Ampicillin-sulbactam Combination Research Articles

The effect of bioenhancers on ampicillin-sulbactam as a treatment against A. baumannii

As more bacteria develop antibiotic resistance, bioenhancers – substances that enhance antibiotic performance – are emerging as potential solutions. However, the effectiveness of bioenhancers has not been measured on highly antibiotic-resistant pathogens. We hypothesized that the bioenhancer piperine, derived from black pepper, combined with the drug ampicillin-sulbactam, would lead to decreased growth of Acinetobacter baumannii, a highly resistant bacterium, compared to the drug alone. Broth dilution was used to find the minimum concentration of drug needed to inhibit three strains of A. baumannii, with Escherichia coli as a control, providing a baseline for the strain’s resistance levels. The strains were exposed to four treatments: varying concentrations of ampicillin-sulbactam alone, piperine alone, a combination of ampicillin-sulbactam and piperine, and no treatment to analyze the antibiotic-bioenhancer synergy. Treatments were also incubated with macrophages, cells of the mammalian innate immune response, measure drug efficacy under conditions mimicking early stages of infection. The results indicated that combining piperine with ampicillin-sulbactam at 64 mg/L and 32 mg/L reduced bacterial growth for two A. baumannii strains compared to treatment with antibiotic alone. However, the third strain had no significant difference in bacterial growth. However, at a drug concentration of 16 mg/L, the addition of piperine led to significantly reduced bacterial growth for all three strains (p < 0.001, p < 0.0001, p < 0.0001). These studies showed that piperine enhanced ampicillin-sulbactam efficacy against A. baumannii. The addition of piperine led to lower minimum inhibitory concentrations of the antibiotic against drug-resistant A. baumannii.

Synergistic Activity of Cefiderocol in Combination with Piperacillin-Tazobactam, Fosfomycin, Ampicillin-Sulbactam, Imipenem-Relebactam and Ceftazidime-Avibactam against Carbapenem-Resistant Gram-Negative Bacteria.

Limited treatment options are among the main reasons why antimicrobial resistance has become a leading major public health problem. In particular, carbapenem-resistant Enterobacteriales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii have been included by the World Health Organization (WHO) among the pathogens for which new therapeutic agents are needed. The combination of antibiotics represents an effective strategy to treat multidrug-resistant (MDR) pathogen infections. In this context, the aim of this study is to evaluate the in vitro activity of cefiderocol (CFD) in combination with different antimicrobial molecules against a collection of well-characterized clinical strains, exhibiting different patterns of antimicrobial susceptibility. Clinical strains were genomically characterized using Illumina iSeq100 platform. Synergy analyses were performed by combining CFD with piperacillin-tazobactam (PIP-TAZ), fosfomycin (FOS), ampicillin-sulbactam (AMP-SULB), ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL). Our results demonstrated the synergistic effect of CFD in combination with FOS and CAZ-AVI against CRE and carbapenem-resistant Acinetobacter baumannii (CR-Ab) clinical strains owing CFD-resistant profile, while the CFD and AMP-SULB combination was effective against CR-Pa strain displaying AMP-SULB-resistant profile. Moreover, the combination of CAZ-AVI/SULB showed synergistic activity in CAZ-AVI-resistant CRE strain. In conclusion, although further analyses are needed to confirm these results, our work showed the efficacy of CFD when used for synergistic formulations.

Growth kinetics of multiple Acinetobacter baumannii resistotype after meropenem-based antibiotic combination exposure.

