Combination Of Aminoglycoside Research Articles

Antibacterial Therapy for Nosocomial Pneumonias Caused by Multidrug-Resistant Microorganisms in Critical 1ll Patients

The paper presents the results of using the fourth-generation cephalosporin maxicef in the treatment of 20 patients with nosocomial pneumonia and severe concomitant injury. A control group comprised 20 patients receiving a combination of ceftazidime and amikacin. The total efficiency of the antibacterial therapy was 68.5% in the maxicef group and 40.9% in the control group (р<0.05). The therapy had to be modified in 42% of the maxicef group and in 72.7% in the control group (р<0.05). The average treatment cost was US $518 (429—606) and US $482 (368—596) in the maxicef and control groups, respectively. Nephrotoxicity was observed in 9% of the patients receiving a combination of the antibiotics. The activity of maxicef was also analyzed in vitro. Results. Maxicef was demonstrated to be highly active against the majority of gram-negative and gram-positive bacteria in vitro. Its efficacy against the most common bacteria (P.aeruginosa, S.aureus, E.coli, K.pneumonia) causing infections in severe injury was in vitro significantly higher than that of ceftazidime. The comparative study indicates that the fourth-generation cephalosporin maxicef may be used as an alternative to the standard combined therapy. Key words: concomitant injury, maxicef, nosocomial pneumonia, a combination of ceftazidime and aminoglycoside, nosocomial infection pathogens.

The Lon protease of Pseudomonas aeruginosa is induced by aminoglycosides and is involved in biofilm formation and motility

Pseudomonas aeruginosa is an important nosocomial opportunistic human pathogen and a major cause of chronic lung infections in individuals with cystic fibrosis. Serious infections by this organism are often treated with a combination of aminoglycosides and semi-synthetic penicillins. Subinhibitory concentrations of antibiotics are now being recognized for their role in microbial persistence and the development of antimicrobial resistance, two very important clinical phenomena. An extensive screen of a P. aeruginosa PAO1 luciferase gene fusion library was performed to identify genes that were differentially regulated during exposure to subinhibitory gentamicin. It was demonstrated that subinhibitory concentrations of gentamicin and tobramycin induced a set of genes that are likely to affect the interaction of P. aeruginosa with host cells, including the gene encoding Lon protease, which is known to play a major role in protein quality control. Studies with a lon mutant compared to its parent and a complemented strain indicated that this protein was essential for biofilm formation and motility in P. aeruginosa.

Healthcare Epidemiology: Does Antibiotic Selection Impact Patient Outcome?

Inadequate antibiotic therapy, generally defined as microbiologically ineffective anti-infective therapy against the causative pathogen, can influence patient outcome. However, the detrimental effects of inadequate antibiotic therapy seem to become weaker in the most severely ill patients with short life expectancies. In addition to severity of illness, other methodological issues should be carefully examined in studies assessing the excess mortality due to inadequate therapy. To adjust for confounding as much as possible in order to obtain an unbiased estimate of the magnitude of the effect of inadequate therapy is a key methodological challenge for future research. With regard to the choice of antibiotic agents, beta-lactam and aminoglycoside combination therapy does not seem to improve clinical outcome in most cases of sepsis caused by gram-negative bacteria, including Pseudomonas aeruginosa bacteremia. A potential benefit of combination therapy in the treatment of severe pneumococcal sepsis has been suggested in several observational studies, but recently published data have disputed this hypothesis. Finally, better risk scores and laboratory tools are urgently needed to improve the adequacy of empirical antibiotic therapy and patient outcomes.

