III Infection Fighters
A. High-dose AP for PCP?
Background
Doctors in Toronto enrolled 14 subjects with AIDS who had developed the life-threatening
lung infection PCP despite use of aerosol pentamidine (AP) 300 mg/month. None of the
subjects could tolerate Bactrim/Septra® or dapsone. Doctors increased the dose of AP to
"300 mg every two weeks."
Results
Eight subjects died (cause of death was not released) and 6 subjects remained on the
high-dose AP protocol and did not develop PCP. The increased dose has not caused any
increased toxicity. Long-term observation continues.
Reference:
- Lee-Pack L, Favell K, Lewis C, et al. High-dose aerosol pentamidine for secondary
prophylaxis of pneumocystis carinii pneumonia in patients intolerant of other systemic
therapy. Tu.B. 2290.
B. Nitazoxanide for crypto
Study details
Researchers in Mexico recruited 15 adults with AIDS who had diarrhea caused by the
parasite C. parvum (crypto). The subjects had already tried other drugs
including:
- azithromycin
- somatostatin (Octreotider)
- spiramycin
but their diarrhea continued. Doctors gave some subjects NTZ (nitazoxanide) 1 gram/day
and others 2 g/day for between "10 to 30 days."
Results
Ten subjects recovered from crypto and technicians could not find any parasites in their
stool samples. The remaining 4 subjects appeared to have diarrhea caused by CMV or
bacteria. Doctors interested in obtaining NTZ for their patients with crypto may call
Sandy Faulkner at Unimed Pharmaceuticals at 708-541-2525.
Reference:
- Feregrino GM, Higuera RF, Rossignol JF, et al. Extraordinary potency of the
nitozoxanide. A new antiparasitary against the Cryptosporidium parvum infections in
advanced AIDS. Th.b.4213.
C. Garlic enemas for crypto?
Doctors in Los Angeles have conducted a study using a chemical found in garlic called
allicin. The doctors told subjects with crypto to mix 30 mg of allicin with 90 ml of water
and drink. They were then instructed to give themselves a "retention enema" with
the second dose. Fifteen of eighteen subjects in this study had less than 30 CD4+ cells.
Results
The doctors reported results from 18 subjects who had used the drug for "at least 3
weeks." Eight subjects reported reduced diarrhea and either gained weight or stopped
losing weight. By the 6th week of the study, 10 of 16 subjects had fewer bowel movements
and their weight stabilized or increased. In the 12th week of the study, technicians could
not find any crypto in stool samples from 4 subjects. Subjects complained about the taste
and smell of the garlic preparation, but no toxicity was reported. Further studies are
underway.
Reference:
- Fareed G, Scolaro M, Jordan W, et al. The use of a high-dose garlic preparation
for the treatment of cyrptosporidium parvum diarrhea. Th.B.4215.
D. Roxithromycin for crypto?
Background
Doctors in Brazil recruited 2 women and 21 men with AIDS who had diarrhea for at least 1
month. These subjects were infected with the parasite crypto. The average CD4+ cell count
was 151 cells. Doctors gave subjects roxithromycin 300 mg orally twice daily for 1 month.
Roxithromycin is 'related' to the antibiotics azithromycin, clarithromycin and
erythromycin.
Results
Eleven subjects recovered from diarrhea while 7 had less frequent diarrhea or reduced
numbers of C. parvum in their stool samples. Five subjects did not respond to the
drug. Roxithromycin caused minor liver damage which healed once subjects reduced the dose
by 50% or stopped taking the drug.
Reference:
- Sprinz E, Barcellos S, Bem DD, et al. A phase II trial with roxithromycin in
AIDS-related cryptosporidium diarrhea. Th.B. 4211.
E. Three options for preventing MAC; which is best?
Background
In North America, when CD4+ cell counts fall to between 75 and 50 cells, people with
HIV/AIDS are at increased risk for developing a certain bacterial infection called MAC (mycobacterium
avium complex). Symptoms of MAC can include:
- fever
- night sweats
- weight loss
- painful intestines
- diarrhea
- loss of appetite
- tiredness
A report on treatment for MAC appear later in this issue. The antibiotic rifabutin
taken at a dose of 300 mg/day can delay the appearance of symptoms of MAC infection. We
now report results from a study comparing the effects of:
- azithromycin 1200 mg once a week
- rifabutin 300 mg/day
- a combination of both regimens
Neither doctors nor subjects were supposed to know which drugs subjects received. The
CD4+ cell counts ranged between 47 and 57 cells. About 5% of subjects were female and 95%
male. Researchers randomly assigned the following subjects to receive:
- azithromycin 233 subjects
- rifabutin 236 subjects
- combination 224 subjects
Results -- protection from MAC
After 1 year the researchers found that the following proportion of subjects in each group
developed MAC:
- azithromycin 7.6%
- rifabutin 15%
- combination 3%
These differences were statistically significant. Clearly subjects who received
azithromycin were 50% less likely to develop MAC than those who received rifabutin.