Background: Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter baumannii infections, but the emergence of carbapenem-resistant A. baumannii (CRAB) has rendered it ineffective in the vast majority of cases. Combination therapy has grown in popularity over the last decade; this study aims to analyze A.baumannii growth kinetics after exposure to meropenem and ampicillin-sulbactam compared with meropenem and amikacin antibiotic combinations in clinically relevant concentrations. Methods: This experimental laboratory study was conducted on the A. baumannii ATCC 19606 isolate and three clinical isolates that were intermediate or resistant to tested antibiotics. Meropenem and ampicillin-sulbactam, as well as meropenem and amikacin, were tested at four different concentrations against isolates. Turbidity measurements were taken at predetermined time points of 0, 1, 2, 4, 6, 8, and 24 hours following exposure; bacterial concentration was enumerated using the agar plate method, with the results plotted in a time-kill curve. Results: A bactericidal effect was achieved in isolates that were intermediate to ampicillin-sulbactam and resistant to meropenem after the administration of meropenem and ampicillin-sulbactam combination with a concentration of 4 µg/ml and 16/8 µg/ml, respectively. The combination of meropenem and ampicillin-sulbactam demonstrated bacteriostatic activity against isolates that were resistant to both antibiotics. Isolates treated with resistant antibiotics showed an increased growth rate compared to the growth control. Conclusion: The combination of meropenem and ampicillin-sulbactam could be a promising combination therapy in treating CRAB infections. The mechanism and degree of antibiotic resistance in the isolates affect the efficacy of antibiotic combinations; further research is needed to corroborate the findings of this study.

Growth kinetics of multiple Acinetobacter baumannii resistotype after meropenem-based antibiotic combination exposure.

Background: Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter baumannii infections, but the emergence of carbapenem-resistant A. baumannii (CRAB) has rendered it ineffective in the vast majority of cases. Combination therapy has grown in popularity over the last decade; this study aims to analyze A.baumannii growth kinetics after exposure to meropenem and ampicillin-sulbactam compared with meropenem and amikacin antibiotic combinations in clinically relevant concentrations. Methods: This experimental laboratory study was conducted on the A.baumannii ATCC 19606 isolate and three clinical isolates that were intermediate or resistant to tested antibiotics. Meropenem and ampicillin-sulbactam, as well as meropenem and amikacin, were tested at four different concentrations against isolates. Turbidity measurements were taken at predetermined time points of 0, 1, 2, 4, 6, 8, and 24 hours following exposure; bacterial concentration was enumerated using the agar plate method, with the results plotted in a time-kill curve. Results: A bactericidal effect was achieved in isolates that were intermediate to ampicillin sulbactam and resistant to meropenem after the administration of meropenem and ampicillin-sulbactam combination with a concentration of 4 µg/ml and 16/8 µg/ml, respectively. The combination of meropenem and ampicillin-sulbactam demonstrated bacteriostatic activity against isolates that were resistant to both antibiotics. Isolates treated with resistant antibiotics showed an increased growth rate compared to the growth control. Conclusion: The combination of meropenem and ampicillin-sulbactam could be a promising combination therapy in treating CRAB infections. The mechanism and degree of antibiotic resistance in the isolates affect the efficacy of antibiotic combinations; further research is needed to corroborate the findings of this study.

A Multi-class Machine Learning Framework to Predict Ampicillin-Sulbactam Resistance of Acinetobacter baumannii

Acinetobacter baumannii is a serious pathogen responsible for many of the hospital-acquired infections. The emergence of multi-drug and pan-drug resistant strains of A. baumannii has been a growing concern. Ampicillin-sulbactam combination has proven to be effective in treatment of several resistant strains. However, strains resistant to ampicillin-sulbactam combination have also emerged necessitating other combination therapy. Rapid and accurate identification of the phenotype of the organism is essential for starting the right treatment. To this end, genome-based approaches have garnered much attention. In this work, we report a multi-class machine-learning based approach to predict the ampicillin-sulbactam resistance phenotype and MIC of Acinetobacter baumannii based on the presence/absence of AMR genes in the genome of strains isolated in the USA region. Our model achieves an accuracy of about 94% indicating that the gene presence/absence itself can capture the resistance phenotype. Further, we show that our model, built based on the USA strains, does not predict reliably the AMR phenotypes of Indian isolates pointing to the need for building machine learning models from region-specific data.