The Use of Combination Antimicrobials in Critically-Ill Ventilated Patients with Pseudomonal Pneumonia

Purpose Recent 2005 American Thoracic Society and Infectious Diseases Society of America ventilator-associated pneumonia (VAP) guidelines suggest combination antimicrobial therapy for Pseudomonas aeruginosa VAP based on limited non-VAP evidence. We reviewed antimicrobial use in patients with P. aeruginosa VAP within our tertiary teaching institution to evaluate patient factors, antimicrobial selection, and outcomes. Methods Intubated patients with a P. aeruginosa sputum culture, infiltrate on chest x-ray, and increased white blood cell count were retrospectively enrolled. Collected data identified illness acuity using the Simplified Acute Physiology Score II (SAPS), culture sensitivities, antimicrobial use, and patient survival at hospital discharge. Results Fifty-nine patients were analyzed between January 2003 and November 2004. Average age was 57 ± 15.7, body mass index (BMI) of 28.5 ± 6.1, and SAPS of 45.1 ± 13.7. Survival was significantly higher among patients on two culture-sensitive antimicrobials (23/28, 82%) vs less than two agents (12/31, 39%; P = 0.0018). Almost all patients who received the beta-lactam and aminoglycoside (BL/Ag) combination survived (15/16; P = 0.0015). While fewer severely ill patients lived (SAPS greater than 54; 4/16; P = 0.0029), none were placed on the BL/Ag combination, and few on appropriate antimicrobials (6/37; P = 0.0324). Lower survival was seen among obese patients (BMI higher than 30; 9/25; P = 0.0043); although, 5/6 obese patients on BL/Ag survived ( P = 0.0237). Patients more than 64-years-old were more often on two appropriate antimicrobials ( P = 0.0143) and had a higher survival ( P = 0.0241). Unfortunately, we observed a lack of culture follow-up, as only 60% (30/50) of inappropriate antimicrobials were switched to sensitive agents. Conclusions Our results emphasize the need to use combination BL/Ag antimicrobials for P aeruginosa VAP as the current guidelines suggest, and to ensure that antimicrobials are optimized based on culture results.

Nosocomial pneumonia

This review describes the most recent advances in the management and prevention of nosocomial pneumonia. The new ATS guidelines in particular are most likely to affect clinical practice outside the USA. The problem of multidrug-resistant bacteria causing nosocomial pneumonia seems to be increasing. This is particularly true for methicillin-resistant Staphylococcus aureus. While the diagnosis of ventilator associated pneumonia remains a conflictive issue, serial tracheobronchial aspirates may improve the selection of adequate antimicrobial treatment. Combined beta-lactam and aminoglycoside therapy is inferior to beta-lactam monotherapy, both in terms of clinical outcome and in the prevention of resistance during treatment; in addition, it carries an increased risk of nephrotoxicity. The updated ATS guidelines will considerably impact clinical approaches to nosocomial and healthcare-related pneumonia. Serial tracheobronchial aspirates can be used to guide selection of antimicrobial treatment in ventilator associated pneumonia. The combination of beta-lactams and aminoglycosides is likely to be abandoned in the future. New potent treatment options for pneumonia due to nonfermenters are urgently needed.

Piperacillin/tazobactam monotherapy versus combination ceftazidime plus amikacin for the treatment of febrile neutropenia in patients with cancer: A Hellenic Co-Operative Oncology Group Study

18590 Background: Combinations of β-lactam antibiotics and aminoglycosides are considered standard therapy for febrile neutropenia. Monotherapies have been proposed as standard treatments, demonstrating equal efficacy and better safety. Methods: This is a prospective, multi-centre, randomized clinical trial. Cancer patients with absolute neutrophil count (ANC) &lt;1,000/mm3 and fever &gt;38oC for ≥ 2 hours were randomized to either piperacillin/tazobactam 4.5 g every 8 h i.v. (group A) or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day (group B). In case of fever &gt;38oC 48 h after initiation of the therapy, vancomycin 500 mg every 6 h i.v. was added. Minimal duration of treatment was 72 hours. Treatment was continued for 7 days in case of improvement, otherwise vancomycin was added or the study therapy was discontinued. Early efficacy was assessed on day 3 and overall response 4 days after the end of treatment. Complete success was defined the patient to become afebrile and no other antibiotics to be added. Treatment failures were classified in two categories, those in which vancomycin was added to the study regimen, and those in which other antibiotics were used. Categorical variables were compared between treatment groups with the use of Fisher’s exact test, while for continuous Wilcoxon’s rank sum test was used. Results: One hundred twenty-seven febrile episodes were treated (group A: 66, group B: 61). Patient characteristics were well balanced in terms of age, underlying malignancies, ANC, and granulocyte-colony stimulating factor (G-CSF) support. Both treatments were well tolerated. No significant differences were seen in terms of success to treatment. Complete success was achieved in 45 (68%) of patients in group A and 40 (66%) in group B, while another 8 patients in group A (12%) and 6 in group B (10%) required addition of pre-defined anti-staphyloccocci antibiotic. Conclusions: Empirical treatment of febrile neutropenic episodes with piperacillin/tazobactam monotherapy appears to be as effective as the “standard” ceftazidime/amikacin combination. No significant financial relationships to disclose.

