was achieved in all three cases. In two cases, synergistic antibiotic combinations were used. In one case, plasmid-mediated resistance to amikacin sulfate (Amikan, British; no comparable US product) emerged during therapy. The two patients with prosthetic valves received combined surgical and antibiotic therapy.

Significance of antimicrobial synergism for the outcome of gram negative sepsis

Amikacin plus penicillin (A+P) was compared to amikacin plus carbenicillin (A+C) in a double-blind study. Therapy with one of these combinations was given, as soon as servere infection was suspected, to 117 patients with proved gram negative infection, none of whom was granulocytopenic. Gram negative bacteremia was documented retrospectively in 52 patients; 25 had received A+P and 27 had been treated with A+C. All the isolated gram negative pathogens were sensitive to amikacin (MIC less than 12 microng/ml). In the A+P group, 55 per cent of the patients responded favorably while in the A+C group 63 per cent did respond; the difference was more striking for bacteremic patients: 52 per cent responded in the A+P group and 70 per cent in the A+C group. This difference, however, was not statistically significant. The outcome of patients whose infection was treated by synergistic combinations against the offending pathogen was better (66 per cent) than that observed in patients who received nonsynergistic combinations (48 per cent) (p less than 0.05). Once again the results were more striking in the bacteremic patients (p less than 0.01). A favorable outcome was associated also with a high (larger than or equal to 1/8) bactericidal activity of the diluted serum of the treated patient against the offending pathogen (p less than 0.05). This study suggests that the optimal therapy in gram negative septicemia might be the administration of synergistic combinations of antibiotics.

6 - The Use of Synergistic Combinations of Antibiotics in Patients with Haematological Diseases

6 - The Use of Synergistic Combinations of Antibiotics in Patients with Haematological Diseases

Antimicrobial therapy of experimental enterococcal endocarditis.

The successful therapy of enterococcal endocarditis requires prolonged administration of synergistic antibiotic combinations. Controversy has arisen regarding optimal therapy (i) when the organism possesses high-level streptomycin resistance, and (ii) when the patient is allergic to penicillin. This study examines these questions in vitro and in a rabbit model of enterococcal endocarditis. The combination of penicillin with either streptomycin or gentamicin increased the rate of bacterial killing in vitro and in vivo when compared with penicillin alone (P < 0.05) when the test strain was relatively susceptible to streptomycin (minimal inhibitory concentration, 128 mug/ml). Only the combination of penicillin and gentamicin was consistently more effective than penicillin alone (P < 0.01) when the test strain was highly resistant to streptomycin (minimal inhibitory concentration > 150,000 mug/ml). The combination of vancomycin and streptomycin was more rapidly bactericidal than vancomycin alone in vitro and in the animal model against the streptomycin-susceptible strain (P < 0.01). The relative rate of in vitro bacterial killing by various antibiotics and combinations was predictive of the efficacy of these drugs in eradicating enterococci from cardiac vegetation in experimental endocarditis.

Synergistic effect of combinations of cephalothin and kanamycin on strains of E. coli.

TREATMENT of urinary infections caused by Gram negative bacteria is often very difficult. It is frequently necessary to administer antibiotics in large doses, which presents a hazard to patients with impaired renal function. In many cases relapses occur as a result of bacterial resistance1. This study was undertaken to establish in vitro a synergistic combination of antibiotics against several strains of E. coli isolated from urinary infections.