CAPNOCYTOPHAGA CANIMORSUS CAUSING SEPTIC SHOCK IN AN ASPLENIC PATIENT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: The Capnocytophaga spp. are fusiform, gram-negative rods with gliding motility and grow best in capnophilic environments. There has been concern for antimicrobial resistance among the Capnocytophaga spp. The purpose of this case is to present a patient with isolated C. canimorsus bacteremia causing septic shock and to discuss antimicrobial treatments. CASE PRESENTATION: The patient is a 63-year-old male with a past medical history of Epstein Barr Virus infection resulting in a splenectomy however, his vaccinations were up to date. The patient presented with fatigue for one day and had petechiae on his abdomen, lower extremities and nose. He was febrile at 38.9 degrees Celsius and was started on vancomycin, azithromycin and piperacillin-tazobactam. He then became hypotensive and received the sepsis fluid bolus with no change in his blood pressure. The patient required vasopressor support and then became hypoxic requiring endotracheal intubation. Due to worsening acidosis and vasopressor support the patient was started on continuous renal replacement therapy. The patient's initial blood cultures revealed gram negative rods however, the Biofire BCID (Biomérieux) molecular probe was negative. C. canimorsus was isolated from blood cultures. The antibiotic was then de-escalated to ceftriaxone. Literature review showed the possibility of beta-lactamase production in this bacterium. Given the overall critical illness of the patient, his antibiotic was changed to a combination of ampicillin-sulbactam and clindamycin. He finished a 7-day course of clindamycin and 14-day course of ampicillin-sulbactam. He received a total of 21 days of antibiotic therapy. DISCUSSION: The Capnocytophaga spp. found in the oral cavity of cats and dogs can cause wound infections, endocarditis, sepsis and meningitis. Capnocytophaga spp. have been known to cause more severe infections in immunocompromised patients. The Capnocytophaga spp. have been susceptible to many different classes of antibiotics including penicillins, macrolides, fluoroquinolones, cephalosporins and clindamycin. Recent literature has shown that there are strains of Capnocytophaga that produce beta-lactamase. Other literature has shown some Capnocytophaga spp. to be resistant to 3rd generation cephalosporins and fluoroquinolones. There was one report of a strain of C. sputigena with production of an extended spectrum beta-lactamase. CONCLUSIONS: The patient presented had C. canimorsus bacteremia. Sensitivities were unable to be done as there are no clear Clinical Laboratory and Standards Institute breakpoints for this organism. Literature had shown that C. canimorsus to be sensitive to penicillins. However, there have also been reports of beta-lactam production among other Capnocytophaga spp. Since the patient was critically ill and, sensitivities were unable to be done, the patient was switched to ampicillin-sulbactam and clindamycin. REFERENCE #1: Jolivet-Gougeon, A., Sixou, J., Tamanai-Shacoori, Z., & Bonnaure-Mallet, M. (2007). Antimicrobial treatment of Capnocytophaga infections. International Journal of Antimicrobial Agents, 29(4), 367-373. doi:10.1016/j.ijantimicag.2006.10.005 REFERENCE #2: Zangenah, S., Andersson, A. F., Özenci, V., & Bergman, P. (2017). Genomic analysis reveals the presence of a class D beta-lactamase with broad substrate specificity in animal bite associated Capnocytophaga species. European Journal of Clinical Microbiology & Infectious Diseases?: Official Publication of the European Society of Clinical Microbiology, 36(4), 657–662. https://doi-org.cuhsl.creighton.edu/10.1007/s10096-016-2842-2 REFERENCE #3: Gomez-Garces, J. L., Alos, J. I., Sanchez, J., & Cogollos, R. (1994). Bacteremia by multidrug-resistant Capnocytophaga sputigena. Journal of Clinical Microbiology, 32(4), 1067-1069. doi:10.1128/jcm.32.4.1067-1069.1994 DISCLOSURES: No relevant relationships by Muhammad Khan, source=Web Response No relevant relationships by Kenneth Mueller, source=Web Response No relevant relationships by David Quimby, source=Web Response

Treatment of odontogenic abscesses: comparison of primary and secondary removal of the odontogenic focus and antibiotic therapy.

