Assessment of New Therapies for Infection Due to the Mycobacterium avium Complex: Appropriate Use of In Vitro and In Vivo Testing

OBJECTIVE: To discuss the mechanism of action, in vitro and in vivo activity, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosage guidelines of rifabutin. DATA SOURCES: Pertinent literature published between 1982 and 1993 was identified via a MEDLINE search. Published proceedings of selected conferences were also reviewed. STUDY SELECTION: Selected basic science, microbiologic, and pharmacokinetic articles were evaluated. Because only limited data regarding rifabutin were available in the literature, all clinical trials involving the use of rifabutin in the prevention of Mycobacterium avium complex (MAC) infection in AIDS patients were reviewed. DATA SYNTHESIS: Rifabutin is a rifamycin derivative that was approved recently for the prevention of disseminated MAC disease in patients with advanced HIV infection. The drug has in vitro and in vivo activity against gram-positive bacteria, gram-negative bacteria, and mycobacteria. Two prospective, randomized, double-blind, placebo-controlled, multicenter trials demonstrated that rifabutin decreased the progression to MAC bacteremia in AIDS patients by about 50 percent. Adverse effects that resulted in the discontinuation of rifabutin prophylaxis occurred in 16 percent of patients. Rifabutin induces hepatic enzymes to a lesser extent than does rifampin, but dosage adjustment of drugs that are known to interact with rifampin may be required. CONCLUSIONS: Rifabutin is the only drug shown to be effective in the prevention of MAC bacteremia in AIDS patients; therefore, it should be made available as a formulary agent. It may be reasonable to delay initiation of rifabutin prophylaxis until CD4 lymphocyte counts are less than 75–50/mm3.

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In vitro and in vivo synergistic effect of isoniazid with streptomycin and clofazimine against Mycobacterium avium complex (MAC)

Tubercle and Lung Disease ◽

10.1016/0962-8479(94)90010-8 ◽

1994 ◽

Vol 75 (3) ◽

pp. 208-212 ◽

Cited By ~ 5

Author(s):

M.Venkata Reddy ◽

S. Srinivasan ◽

P.R.J. Gangadharam

Keyword(s):

Synergistic Effect ◽

Mycobacterium Avium ◽

Mycobacterium Avium Complex

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Activity of Picolinic Acid in Combination with the Antiprotozoal Drug Quinacrine against Mycobacterium avium Complex

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01510-05 ◽

2006 ◽

Vol 50 (9) ◽

pp. 3186-3188 ◽

Cited By ~ 5

Author(s):

Toshiaki Shimizu ◽

Haruaki Tomioka

Keyword(s):

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Picolinic Acid ◽

Antimicrobial Activities ◽

Clinical Control

ABSTRACT We studied the in vitro and in vivo antimicrobial activities of picolinic acid (PA) in combination with the antiprotozoal drug quinacrine against intramacrophage Mycobacterium avium complex (MAC). Quinacrine significantly potentiated the anti-MAC activity of PA, suggesting the usefulness of this combination in the clinical control of MAC infection.

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In vitro and in vivo activities of clarithromycin against the Mycobacterium avium complex

International Journal of Antimicrobial Agents ◽

10.1016/0924-8579(94)90006-x ◽

1994 ◽

Vol 4 (3) ◽

pp. 175-181 ◽

Cited By ~ 2

Author(s):

Hajime Saito ◽

Haruaki Tomioka ◽

Katsumasa Sato ◽

Satoshi Dekio

Keyword(s):

Mycobacterium Avium ◽

Mycobacterium Avium Complex

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Activities of bay Y 3118, levofloxacin, and ofloxacin alone or in combination with ethambutol against Mycobacterium avium complex in vitro, in human macrophages, and in beige mice.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.3.546 ◽

1996 ◽

Vol 40 (3) ◽

pp. 546-551 ◽

Cited By ~ 22

Author(s):

L E Bermudez ◽

C B Inderlied ◽

P Kolonoski ◽

M Wu ◽

L Barbara-Burnham ◽

...

Keyword(s):

