Antagonism between Bacteriostatic and Bactericidal Antibiotics Is Prevalent

Combination therapy is rarely used to counter the evolution of resistance in bacterial infections. Expansion of the use of combination therapy requires knowledge of how drugs interact at inhibitory concentrations. More than 50 years ago, it was noted that, if bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Our goal here was to investigate this hypothesis systematically. We first constructed time-kill curves using five different antibiotics at clinically relevant concentrations, and we observed antagonism between bactericidal and bacteriostatic drugs. We extended our investigation by performing a screen of pairwise combinations of 21 different antibiotics at subinhibitory concentrations, and we found that strong antagonistic interactions were enriched significantly among combinations of bacteriostatic and bactericidal drugs. Finally, since our hypothesis relies on phenotypic effects produced by different drug classes, we recreated these experiments in a microfluidic device and performed time-lapse microscopy to directly observe and quantify the growth and division of individual cells with controlled antibiotic concentrations. While our single-cell observations supported the antagonism between bacteriostatic and bactericidal drugs, they revealed an unexpected variety of cellular responses to antagonistic drug combinations, suggesting that multiple mechanisms underlie the interactions.     

Assessment of timed bacteriostatic and bactericidal activities of cephalothin against gram-positive and gram-negative bacteria

The comparative bacteriostatic and bactericidal activities of cephalothin were assessed in broth medium with special reference to the period of exposure of microbes to the drug. The bacteriostatic concentration with a brief period of exposure (6 h) was lower than the conventional MIC for Escherichia coli and Klebsiella sp. When the period of exposure was prolonged (18-42 h), the bacteriostatic concentration almost corresponded with the MIC. In contrast to these gram-negatives, the bacteriostatic concentration with a brief period of exposure roughly corresponded with the MIC for strains of Staphylococcus aureus and was higher for enterococcus. When a comparison of the bacteriostatic and the bactericidal concentrations was used as the criterion for assessment, the mode of action of cephalothin appeared to be bactericidal to most of the gram-negatives. This drug was bacteriostatic to a number of strains of gram-positives, in particular to enterococcus, especially when microbes were exposed to the drug over a brief period of time.     

Treatment of pneumonia: new strategies for changing pathogens.

Changes in the etiologic agents that cause pneumonia pose new challenges for empiric antimicrobial therapy. Ofloxacin is a new oral quinolone antibiotic with good to excellent activity against many of the usual and atypical pulmonary pathogens. Clinical trials have demonstrated high clinical and microbiological cure rates with ofloxacin and comparable efficacy to standard antibiotics used to treat pneumonia. Compared with ciprofloxacin, ofloxacin provides greater bioavailability, extended inhibitory concentrations in the blood, similar activity against gram-negative pathogens, better activity against gram-positive bacteria, in vitro activity against atypical pathogens, renal elimination, and a lower potential for interactions with theophylline and caffeine. These advantages suggest that ofloxacin should be the first-choice quinolone when Staphylococcus aureus is suspected, when higher and prolonged serum and tissue concentrations are needed, and when the patient is also receiving theophylline. In addition, the substitution of a potent oral antibiotic such as ofloxacin for intravenous agents may enable some hospital patients to continue their therapy as outpatients, thus reducing health-care costs.     

Bacteriostatic and bactericidal activities of beta-lactam antibiotics enhanced by the addition of low concentrations of gentamicin

The combined effects of low concentrations of gentamicin on certain beta-lactam antibiotics were studied by the agar plate method. the combination of gentamicin with cephalothin produced synergism against 17 of 26 strains of Escherichia coli and 19 of 27 strains of Klebsiella sp. if assessed at the bacteriostatic (minimal inhibitory concentration) level. Synergy against many more strains was apparent when bactericidal concentrations were used. Synergy against most of these strains was observed if bactericidal concentrations with brief exposure times (3 h) to the antibiotics were used for measurement. Additive effects were observed in almost all of the remaining strains. The combination of gentamicin and carbenicillin were synergistic against most strains of Pseudomonas aeruginosa when any bacteriostatic or bactericidal measurement was used as the criterion.     