To examine the time of removal of the odontogenic focus, antibiotic therapy and risk factors in odontogenic abscesses. From January 2012 to December 2015, inpatients undergoing incision due to odontogenic abscesses were identified in a retrospective study. All the patients were evaluated for time of removal of the odontogenic focus, antibiotic therapy, germ spectrum, complications and risk factors. Two hundred ten patients completed the study. In 89 cases (42.4%), the odontogenic focus was removed as part of the abscess treatment (group A). In 121 cases (57.6%), the focus was secondarily removed (group B). On average, 2 ± 4 teeth were removed in group A, and 6 ± 5 teeth in group B (p< 0.0001). An average of 1.2 ± 0.4 surgical interventions were performed in group A, and 2 ± 0.2 operations in group B (p< 0.0001). Microbiological examination was positive in one-third of the cases (70 cases). Most commonly, streptococci (27%) were isolated. A resistance screening was possible in 57 of the detected germs (68.7%). In 89% of these patients, the combination of ampicillin-sulbactam was effective. The hospital stay was 4.8 ± 2days for group A and 7.6 ± 3days for group B (p< 0.0001). The clinical evaluation revealed 12 intermediate (5.7%) and three long-term (1.4%) complications. The long-term complications included a recurrence in two cases (1%) and an osteomyelitis in one case (0.5%). A logistic regression analysis identified no significant risk factor in relation to these complications. The study shows that a primary removal of the odontogenic focus may have advantages over a secondary removal: (1) fewer operations, (2) shorter hospital stay and (3) shorter antibiotic therapy. Broad-spectrum penicillins in combination with beta-lactamase inhibitors are a possible, sufficient antibiotic regimen. Long-term complications are rare. No risk factors are identified in relation to these complications.

Case report: vertebral osteomyelitis secondary to a dental abscess

BackgroundVertebral osteomyelitis can be attributed to many factors including immunosuppression, diabetes, malignancy, collagen disease, periodontal disease, open fractures, and endoscopic procedures. Anaerobic bacteria, such as Veillonella species, are found in the oral cavity and are rarely implicated in the infection. This report describes vertebral osteomyelitis secondary to a dental abscess with positive Veillonella cultures.Case DescriptionA 76-year-old man presented to the hospital due to back pain with a four-day history of fever and chills. CT scans revealed several abscesses in the lumbar region as well as indications of vertebral osteomyelitis. After a psoas drain, the patient began antibiotics with a combination of ampicillin-sulbactam, metronidazole, and levofloxacin, but due to the patient’s penicillin allergy, he was initially desensitized to this antibiotic for a significant period of time. Laminectomies, foraminotomies, and facetectomies were performed, but the infection spread to vertebral levels. The patient was then switched to a combination of vancomycin, metronidazole, and levofloxacin which eliminated the infection. Final laminectomy was performed with posterior segmental instrumentation and arthrodesis. Post-operatively, there were no signs of infection. The patient recovered well and regained mobility. Deeper examination of the patient’s medical history revealed a severe tooth abscess immediately before the onset of bacteremia.ConclusionWe believe that a delay in the onset of antibiotic treatment is what led to the initial bacteremia that ultimately took root in the lower lumbar vertebrae. To the best of our ability, we could identify only one other case that linked vertebral osteomyelitis to the oral cavity.

Colistin-Resistant Acinetobacter baumannii: Beyond Carbapenem Resistance

With an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging. Patients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry. Twenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates. Colistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

Molecular characterization and evaluation of antimicrobial susceptibility of enteropathogenic E. coli (EPEC) isolated from minas soft cheese

Foodborne disease caused by microorganisms is a problem of public health. Minas soft cheese is a national product manufactured using simple technology; it has high level of acceptance in the country making its production an important economic activity. Many microorganisms may be present in foods including the bacterium Escherichia coli (E. coli). Overall, E. coli is a harmless commensal bacterium; however, some strains may have a pathogenic potential. Several outbreaks of foodborne diseases associated with consumption of contaminated cheese have been reported, and the presence of pathogenic strains of E. coli has increased. The objective of this study was to isolate, evaluate the antimicrobial susceptibility, and characterize, by Multiplex PCR, the pathogenic E. coli strains isolated from Minas cheese commercialized in Rio de Janeiro. Thirty samples were analyzed and five strains of E. coli (EPEC) were identified. The assessment of antimicrobial susceptibility revealed 40% of the isolates resistant to ampicillin and 40% with intermediate resistance to ampicillin-sulbactam combination. These findings are a warning signal to health authorities since Minas cheese is a ready to eat food product, and therefore should not pose health risks to the population.