REPLY

9 November 2005 Dear Editor, We thank Coulthard et al. for their comments on our case report, in particular their remarks regarding therapeutic drug monitoring (TDM) of extended interval aminoglycoside dosing (EIAD) in children, which is an area of ongoing debate. The results of a recent meta-analysis of studies in children1 suggest that once-daily dosing is as efficacious as thrice-daily dosing and, as the results of a subsequent randomized controlled trial of patients with cystic fibrosis2 support, EIAD may potentially be less nephrotoxic. However, as highlighted by Coulthard, the most appropriate method of TDM for EIAD has not been decided upon. To our knowledge, the question of whether use of an area under the curve method reduces toxicity has not been studied but certainly warrants consideration. We accept that according to an area under the curve method of TDM, our patient was exposed to potentially toxic levels of gentamicin; however, we must wonder whether this is the case for many children receiving extended courses of aminoglycosides who do not develop acute renal failure. Therefore, we believe that a salient feature of our case remains the potential combined nephrotoxicity of ceftazidime and aminoglycosides – which would be heightened if serum levels of the latter are elevated. We would also like to point out that many of the cases of acute renal failure in CF patients from the UK noted by Smyth et al.,3 occurred in patients prescribed the combination of ceftazidime and aminoglycosides (personal communication from A Smyth). We also agree that measurements of serum creatinine are an insensitive indicator of changing renal function, a fact which further highlights the need for more precise dosing regimens and monitoring procedures. We welcome further research in the area.

Clinical guidelines for the management of neutropenic patients with unexplained fever in Japan: validation by the Japan Febrile Neutropenia Study Group

The Japan Febrile Neutropenia Study Group (JFNSG) Trial was a multicenter, open, randomized study designed to validate the first Japanese guidelines for the management of neutropenic cancer patients with unexplained fever issued in 1998. The trial compared cefepime monotherapy with cefepime plus amikacin combination therapy in febrile neutropenic patients with hematological disorders. The JFNSG found that monotherapy with cefepime was, in general, as effective as combination therapy. In terms of subset analyses, defervescence appeared to occur more frequently in leukemic patients and in those with profound neutropenia treated with the dual combination. The conclusion of the trial was that the 1998 guidelines were applicable to the Japanese febrile neutropenic patient population. The JFNSG met again in 2003 to revise these guidelines. An important addition to the guidelines was a distinction between low- and high-risk patients. Low-risk febrile neutropenic patients can receive oral ciprofloxacin or levofloxacin, with or without amoxicillin/clavulanic acid, on an outpatient basis, or intravenous (i.v.) monotherapy with cefepime, ceftazidime or a carbapenem. High-risk patients can receive i.v. cefepime, ceftazidime or a carbapenem, or an i.v. dual combination with cefepime, ceftazidime or a carbapenem plus an aminoglycoside. Those patients with a documented infection with methicillin-resistant Staphylococcus aureus should also receive a glycopeptide. It remains to be determined whether existing assessment scoring systems apply to Japanese patients; whether a broad-spectrum cephalosporin plus an aminoglycoside combination is required as the initial management of patients with acute leukemia and/or profound neutropenia; which antibacterial drugs should be used when first- and second-line agents fail; what are the appropriate oral agents and dosing regimens for low-risk patients; whether serology or the polymerase chain reaction should be the preferred marker for initiating pre-emptive antifungal therapy; and whether the azoles or the candins should be the preferred antifungal agents.