Results -- protection from other infections
Subjects receiving rifabutin were twice as likely to develop certain bacterial infections
in the lungs and sinuses than subjects who received azithromycin.
Results -- survival
A total of 249 deaths were reported during this study, of which an equal number occurred
in each group.
Results -- toxicity
The proportion of subjects in the following groups reported side effects:
- combination 90%
- azithromycin 86%
- rifabutin 76%
Thus, subjects assigned to receive azithromycin alone or in combination had more side
effects than subjects who did not receive that drug. Side effects included:
- painful intestines
- diarrhea
- nausea
- vomiting
Deciding which regimen is suitable
- Results from this study clearly suggest that azithromycin alone or in combination with
rifabutin is "more effective than rifabutin [alone]".
- The advantage of using azithromycin is that it need only be taken once weekly, unlike
rifabutin. Only about 11% of subjects using azithromycin developed bacteria that were
resistant to that drug.
- The combination of azithromycin and rifabutin is clearly the most effective of the three
regimens. Since azithromycin need only be taken once weekly, side effects due to
azithromycin are limited to a few hours on one day.
Drug interactions
A disadvantage in using rifabutin is that it will interact with the new anti-HIV drugs
ritonavir and indinavir. Taking these drugs can increase the concentration of rifabutin in
the blood from 2 to 7 times above normal. Indinavir and ritonavir do not have this effect
on azithromycin.
Reference:
- Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated
mycobacterium avium complex with weekly azithromycin, daily rifabutin or both. New England
Journal of Medicine 1996;335(6):392-398.
F. Using Biaxin® to prevent MAC, a risky decision?
Study details
Doctors in England, France, Germany and the US recently reported their results using the
antibiotic clarithromycin (also know as Biaxin, Klaricid, Mavid and Zeclar) to prevent MAC
infection in 667 subjects with AIDS. Researchers assigned subjects at random to receive
clarithromycin 500 mg taken every 12 hours or fake clarithromycin (placebo). Roughly 90%
of subjects were male and 10% female. At least half of the 333 subjects who received the
antibiotic had a CD4+ cell count of 30 cells and a CD8+ cell count of 560 cells.
Infections that subjects had before entering this study included:
- yeast infections in the mouth
- PCP
- hairy leukoplakia
- shingles
Results -- who developed infections?
Six percent of subjects who received clarithromycin developed MAC, as did 16% of subjects
on placebo. This difference was statistically significant.
Results -- survival
About 32% of subjects in the clarithromycin group died during the study as did 41% of
subjects who received placebo, a difference that was statistically significant. The
difference in survival continued for about 2 years. By that time, however, only 28
subjects remained on clarithromycin and 20 on placebo. Once subjects developed MAC, the
length of time they survived was the same whether or not they received clarithromycin.
Overall, subjects whose blood had MAC were twice as likely to die as subjects who did not
have MAC in their blood.
Technicians were able to study samples of MAC-infected blood from 19 subjects who
received clarithromycin. They found that roughly 60% had MAC that could resist the effects
of clarithromycin.
Results -- other infections
Subjects in the clarithromycin group had fewer bacterial chest infections (2%) than
subjects on placebo (6%). More subjects on placebo (57%) needed to stay in a hospital than
did subjects taking clarithromycin (47%).
Toxicity
Subjects receiving clarithromycin were more likely to experience certain side effects
including:
- nausea and/or vomiting
- altered sense of taste
than subjects on placebo. Seventeen percent of subjects on placebo left the study
because of side effects as did 18% on clarithromycin.
What next?
Results from this study show that clarithromycin 500 mg every 12 hours can provide some
protection against:
- life-threatening MAC infection
- bacterial chest infections
- infection with a certain parasite (giardia)
Clarithromycin is one of two antibiotics that can suppress MAC infection, the other
being azithromycin. Most subjects on clarithromycin who develop MAC were also likely to
have MAC that could withstand azithromycin. This event limits their options for effective
treatment. Some doctors may prefer to save clarithromycin for later use as part of a
treatment regimen. Others may use the 2 antibiotics sparingly. Consider, for example, the
previous study where azithromycin was taken once a week with or without rifabutin.