Early Insights into the Interactions of Different β-Lactam Antibiotics and β-Lactamase Inhibitors against Soluble Forms of Acinetobacter baumannii PBP1a and Acinetobacter sp. PBP3

Acinetobacter baumannii is an increasingly problematic pathogen in United States hospitals. Antibiotics that can treat A. baumannii are becoming more limited. Little is known about the contributions of penicillin binding proteins (PBPs), the target of β-lactam antibiotics, to β-lactam-sulbactam susceptibility and β-lactam resistance in A. baumannii. Decreased expression of PBPs as well as loss of binding of β-lactams to PBPs was previously shown to promote β-lactam resistance in A. baumannii. Using an in vitro assay with a reporter β-lactam, Bocillin, we determined that the 50% inhibitory concentrations (IC(50)s) for PBP1a from A. baumannii and PBP3 from Acinetobacter sp. ranged from 1 to 5 μM for a series of β-lactams. In contrast, PBP3 demonstrated a narrower range of IC(50)s against β-lactamase inhibitors than PBP1a (ranges, 4 to 5 versus 8 to 144 μM, respectively). A molecular model with ampicillin and sulbactam positioned in the active site of PBP3 reveals that both compounds interact similarly with residues Thr526, Thr528, and Ser390. Accepting that many interactions with cell wall targets are possible with the ampicillin-sulbactam combination, the low IC(50)s of ampicillin and sulbactam for PBP3 may contribute to understanding why this combination is effective against A. baumannii. Unraveling the contribution of PBPs to β-lactam susceptibility and resistance brings us one step closer to identifying which PBPs are the best targets for novel β-lactams.

Molecular characterization and evaluation of antimicrobial susceptibility of enteropathogenic E. coli (EPEC) isolated from minas soft cheese

Foodborne disease caused by microorganisms is a problem of public health. Minas soft cheese is a national product manufactured using simple technology; it has high level of acceptance in the country making its production an important economic activity. Many microorganisms may be present in foods including the bacterium Escherichia coli (E. coli). Overall, E. coli is a harmless commensal bacterium; however, some strains may have a pathogenic potential. Several outbreaks of foodborne diseases associated with consumption of contaminated cheese have been reported, and the presence of pathogenic strains of E. coli has increased. The objective of this study was to isolate, evaluate the antimicrobial susceptibility, and characterize, by Multiplex PCR, the pathogenic E. coli strains isolated from Minas cheese commercialized in Rio de Janeiro. Thirty samples were analyzed and five strains of E. coli (EPEC) were identified. The assessment of antimicrobial susceptibility revealed 40% of the isolates resistant to ampicillin and 40% with intermediate resistance to ampicillin-sulbactam combination. These findings are a warning signal to health authorities since Minas cheese is a ready to eat food product, and therefore should not pose health risks to the population.

Short Communication: Pharmacokinetics of an Ampicillin–Sulbactam (2:1) Combination after Intravenous and Intramuscular Administration to Chickens

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination were studied in 6 sheep, after intravenous and intramuscular injection at a single dose rate of 20 mg/kg body weight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam). The drugs were distributed according to an open 2-compartment model after intravenous administration and a onecompartment model with first order absorption after intramuscular administration. The apparent volumes of distribution calculated by the area method of ampicillin and sulbactam were 0.32 ± 0.06 L/kg and 0.42 ± 0.04 L/kg, respectively and the total body clearances were 0.69 ± 0.07 and 0.38 ± 0.03 L/kg-h, respectively. The elimination halflives of ampicillin after intravenous and intramuscular administration were 0.32 ± 0.05 h and 0.75 ± 0.27 h, respectively, whereas for sulbactam the half-lives were 0.74 ± 0.10 h and 0.89 ± 0.16 h, respectively. The bioavailability after intramuscular injection was high and similar in both drugs (72.76 ± 9.65 % for ampicillin and 85.50 ± 8.35% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.25 ± 0.10 h and 0.24 ± 0.08 h, respectively) and peak concentrations were also similar but nonproportional to the dose of both products administered (13.01 + 7.36 mg/L of ampicillin and 10.39 3.95 mg/L of sulbactam). Both drugs had a similar pharmacokinetic behavior after intramuscular administration in sheep. Since the plasma concentrations of sulbactam where consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillinsulbactam combination in a higher than 2:1 ratio.