Bactericidal Effect of Combinations of Antimicrobial Drugs and Antineoplastic Antibiotics Against Staphylococcus aureus

Six antineoplastic antibiotics were tested against ten strains of Staphylococcus aureus. Four showed bacteriostatic and/or bactericidal activity against each of the ten strains, and two were only bacteriostatic for seven and nine strains, respectively. Using the cellophane transfer technique, combinations of these antineoplastic antibiotics with 16 antibacterial drugs were screened for combined bactericidal activity. Synergism or antagonism was demonstrated in about one-third of the combinations. Checkerboard titrations and killing curves confirmed these findings and indicated that the effective concentrations of the antibacterial agents were similar to those attainable in the serum after therapeutic doses of these drugs. Although the pharmacokinetics of the six antineoplastic antibiotics in humans are not fully known, at least one of them has a peak serum level corresponding to those values at which a bactericidal effect was produced in vitro.     

Studies of the killing kinetics of benzylpenicillin, cefuroxime, azithromycin, and sparfloxacin on bacteria in the postantibiotic phase.

Most antibiotics are known to be incapable of killing nongrowing or slowly growing bacteria with few exceptions. Bacterial cell division is inhibited during the postantibiotic phase (PA phase) after short exposure to antibiotics. Only scarce and conflicting data are available concerning the ability of antibiotics to kill bacteria in the PA phase. The aim of the present study was to investigate the killing effect of four different antibiotics on bacteria in the PA phase. A postantibiotic effect (PAE) was induced by exposing Streptococcus pyogenes and Haemophilus influenzae to 10x MICs of benzylpenicillin, cefuroxime, sparfloxacin, and azithromycin. The bacteria were thereafter reexposed to a 10x MIC of the same antibiotic used for the induction of the PAE at the beginning of and after 2 and 4 h in the PA phase. Due to a very long PAE, the bacteria in PA phase induced by azithromycin were also exposed to 10x MICs after 6 and 8 h. A previously unexposed culture exposed to a 10x MIC was used as a control. The results seem to be dependent on both the antibiotic used and the bacterial species. The antibiotics exhibiting a fork bactericidal action gave significantly reduced killing of the bacteria in PA phase (cefuroxime with S. pyogenes, P < 0.01, and sparfloxacin with H. influenzae, P < 0.001), which was restored at 4 h for cefuroxime with S. pyogenes. There was a tendency to restoration of the bactericidal activity also with sparfloxacin and H. influenzae, but there was still a significant difference in killing between the control and the test bacteria in PA phase at 4 h. However, in the combinations with a lesser bactericidal effect (benzylpenicillin with S. pyogenes and sparfloxacin with S. pyogenes), there was no difference in killing between the control and the test bacteria in PA phase. Azithromycin induced long PAEs in both S. pyogenes and H. influenzae and exhibited a slower bactericidal action on both the control and the bacteria in PA phase especially at the end of the PAE, when the killing was almost bacteriostatic. Our findings in this study support the concept that a long interval (> 12 h) between doses of azithromycin, restoring full bactericidal action, may be beneficial to optimize efficacy of this drug but is not necessary for the other antibiotics evaluated, since the bactericidal effect seems to be restored already at 4 h.     

Variation in the Susceptibility of Strains of Staphylococcus aureus to Oxacillin, Cephalothin, and Gentamicin

Three cases of staphylococcal bacteremia caused by organisms that were inhibited by low concentrations of oxacillin, but were resistant to the killing effects of oxacillin, stimulated us to screen 60 clinical isolates of Staphylococcus aureus for their susceptibility to oxacillin, cephalothin, and gentamicin. All 60 strains were inhibited by low concentrations of the antibiotics. The antibiotics were bactericidal against 27 of the 60 strains and only bacteriostatic against the other 33 after 24 h of incubation. However, after 48 h of incubation, the antibiotics were also bactericidal against the latter group.     

Activities of oral and parenteral agents against penicillin-susceptible and -resistant pneumococci.