Combined Effects of Panipenem and Aminoglycosides on Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa in vitro

Background: Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are the main causes of refractory infections that are often resistant to antimicrobial agents. In these cases, combination of agents with antimicrobial activity is being examined. However, few studies have investigated combined effects with antimicrobial agents including carbapenem and aminoglycosides. Methods: We evaluated the effects of panipenem (PAPM) combined with 3 aminoglycosides, arbekacin, amikacin, and netilmicin, and vancomicin (VCM) with an agar dilution checkerboard technique and the fractional inhibitory concentration index against 47 strains of MRSA and 56 strains of P. aeruginosa. Results: PAPM combined with VCM achieved a synergic effect against MRSA in 80.9%. PAPM combined with aminoglycosides showed only additive effects against MRSA and P. aeruginosa. When comparing the activity of Mueller-Hinton agar (MHA) medium with MHA medium diluted 40-fold (1/40 MHA) against P. aeruginosa, the mean minimum inhibitory concentration of PAPM was decreased to 1/16. Conclusions: Combination of PAPM and VCM is effective against MRSA. Combinations of PAPM and aminoglycosides showed additive effects against MRSA and P. aeruginosa.

Nosocomial Infections Due to Multidrug-ResistantPseudomonas aeruginosa: Epidemiology and Treatment Options

Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. The increasing frequency of multi-drug-resistant Pseudomonas aeruginosa (MDRPA) strains is concerning as efficacious antimicrobial options are severely limited. By searching MEDLINE from January 1966-February 2005 and relevant journals for abstracts, we reviewed the frequency, risk factors, and patient outcomes of MDRPA nosocomial infections in critically ill patients, determined the available antimicrobial therapies, and then provided recommendations for clinicians. The definition of MDRPA was established as isolates intermediate or resistant to at least three drugs in the following classes: beta-lactams, carbapenems, aminoglycosides, and fluoroquinolones. Reported rates of MDRPA varied from 0.6-32% according to geographic location and type of surveillance study. Risk factors for MDRPA infection included prolonged hospitalization, exposure to antimicrobial therapy, and immunocompromised states such as human immunodeficiency virus infection. Emergence of MDRPA isolates during therapy was reported in 27-72% of patients with initially susceptible P. aeruginosa isolates. Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone rather than aminoglycoside and fluoroquinolone combinations, to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application reported in two centers. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent in MDRPA when antimicrobial options are limited, but patients should be monitored closely for toxicities associated with this agent. Standardization of terminology for MDRPA isolates is needed for consistency and comparability of surveillance and institutional reports. Clinical studies are needed to identify risk factors for MDRPA development and to determine the economic impact of these infections, as well as to determine the most efficacious antimicrobial regimens and duration of therapy to maximize outcomes in the treatment of MDRPA infections.

The combination of aminoglycosides with ??-lactams is no better at preventing the emergence of antimicrobial resistance than ??-lactams alone,

The combination of aminoglycosides with ??-lactams is no better at preventing the emergence of antimicrobial resistance than ??-lactams alone,

Antibiotic regimens for suspected late onset sepsis in newborn infants

Late onset neonatal sepsis (systemic infection after 48 hours of age) continues to be a significant cause of morbidity and mortality. Early treatment with antibiotics is essential as infants can deteriorate rapidly. It is not clear which antibiotic regimen is most suitable for initial treatment of suspected late onset sepsis. To compare the effectiveness and adverse effects of different antibiotic regimens for treatment of suspected late onset sepsis in newborn infants. The standard search strategy of the Cochrane Neonatal Review Group was used. This includes electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004), MEDLINE (1966 - Dec 2004), EMBASE (1980 - Dec 2004) and CINAHL (1982 - Dec 2004), electronic abstracts of Pediatric Academic Society meetings (1996 - Dec 2004) and previous reviews including cross references (all articles referenced). Randomised and quasi randomised controlled trials comparing different initial antibiotic regimens in neonates with suspected late onset sepsis were evaluated. Both reviewer authors screened abstracts and papers against the inclusion criteria, appraised the quality of and extracted data from papers. For dichotomous outcomes, treatment effect was expressed as relative risk and risk difference with 95% confidence intervals. NNT was calculated for outcomes for which there was a statistically significant reduction in risk difference. Thirteen studies were identified as possibly eligible for inclusion. The majority of studies were excluded as they did not separate data for early and late onset infection. Two studies are still awaiting assessment. Only one small study, in 24 neonates, was included in this review. It compared beta-lactam therapy with a combination of beta lactam plus aminoglycoside. The study did not meet our prespecified criteria for good methodological quality. In babies with suspected infection there was no significant difference in mortality (RR 0.17, 95% CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to 3.23). Antibiotic resistance was assessed and there were no cases in either group. There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.