Pharmacokinetics of an ampicillin–sulbactam combination after intravenous and intramuscular administration to neonatal calves

The pharmacokinetics of a 2:1 ampicillin–sulbactam combination after intravenous (i.v.) and intramuscular (i.m.) injection at a single dose rate of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were studied in 10-day-old neonatal calves ( n=10). The plasma concentration–time data of both antibiotics were best fitted to an open two-compartment model after i.v. administration. After i.m. administration, an open two-compartment model demonstrated first order absorption. The apparent volumes of distribution of ampicillin and sulbactam, calculated by the area method, were 0.20 ± 0.01 and 0.18 ± 0.01 L/kg, respectively, and the total body clearances were 0.51 ± 0.03 and 0.21 ± 0.01 L/kg h. The elimination half-lives of ampicillin after i.v. and i.m. administration were 0.99 ± 0.03 and 1.01 ± 0.02 h, respectively, whereas for sulbactam the half-lives were 2.24 ± 0.02 and 3.44 ± 0.94 h. The bioavailability after i.m. injection was high and similar for both drugs (70.31 ± 0.2% for ampicillin and 68.62 ± 4.44% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.47 ± 0.02 and 0.72 ± 0.01 h, respectively) and peak concentrations were also similar but not proportional to the dose administered (17.88 ± 0.91 mg/L of ampicillin and 12.92 ± 0.79 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after i.m. administration. Since the plasma concentrations of sulbactam were consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillin–sulbactam combination in a ratio higher than 2:1.

Tuberculous Parotitis

Tuberculous Parotitis

Pharmacokinetics of an ampicillin/sulbactam (2:1) combination in rabbits.

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination in six rabbits, after intravenous and intramuscular injection at a single dosage of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were investigated by using a high performance liquid chromatographic method for determining plasma concentrations. The plasma concentration-time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The disposition curves for both drugs were best described by an open two-compartment model after intravenous administration and a one-compartment model with first order absorption after intramuscular administration. The apparent volumes of distribution calculated by the area method for ampicillin and sulbactam were 0.62 +/- 0.09 and 0.45 +/- 0.05 L/kg, respectively, and the total body clearances were 0.65 +/- 0.04 and 0.42 +/- 0.05 L/kg h, respectively. The elimination half-lives of ampicillin after intravenous and intramuscular administration were 0.64 +/- 0.11 and 0.63 +/- 0.16 h, respectively, whereas for sulbactam the half-lives were 0.74 +/- 0.12 and 0.77 +/- 0.17 h, respectively. The bioavailability after intramuscular injection was high and similar in both drugs (73.34 +/- 10.08% for ampicillin and 83.20 +/- 7.41% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.20 +/- 0.09 and 0.34 +/- 0.15 h, respectively) and peak concentrations were also similar but nonproportional to the dose of both products administered (13.07 +/- 3.64 mg/L of ampicillin and 8.42 +/- 1.74 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after intramuscular administration in rabbits.

Activities of trovafloxacin and ampicillin-sulbactam alone or in combination versus three strains of vancomycin- intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model.

The recent isolation of clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) with intermediate susceptibility (MICs, 8 microg/ml) to vancomycin (vancomycin-intermediate S. aureus [VISA]) emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment. We studied the activities of ampicillin-sulbactam and trovafloxacin alone or in combination against three unique strains of VISA in an in vitro infection model. Two VISA strains were trovafloxacin susceptible (MICs, < or =2 microg/ml); one VISA strain was trovafloxacin resistant (MIC, 4 microg/ml). Trovafloxacin was administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam was administered to simulate a dose of 3 g every 6 h. Samples were removed from the infection models over 48 h, and reductions in colony counts were compared between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA strain over the 48-h experiment but produced only slight killing of all three VISA strains. The higher dose of trovafloxacin improved killing but did not produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid bactericidal activity against all four strains tested, and colony counts at 8 h were at the limits of detection. However, regrowth occurred by 48 h for each strain. The combination of ampicillin-sulbactam and trovafloxacin provided additive activity against two of the three VISA strains. In conclusion, trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity against the VISA strains for the 48-h evaluation period, but the combination could help improve activity against some strains of VISA.