This study examined bacteriostatic and bactericidal activities of oral and parenteral antibiotics for penicillin-susceptible and intermediately and fully penicillin-resistant pneumococci. beta-Lactamase inhibitors did not affect beta-lactam results. The activities of ampicillin, amoxicillin +/- clavulanate, WY-49605, cefuroxime, cefpodoxime, cefdinir, cefixime, and cefaclor against two penicillin-susceptible, two intermediately penicillin-resistant, and two fully penicillin-resistant pneumococcal strains were tested. For all three groups, bacteriostatic values of amoxicillin and WY-49605 were lower than were those of other beta-lactams tested. Of the cephalosporins, cefdinir, cefuroxime, and cefpodoxime yielded the lowest bacteriostatic values. All beta-lactams were bactericidal (reduced original counts by > or = 3 log10 CFU/ml) at 1 dilution above bacteriostatic values, except for cefpodoxime (bactericidal at 2 dilutions above bacteriostatic values for one susceptible strain and one intermediately resistant strain), cefuroxime (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain), and ampicillin (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain). The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftriaxone, ceftazidime, and ciprofloxacin against four penicillin-susceptible, two intermediately penicillin-resistant, and four fully penicillin-resistant pneumococcal strains were evaluated. Bacteriostatic values of piperacillin, ampicillin, and ceftriaxone for all groups were lower than were those of ticarcillin and ceftazidime. Bacteriostatic values of ciprofloxacin were unaffected by penicillin susceptibility. All beta-lactams were bactericidal at 1 dilution above the bacteriostatic value, except for piperacillin (bactericidal at 2 dilutions above the bacteriostatic value for one intermediately resistant strain), ticarcillin (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain and one resistant strain), ampicillin (bactericidal at 2 dilutions above the bacteriostatic value for two resistant strains), ceftriaxone (bactericidal at 2 dilutions above the bacteriostatic value for one resistant strain), and ceftazidime (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain).     

Phosphonopeptides as Antibacterial Agents: Alaphosphin and Related Phosphonopeptides

Alaphosphin, l-alanyl-l-1-aminoethylphosphonic acid, was selected from a range of phosphonopeptides for evaluation in humans on the basis of its antibacterial activity, pharmacokinetics, and stability to intestinal and kidney peptidases. In vitro, the antibacterial action was antagonized by small peptides, resulting in low activity on peptone media. On an antagonist-free medium alaphosphin was bactericidal and rapidly lysed most susceptible gram-negative bacteria, but it was largely bacteriostatic and essentially nonlytic against gram-positive organisms. Its spectrum included most strains normally isolated from urinary tract infections, but potency was greatly reduced by very high inoculum levels and by alkaline pH. Although strains of Proteus and Pseudomonas were less susceptible to alaphosphin than were other common gram-negative bacteria, like other species they formed spheroplasts when exposed under appropriate conditions. Alaphosphin was equally effective against penicillin-susceptible and -resistant strains and showed no cross-resistance with known antibiotics. Good synergy and increased bactericidal activity were demonstrated with combinations of alaphosphin and d-cycloserine or beta-lactam antibiotics.     

Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination.

The in vivo efficacy of daptomycin, a new cell wall-active anti-gram-positive-bacterial agent, was compared to those of cloxacillin and vancomycin in a rat model of Staphylococcus aureus endocarditis. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains were used. When therapy was initiated early (8 h) after infection, at the time when valvular bacterial counts were relatively low (approximately 10(6) CFU/g of vegetation), 3 days of therapy was found to be effective against the MSSA strains whatever the antibiotic regimen. In contrast, when the onset of therapy was delayed up to 15 h after infection, so that higher bacterial counts could develop on the valves (approximately 10(9) CFU/g of vegetation), a longer period of treatment (6 days) was required to cure infection. Under these conditions after 3 days of therapy, daptomycin was more effective than cloxacillin and vancomycin against the MSSA strains. Similarly, daptomycin showed a greater activity than vancomycin against the MRSA strain after 3 days of treatment, but after 6 days both antibiotics were equally effective. Decreasing doses of daptomycin showed decreasing activity: 10 mg/kg of body weight every 12 h (q12h) was better than 5 mg/kg q12h, whereas 5 mg/kg q24h (providing drug levels in blood detectable only during the first 12 h) failed to cure infection. In vitro, daptomycin was highly bactericidal at high concentrations (25 and 60 micrograms/ml, corresponding to peak levels in serum after doses of 5 and 10 mg/kg, respectively) and bacteriostatic at lower concentrations (0.5 to 2.5 micrograms/ml, corresponding to trough levels in serum). In conclusion, against low-bacterial-count S. aureus endocarditis, daptomycin showed an efficacy similar to those of vancomycin and cloxacillin. Against high-bacterial-count S. aureus endocarditis, daptomycin showed a higher bactericidal activity than cloxacillin (against the MSSA strains) and vancomycin (against both the MSSA and MRSA strains).     

Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia

BACKGROUND: The value of elevated serum procalcitonin concentration for differentiating between typical and atypical community-acquired pneumonia was assessed and compared with other parameters that are usually used in clinical practice. PATIENTS AND METHODS: Thirty consecutive adult patients with community-acquired bacterial pneumonia admitted to the Department of Infectious Diseases, University Medical Center Ljubljana, Slovenia, were included in this prospective study. Only those patients for whom the etiology of bacterial pneumonia was confirmed participated in the study. RESULTS: The median serum procalcitonin level in patients with typical pneumonia was 7.64 ng/ml (range 0.26-63.16) and in the group with atypical pneumonia 0.80 ng/ml (range 0.13-34.90). A significant difference between the typical and atypical pneumonia groups was found only for the procalcitonin serum concentration on admission. The standard laboratory markers of bacterial infections, such as C-reactive protein, total leukocyte count and immature polymorphonuclear cells, did not discriminate between typical and atypical etiology. Median procalcitonin levels were significantly higher among patients with bacteremic pneumonia. CONCLUSIONS: Determination of the procalcitonin level may provide useful additional diagnostic information on the etiology of pneumonia and could have a crucial influence on the initial antimicrobial therapy.     

A CASE OF RELAPSING PSITTACOSIS ASSOCIATED WITH A STROKE

Psittacosis, caused by Chlamydia psittaci, is mainly associated with an atypical pneumonia. We report a case of psittacosis where onset of respiratory symptoms was soon followed by the onset of focal neurological signs, a very uncommon feature. Despite adequate treatment with erythromycin, the patient relapsed when re-exposed to a sick pet bird. A prolonged course of doxycycline led to resolution of the pneumonia, but it is important to recall that successful management must also include the elimination of the precipitating cause of the infection.     

传染性非典型肺炎--附首例报告

目的：报道广州呼吸疾病研究所处理首例传染性非典型肺炎的临床诊断和治疗经验。方法：回顾性分析该例的临床资料及治疗经过。结果：该病人有2个多月呼吸道疾病失，病情突然加剧，表现为间质性肺炎及急性呼吸窘迫综合征，白细胞计数基本正常，但淋巴细胞比例偏低，经多种抗生素治疗无明显疗效。使用肾上腺皮质激素及机械通气等对症治疗78日痊愈出院。8位医护人员被感染。结论：该例为传染性非典型肺炎，起病突然及病情发展凶险，可能为一种新病原体感染，值得引起重视。     

Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone.

We evaluated the in vitro interaction at clinically attainable concentrations of cefotaxime and ceftriaxone with chloramphenicol against 26 clinical isolates of gram-negative rods, group B streptococci, and Staphylococcus aureus. Cefotaxime and ceftriaxone were bactericidal against all 26 organisms (MBC, 0.03 to 4 micrograms/ml). Chloramphenicol was bacteriostatic against 24 organisms (MBC, greater than or equal to 32 micrograms/ml) and bactericidal against two Escherichia coli isolates (MBC, 8 micrograms/ml). Checkerboard testing showed chloramphenicol to be antagonistic to the bactericidal activity of cefotaxime and ceftriaxone for all 24 bacteria for which chloramphenicol was bacteriostatic. Time kill curves for selected strains of E. coli and group B streptococci for which chloramphenicol was bacteriostatic showed antagonism of chloramphenicol to both cephalosporins. The combination of chloramphenicol with either cephalosporin was antagonistic in cases in which chloramphenicol was bacteriostatic against the above organisms and should be avoided in the treatment of infections caused by such organisms if bactericidal therapy is desired.     