Antibiotic‐related renal failure and cystic fibrosis

Recently published reports suggest that the combination of aminoglycosides with ceftazidime may increase the risk of renal disease in cystic fibrosis. We describe a case of unusually severe acute tubular necrosis occurring in an adolescent with cystic fibrosis receiving i.v. gentamicin plus ceftazidime and discuss the possible mechanisms.

Imipenem/cilastatin versus piperacillin/tazobactam plus amikacin for empirical therapy in febrile neutropenic patients: results of the COSTINE study

ABSTRACTBackground: Combinations of beta-lactams plus aminoglycosides have become standard therapy for suspected infections in patients with profound neutropenia. However, it is not clear whether such combinations are advantageous over therapy with a broad-spectrum antibiotic.Objective: To assess the clinical effectiveness and the cost-effectiveness ratio of empirical therapy of febrile neutropenia with imipenem/cilastatin (I/C) versus piperacillin/tazobactam plus amikacin (P/T+A).Research design and methods: Prospective, multicenter observational study with 2 matched parallel cohorts treated with I/C (500 mg/6 h iv) or P/T+A (P/T: 4 g/6 h iv; A: 20 mg/kg/day iv).Main outcome measures: Therapeutic success was defined as the resolution of fever following ≥ 7 days of unchanged antibiotic treatment. An economic comparison was conducted focusing on the daily treatment costs, and the management of its toxicity.Results: There were 343 eligible patients (180 I/C, 163 P/T+A), of whom 290 were evaluable for the primary clinical effectiveness analysis. Follow-up information beyond 7 days of study inclusion was only available for 52% of all evaluable patients. Treatment success was observed in 42% of I/C patients compared with 31% of P/T+A patients (95% CI: –0.01, 21.4). The incidence of drug-related adverse experiences was 13% for I/C and 6% for P/T+A, with no differences in moderate or severe adverse experiences nor in those causing discontinuation of antibiotic therapy. Treatment costs were 189.55 euros (95% CI: 127.46–251.46) lower per episode of febrile neutropenia for patients treated with I/C.Conclusions: The clinical effectiveness of I/C was similar to that of P/T+A. In both treatment groups toxicity was low and did not limit antibiotic therapy. Resource consumption was lower with I/C.

Hepatotoxicity of Combined Treatment with Cisplatin and Gentamicin in the Guinea Pig

The damaging effects on the liver tissue of treatment with cisplatin followed by the aminoglycoside antibiotic gentamicin were studied in guinea pigs. The ultrastructural findings revealed foci of damage in the liver parenchyma, including its vascular component. Injurious effects to cytoplasmatic organelles such as mitochondria and endoplasmic reticulum as well as to nuclei were observed. In addition, abundance of lysosomes, autophagic vacuoles, and amorphous-granular bile in the lumina of bile canaliculi was found. Focal sinusoidal lining damage and capillarization of sinusoids were also present. In vascular lumina, some erythrocytes showed a deformed shape (“ropalocytosis”). Taken together, these findings indicate that the combined treatment with cisplatin followed by gentamicin is toxic to components of liver tissue. Since toxic changes have been shown in vessels of the inner ear and in renal–glomerular capillaries, the present observations of hepatotoxicity indicate the potential vascular damage to various tissues. The injurious effects of the cisplatin–aminoglycoside combination should be considered during its use in clinical conditions.

Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

Treatment options for gram-positive resistant bacteria are limited; therefore, efforts to evaluate therapy options in the critical care population are warranted. Cefepime has broad-spectrum activity against gram-negative and gram-positive organisms. We have previously demonstrated that the combination of cefepime with vancomycin, linezolid, or quinupristin-dalfopristin had an improved or enhanced effect against methicillin-resistant Staphylococcus aureus (MRSA). We investigated various regimens of cefepime alone and in combination against two clinical MRSA isolates (R2481 and R2484) in an established in vitro pharmacodynamic model. Human pharmacokinetic regimen simulations were as follows: cefepime, 2 g every 8 h (q8h) (C8) and 12 h (C12), continuous-infusion 2-g loading dose followed by 4 g alone or in combination with gentamicin and tobramycin (1.0 or 2.0 [G1 and G2 or TB1 and TB2] mg/kg of body weight q12h and 5.0 [G5 or TB5] mg/kg q24h), arbekacin (ARB) (100 mg q12h), linezolid (LIN) (600 mg q12h), tigecycline (TIG) (100 mg q24h), or daptomycin (DAP) (6 mg/kg q24h) for 48 h. The MICs for cefepime, gentamicin, tobramycin, ARB, LIN, TIG, and DAP for the two clinical MRSA isolates (R2481 and R2484) were 4 and 4, 0.25 and 0.5, 128 and 0.5, 0.5 and 0.125, 2 and 4, 0.25 and 0.25, and 0.0625 and 0.125 microg/ml, respectively. At 48 h, combinations of C12 and C8 plus ARB, G1, or G5 (range, -2.05- to -4.32-log(10) decrease) demonstrated enhanced lethality against R2481 (resistant to tobramycin) (P < 0.05). A similar relationship was demonstrated against R2484 with cefepime plus ARB, gentamicin, or tobramycin (range, -2.05- to -3.63-log(10) decrease) (P < 0.05). A 99.9% kill was achieved with cefepime plus aminoglycoside combinations as early as 2 h and maintained throughout the 48-h period. TIG was antagonistic when combined with C12 against both isolates. DAP alone achieved 99.9% kill for up to 48 h for both isolates and was the most active agent against R2481 and R2484 (-2.89- and -3.61-log(10) decrease at 48 h); therefore, combination therapy did not enhance lethality. Overall, the most potent combinations noted were cefepime in combination with low- and high-dose aminoglycosides. Further investigations with combination therapies are warranted.

A Randomized, Double-Blind Study to Assess the Optimal Duration of Doxycycline Treatment for Human Brucellosis

Human brucellosis is usually treated with a combination of tetracyclines and aminoglycosides. However, the optimal duration of therapy has not been clearly determined. We conducted a prospective, double-blind, randomized, multicenter study comparing treatment with doxycycline (100 mg po b.i.d.) for 30 days (30-day group) with the same dosage of doxycycline for 45 days (45-day group) in patients with brucellosis without endocarditis, spondylitis, or neurobrucellosis. All patients were treated with gentamicin (240 mg im once daily) for the first 7 days. Therapeutic outcome was evaluated by measuring relapse rates and drug safety. Seventy-three patients were included in each group. During the first 45 days after treatment, the percentage of patients with relapse was significantly higher in the 30-day group than in the 45-day group (12.3% vs. 1.37%; relative risk, 9.00; 95% confidence interval [CI], 1.17-69.2; P=.017). Between day 45 after treatment and 12 months after treatment, no further significant differences were found in relapse rates between groups (9.38% in the 30-day group vs. 11.11% in the 45-day group; relative risk, 0.84; 95% CI, 0.31-2.30; P=.78). Overall, relapses occurred in 15 (20.55%) of 73 patients in the 30-day group and in 9 (12.33%) of 73 patients in the 45-day group (relative risk, 1.67; 95% CI, 0.78-3.56; P=.264). Compliance and adverse effects were comparable in the 2 groups. Doxycycline treatment for 45 days significantly decreased early relapse rates among adults with brucellosis without increasing adverse effects.