Ampicillin-sulbactam is effective in prevention and therapy of experimental endocarditis caused by beta-lactamase-producing coagulase-negative staphylococci.

Optimal strategies for the prophylaxis and therapy of endocarditis caused by oxacillin-resistant, coagulase-negative staphylococci in patients with native or prosthetic valvular heart disease are not well defined. We compared the in vivo efficacies of ampicillin-sulbactam-based regimens with those of vancomycin-based oxacillin-resistant, beta-lactamase-producing coagulase-negative staphylococcal isolate (Staphylococcus haemolyticus SE220). Ampicillin-sulbactam (100 and 20 mg/kg of body weight, respectively, given intramuscularly in a two-dose regimen) was equivalent to vancomycin (30 mg/kg given intravenously in a two-dose regimen) in its prophylactic efficacy against the coagulase-negative staphylococcal strain (93 and 80%, respectively). The combination of ampicillin-sulbactam plus either rifampin or vancomycin did not enhance the prophylactic efficacy compared with that of ampicillin-sulbactam or vancomycin alone. In the therapy of established aortic valve endocarditis in rabbits caused by this same coagulase-negative staphylococcal strain, animals received 7-day ampicillin-sulbactam-based or vancomycin-based regimens with or without rifampin. All treatment regimens were effective at lowering intravegetation coagulase-negative staphylococcal densities and rendering vegetations culture negative compared with the coagulase-negative staphylococcal densities and vegetations of untreated controls, with ampicillin-sulbactam in combination with rifampin or vancomycin being the most active regimen. However, only the regimen of ampicillin-sulbactam in combination with vancomycin effectively prevented relapse of endocarditis posttherapy after a 5-day antibiotic-free period. For animals receiving rifampin-containing regimens, relapses of endocarditis were associated with the in vivo development of rifampin resistance among coagulase-negative staphylococcal isolates in the vegetation. Ampicillin-sulbactam was highly effective in the prevention of experimental endocarditis caused by a beta-lactamase-producing, oxacillin-resistant coagulase-negative staphylococcal strain. Ampicillin-sulbactam was also efficacious for the therapy of coagulase-negative staphylococcal endocarditis, especially when it was combined with vancomycin to prevent posttherapeutic relapses.

Possibilities and limitations of predicting bioavailability of combination drugs using one of the components

The study of the bioavailability of a combination drug, containing two and more active in~edients, is a rather complicated and labour consuming problem. However, this study can be considerably simplified if the pharmacokinetic parameters of one of the components correlate with the parameters of other components. To check this possibility, we have carried out a parallel study of the pharmacokinetics ofampicillin and sulbactam (inhibitor ofl3-1actamases, produced by microorganisms) using a fixed ampicillin-sulbactam combination, which contained the drugs in the form oftosylates.

Combination antibiotics and indomethacin in idiopathic preterm labor: A randomized double-blind clinical trial

Subclinical infection may play a role in the failure of magnesium sulfate tocolysis. Using a double-blind randomized study design, we administered a combination of ampicillin-sulbactam and indomethacin or corresponding placebos to patients in preterm labor who were receiving intravenous magnesium sulfate tocolysis. The mean gestational age at enrollment was 30.1 weeks, and mean cervical dilatation was 2.15 em. No differences were noted between placebo (n = 43) and study patients (n = 43) in gestational age at delivery, term deliveries, days gained, or neonatal outcome. Preterm delivery (<36 weeks) occurred in 61% of the total population. The likelihood of a β error was 0.07 to 0.23 on the basis of outcome analysis. In our population adjunctive ampicillin-sulbactam with indomethacin did not improve the success of magnesium sulfate tocolysis. (AM J OBSTET GYNECOL 1991;165:1753-9.)