β内酰胺类抗生素联用阿米卡星治疗医院获得性肺炎的疗效观察

目的探讨β内酰胺类抗生素联合阿米卡星治疗医院获得性肺炎患者的临床疗效。方法将43例医院获得性肺炎患者分为治疗组（22例）和对照组（21例）。治疗组患者给予β内酰胺类抗生素联合阿米卡星注射液抗感染，对照组患者单用β内酰胺类抗生素抗感染治疗。比较两组患者的治疗效果、住院时间及不良反应。结果两组患者治疗效果的比较差异无统计学意义（P〉0．05）。治疗组患者住院时间较对照组明显缩短（P〈0．05）。除治疗组中有1例患者发生药物过敏，其余患者均未发生不良反应。结论β内酰胺类抗生素联合阿米卡星注射液治疗医院获得性肺炎虽然不能提高药物疗效，但可明显缩短患者住院时间。     

Antagonistic effect of penicillin-amikacin combinations against enterococci.

Amikacin has been shown to antagonize the bactericidal effect of penicillin against strains of Streptococcus faecalis which produce aminoglycoside 3'-phosphotransferase. The mechanism by which this phenomenon occurs was studied with an enzyme-producing strain (8436) and an enzyme-negative strain (8436c) derived by curing the former with novobiocin. Combinations of amikacin with beta-lactam antibiotics were antagonistic against strain 8436 but synergistic against strain 8436c. Against strain 8436 penicillin-amikacin combinations resulted in levels of killing comparable to those seen with high concentrations of penicillin (500 micrograms/ml), which were less bactericidal than lower concentrations of penicillin. No antagonism was observed between amikacin and non-beta-lactam cell wall-active drugs or between penicillin and kanamycin or neomycin, both of which are substrates for the enzyme. At concentrations near the MIC, amikacin was bactericidal against strain 8436c but bacteriostatic against strain 8436 (MIC, 250 micrograms/ml; MBC, 2,000 micrograms/ml). Neither penicillin nor phosphorylated amikacin affected the inhibition of ribosomal protein synthesis by amikacin in a cell-free system. Although antagonism of killing by amikacin in enzyme-positive strains was specific for combinations which included beta-lactam antibiotics, amikacin did not influence the binding of [3H]penicillin to penicillin-binding proteins in isolated bacterial cell membranes or in intact cells and did not detectably affect the autolytic system of cells exposed to penicillin. Antagonism of beta-lactam activity by a bacteriostatic effect of amikacin against the enzyme-producing strain is the most likely explanation for this phenomenon.     

Comparative intracellular (THP-1 macrophage) and extracellular activities of beta-lactams,azithromycin, gentamicin,and fluoroquinolones against Listeria monocytogenes at clinically relevant concentrations