Hair Cell Regeneration Reveals Central Nervous System Plasticity in the Avian Brain

Two separate lines of behavioral research are reported here. Both sets of experiments were begun to examine whether hair cell regeneration in the avian inner ear could support the recovery of complex behaviors. However, both have gone on to reveal new information about the important role of peripheral input for central nervous system plasticity. A series of experiments examined the recovery of vestibular reflexes in hatchling chickens following aminoglycoside ototoxicity to the vestibular epithelium. Treatment with aminoglycosides results in hair cell loss and loss of both the vestibulo-ocular reflex (VOR) and the vestibulo-colic reflex (VCR). We found a good general correspondence between hair cell regeneration and recovery of both the VOR and the VCR. When animals were maintained under normal illumination, recovery of both reflexes was generally complete in 4 weeks. However, when the animals were maintained in illumination provided by a strobe light flashing at 2.5 Hz for 4 weeks, this correlation broke down. Hair cells recovered normally, as did the VCR, but the VOR did not recover. Remarkably, placing the animals in normal illumination for only 48 hours after 4 weeks of strobe rearing resulted in full recovery of the VOR. In another series of experiments, we examined the deterioration and recovery of adult Bengalese finch songs after hair cell loss and during hair cell regeneration. Bengalese finches learn their individual songs only as juveniles and sing stereotyped, stable songs as adults. After deafening by a combination of aminoglycoside and high-intensity noise exposures, the songs of individual birds deteriorated in both syllable order and the structure of individual syllables. Remarkably, because hearing was restored by regeneration of hair cells, songs returned to their original structure in 4 weeks. These results indicate that adult birds retain "blueprints" of their own songs. Following initial song recovery, two of seven adult birds that were housed with other singing birds produced new syllables that mimicked their cage mate's songs. The new syllables were incorporated into the recovered songs, suggesting that hair cell loss and regeneration unmasked neural plasticity not normally seen in the mature avian forebrain. Both sets of experiments show that regenerated hair cells can support the recovery of complex behavior. The increases in behavioral plasticity observed during and after hair cell regeneration suggest that hair cell loss and regeneration either stimulate or reveal the plasticity of neural circuits controlling behavior normally not observed in adult birds.

In vitro activity of β-lactams in combination with other antimicrobial agents against resistant strains of Pseudomonas aeruginosa

Using the chequerboard titration method, the activity in combination of β-lactams, fluoroquinolones and aminoglycosides was investigated against 24 Pseudomonas aeruginosa isolates resistant to these antibiotics. Synergy was detected with one or more antimicrobial combinations against 15 of 24 (63%) isolates and partial synergy was detected with one or more combinations against all 24 isolates. No antagonism was seen with any combination. Ceftazidime and cefepime with aztreonam, amikacin and isepamicin showed synergy or partial synergy against 12–20 (50–80%) isolates. Imipenem and meropenem with amikacin and isepamicin showed synergy or partial synergy against eight to 12 (33–50%) isolates. The results of this study indicate that against P. aeruginosa, synergy may occur between β-lactams, fluoroquinolones and aminoglycosides although the strains are resistant to the individual antibiotics.

Cefepime, piperacillin/tazobactam, gentamicin, ciprofloxacin, and levofloxacin alone and in combination against Pseudomonas aeruginosa

A β-lactam plus an aminoglycoside is the standard for treating severe Pseudomonas aeruginosa infections. However, the fluoroquinolones are safer and have been widely used as an alternative to the aminoglycosides in this setting. In this study we compared the synergistic activities of piperacillin/tazobactam and cefepime when either drug was combined with gentamicin, ciprofloxacin, or levofloxacin against P. aeruginosa. Susceptibility testing and time-kill curves were performed against 12 clinical isolates of P. aeruginosa. All combinations were bactericidal and retained this activity over the 24 hr period except for piperacillin/tazobactam in combination with levofloxacin or ciprofloxacin against 2 isolates and cefepime in combination with levofloxacin against 1 isolate. None of the combinations were antagonistic. No statistical difference in the frequency of synergy exists between the β-lactam plus gentamicin (79%) and the β-lactams plus either ciprofloxacin or levofloxacin combinations (58%, 67%). Furthermore, no differences in synergistic activity were noted between ciprofloxacin combinations (58%) and levofloxacin combinations (67%). In conclusion, the degree of synergy between a β-lactam plus aminoglycoside and a β-lactam plus fluoroquinolone seem to be comparable. Furthermore, there is a similar rate of synergy among different fluoroquinolone-based combinations. However, faster killing, less regrowth, and decrease in the development of resistance were seen with the β-lactam plus aminoglycoside combination.