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Test System ◽

Equivalent Dose ◽

Human Macrophage ◽

Spleen Tissue ◽

Bactericidal Activities ◽

Therapeutic Activities

Levofloxacin, ofloxacin, and Bay Y 3118 are new fluoroquinolones with variable in vitro bacteriostatic and bactericidal activities against the Mycobacterium avium complex (MAC). The potential therapeutic activities of these agents both alone and combined with ethambutol were evaluated in a human macrophage test system and in the beige mouse animal test system with MAC strain 101. Bay Y 3118 at a human-equivalent dose of 30 mg/kg/day for 4 weeks caused a significant reduction in mortality compared with that in untreated controls (P = 0.02). Bay Y 3118 also caused significant reductions in the number of MAC organisms in the blood, liver tissue, and spleen tissue compared with those in untreated controls. Levofloxacin at a human-equivalent dose of 200 mg/kg/day was associated with a significant reduction in mortality (10 versus 39%); however, treatment with either levofloxacin or ofloxacin (200 mg/kg/day) did not result in significant reductions in the numbers of MAC organisms in blood, liver, and spleen compared with those in untreated controls. When Bay Y 3118 was combined with ethambutol, there was no enhancement in therapeutic activity except in the spleen in terms of CFU per gram (reductions of 89% compared with the untreated control, 63% compared with Bay Y 3118 alone, and 72.5% compared with ethambutol alone). Levofloxacin in combination with ethambutol was more active than either drug alone in the reduction of organisms in blood, liver, and spleen. Bay Y 3118 was the most active fluoroquinolone for monotherapy of MAC infection in beige mice, and the combination of ethambutol plus either levofloxacin or ofloxacin was at least additive. In summary, this study demonstrates that quinolones, although active, are inhibitory against MAC in vivo and that there is little correlation between the activity of quinolones in vitro and the activity in mice.

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In Vitro and In Vivo Activity of Azithromycin (CP 62,993) Against the Mycobacterium avium Complex

The Journal of Infectious Diseases ◽

10.1093/infdis/159.5.994 ◽

1989 ◽

Vol 159 (5) ◽

pp. 994-997 ◽

Cited By ~ 43

Author(s):

C. B. Inderlied ◽

P. T. Kownoski ◽

M. Wu ◽

L. S. Young

Keyword(s):

Mycobacterium Avium ◽

Mycobacterium Avium Complex

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Activity of ABT-773 against Mycobacterium avium Complex in the Beige Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.10.2895-2896.2000 ◽

2000 ◽

Vol 44 (10) ◽

pp. 2895-2896 ◽

Cited By ~ 8

Author(s):

M. H. Cynamon ◽

J. L. Carter ◽

C. M. Shoen

Keyword(s):

Body Weight ◽

Mouse Model ◽

Antimicrobial Agent ◽

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Viable Cell ◽

Beige Mouse ◽

Cell Counts

ABSTRACT ABT-773, a new ketolide antimicrobial agent, was evaluated in comparison to clarithromycin (CLA) in vitro against Mycobacterium avium complex (MAC) and in a beige mouse model of disseminated MAC infection. The MICs at which 50 and 90% of the isolates tested were inhibited were 2 and 4 μg/ml, respectively, for CLA and 8 and 16 μg/ml, respectively, for ABT-773. Eight CLA-resistant isolates were found to be resistant to ABT-773 (MICs > 64 μg/ml). In the in vivo study mice were treated with ABT-773 (50, 100, and 200 mg/kg of body weight) or CLA (200 mg/kg). Both ABT-773 (100 and 200 mg/kg) and CLA significantly decreased the viable cell counts in spleens and lungs. ABT-773 (200 mg/kg) and CLA had similar activities in lungs, but the former was more active in spleens.

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Aspiration Revisited: Prospective Evaluation of a Physiologically Pressurized Model With Animal Correlation and Broader Applicability to Filler Complications

Aesthetic Surgery Journal ◽

10.1093/asj/sjab194 ◽

2021 ◽

Author(s):

Hyoung-Jin Moon ◽

Won Lee ◽

Ji-Soo Kim ◽

Eun-Jung Yang ◽

Hema Sundaram

Keyword(s):

Normal Saline ◽

False Negative ◽

Vascular Complications ◽

Filler Injection ◽

Negative Results ◽

Needle Position ◽

False Negative Results ◽

In Vivo Testing

Abstract Background Aspiration testing before filler injection is controversial. Some believe that aspiration can help prevent inadvertent intravascular injection, while others cite false-negative results and question its value given that the needle position always changes somewhat during injection procedures. Objectives To test the relation of false-negative results to the viscosity of the material within the needle lumen and determine whether a less viscous material within the needle lumen could decrease the incidence of false-negative results. Methods In vitro aspiration tests were performed using 30-G and 27-G needle gauges, two cross-linked hyaluronic acid fillers, normal saline bags pressurized at 140 and 10 mmHg to mimic human arterial and venous pressures, and three needle lumen conditions (normal saline, air, and filler). Testing was repeated three times under each study condition (72 tests in total). For in vivo correlation, aspiration tests were performed on femoral arteries and central auricular veins in three rabbits (4–5 aspirations per site, 48 tests in total). Results In vitro and in vivo testing using 30-G needles containing filler both showed false-negative results on aspiration testing. In vitro and in vivo testing using needles containing saline or air showed positive findings. Conclusions False-negative results from aspiration testing may be reduced by pre-filling the needle lumen with saline rather than a filler. The pressurized system may help overcome challenges of animal models with intravascular pressures significantly different from those of humans. The adaptability of this system to mimic various vessel pressures may facilitate physiologically relevant studies of vascular complications.

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