The activities of ampicillin, meropenem, azithromycin, gentamicin, ciprofloxacin, and moxifloxacin against intracellular hemolysin-positive Listeria monocytogenes were measured in human THP-1 macrophages and were compared with the extracellular activities observed in broth. All extracellular concentrations were adjusted to explore ranges that are clinically achievable in human serum upon conventional therapy. In broth, ampicillin, meropenem, and azithromycin were only bacteriostatic, whereas gentamicin, ciprofloxacin, and moxifloxacin were strongly bactericidal in a concentration-dependent manner. In cells, ampicillin, meropenem, azithromycin, and ciprofloxacin were slightly bactericidal (0.3- to 0.8-log CFU reductions), moxifloxacin was strongly bactericidal (2.1-log CFU reduction), and gentamicin was virtually inactive. The difference in the efficacies of moxifloxacin and ciprofloxacin in cells did not result from a difference in levels of accumulation in cells (6.96 +/- 1.05 versus 7.75 +/- 1.03) and was only partially explainable by the difference in the MICs (0.58 +/- 0.04 versus 1.40 +/- 0.17 mg/liter). Further analysis showed that intracellular moxifloxacin expressed only approximately 1/7 of the activity demonstrated against extracellular bacteria and ciprofloxacin expressed only 1/15 of the activity demonstrated against extracellular bacteria. Gentamicin did not increase the intracellular activities of the other antibiotics tested. The data suggest (i) that moxifloxacin could be of potential interest for eradication of the intracellular forms of L. monocytogenes, (ii) that the cellular accumulation of an antibiotic is not the only determinant of its intracellular activity (for fluoroquinolones, it is actually a self-defeating process as far as activity is concerned), and (iii) that pharmacodynamics (activity-to-concentration relationships) need to be considered for the establishment of efficacy against intracellular bacteria, just as they are for the establishment of efficacy against extracellular infections.     

Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence

BACKGROUND: Linezolid is a bacteriostatic oxazolidinone antibiotic that has been proven to be effective for the treatment of patients with pneumonia, skin and soft tissue infections, and possibly bacteraemia, due to Gram-positive cocci. However, the drug is sometimes used for the treatment of patients with endocarditis due to Gram-positive cocci resistant to other antibiotics. METHODS: We carried out a review of the available literature to evaluate whether linezolid is also effective for the treatment of patients with infective endocarditis. RESULTS: We identified 23 case reports and 3 case series reporting the experience with 56 patients with endocarditis treated with linezolid. Evaluable data for 33 patients who received linezolid and for whom individual patient data were reported were further analysed. Prosthetic valve infective endocarditis accounted for 25% of the reviewed cases. Methicillin-resistant Staphylococcus aureus and vancomycin-intermediate S. aureus were the most commonly isolated cocci (24.2% and 30.3% of cases, respectively). Linezolid alone was administered to 66.7% of patients while the rest received the antibiotic in combination with rifampicin, gentamicin, fusidic acid or amikacin. A total of 63.6% (21/33) of patients with endocarditis were cured after linezolid administration. The overall and endocarditis-related mortality was 33.3% (11/33) and 12.1% (4/33), respectively. Thrombocytopenia developed in 30.8% (8/26) of patients for whom relevant data were available. CONCLUSIONS: The limited available evidence suggests that linezolid may be considered as a therapeutic option for the treatment of patients with endocarditis due to multidrug-resistant Gram-positive cocci. However, further published experience is needed to answer the question of whether a bacteriostatic antibiotic could be proven beneficial for patients with an infection for which bactericidal antibiotics have been traditionally used.     

Medium-Dependent Variation in Bactericidal Activity of Antibiotics Against Susceptible Staphylococcus aureus

Staphylococcus aureus resistant to bactericidal activity of antibiotics caused sepsis in three patients. Bacteriological and clinical responses were not achieved until serum and tissue fluid levels of administered antibiotics exceeded the minimum bactericidal concentration (MBC) of the infecting organism. Fifteen clinical isolates of S. aureus were tested in brain heart infusion broth and Mueller-Hinton broth for the MBC of gentamicin, vancomycin, clindamycin, oxacillin, cefazolin, and cephalothin. Results showed significant eightfold or greater broth-dependent differences in the MBC of at least one antibiotic against 87% (13/15) of strains tested. The MBC was unpredictable and varied with the strain, antibiotic, and medium used. No controlled studies are available to indicate the clinical significance of the MBC demonstrated in different media. The necessity for treating serious infection with bactericidal drugs has not yet been established; however, in septicemia such as that caused by bacterial endocarditis, bacteriostatic antibiotics have generally failed to eradicate the infection, whereas bactericidal agents have often been curative. Therefore, in patients unresponsive to usual antistaphylococcal therapy, we suggest that MBC testing be performed in at least two media and that treatment be instituted with antibiotics demonstrating the lowest MBC in all media used.