References:
- Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin
prophylaxis against disseminated mycobacterium avium complex infections in patients with
advanced Acquired Immunodeficiency Syndrome. New England Journal of Medicine
1996;335(6):384-391.
G. A powerful combination for treating MAC in Canada
Study details
Canadian doctors reported results from their study testing two regimens in HIV-infected
subjects who developed symptoms of MAC. All subjects had detectable MAC in their blood,
and were randomly assigned to receive one of two regimens consisting of 3 or 4 drugs. The
3-drug regimen consisted of:
- clarithromycin 2 g/day
- rifabutin 300 mg/day
- ethambutol (see the following note)
A note on ethambutol
The dose of ethambutol was adjusted to the weight of each subject. Those who weighed less
than 60 kg received ethambutol 800 mg/day. To subjects who weighed between 60 and 80 kg,
the researchers gave 1200 mg/day. Subjects who weighed more than 80 kg received 1600
mg/day.
Rifabutin, adjusting the dose
When the study began researchers gave subjects in the 3-drug group rifabutin 600 mg/day.
At that dose many developed eye inflammation so researchers reduced the dose to 300
mg/day.
Five percent of subjects in the 3-drug group were female and 95% male, as were a
similar proportion of subjects in the 4-drug group. Half of the subjects had a CD4+ cell
count of 10 cells. Over 90% of subjects had less than 31 CD4+ cells.
Four antibiotics
Subjects in the 4-drug group received:
- ciprofloxacin 750 mg twice daily
- clofazimine 100 mg
- ethambutol (dose adjusted as above)
- rifampin 600 mg/day
Results -- symptoms
- Subjects in the 3-drug group found that their symptoms of MAC infection became less
severe as early as the 2nd week of the study. By the 12th week, at least 50% of the
subjects in this group had reduced symptoms of MAC infection compared to their pre-study
levels. This change was statistically significant.
- Reducing the dose of rifabutin from 600 mg to 300 mg/day did not affect changes in MAC
symptoms .
- Neither regimen was better or worse than the other in reducing "fever or
diarrhea".
- Subjects receiving the 3-drug regimen lost less weight than other subjects. This
difference was also statistically significant.
- Subjects in the 3-drug group were able to carry out their daily activities better than
subjects in the 4-drug group, a difference that was statistically significant
.
Results -- survival
Half of the subjects in the 3-drug group survived for about 9 months while half the
subjects in in the 4-drug group survived for 5 months. This difference in length of
survival was statistically significant.
Results -- levels of bacteria
It is important to remember that at the start of the study all subjects had detectable MAC
in their blood. Once subjects began to receive treatment, technicians could not detect MAC
in blood samples from 29% of subjects in the 4-drug group and 69% in the 3-drug group.
This difference was statistically significant.
Toxicity
The risk of developing eye inflammation in the 3-drug group was about 50% after 7 months.
After researchers reduced the dose of rifabutin to 300 mg/day the risk fell to 13%. Again,
this difference was statistically significant. One side effect noticed by the 3-drug group
was an altered sense of taste.
What's next?
What results from this study show is that a 3-drug combination of clarithromycin,
ethambutol and rifabutin is better treatment than a combination of 4 older drugs. Compared
to the 4-drug group, the 3-drug combination group experienced:
- increased survival
- reduced symptoms of MAC
- improved quality of life
How much clarithromycin?
It is clear from this and other studies that clarithromycin is an important part of an
anti-MAC treatment regimen. What is not clear is how much clarithromycin is best. Other
studies suggest that lower doses of clarithromycin, ie., 500 mg every 12 hours, are less
toxic than higher doses. Due to their toxicity, higher doses may also reduce survival.
Readers should note that rifabutin and clarithromycin interact. Rifabutin reduces levels
of clarithromycin in the blood by about 50% and clarithromycin increases levels of
rifabutin by 77%. This is why the Canadian researchers used such a high dose of
clarithromycin. According to their calculations, the mix of clarithromycin and rifabutin
used in this study should result in levels of clarithromycin that would be similar to
those found in subjects taking clarithromycin 1 g/day. Results from studies using
azithromycin in combination with other antibiotics as anti-MAC therapy are needed. This
Canadian regimen may not be the best anti-MAC therapy, but it is much better than
combinations of older drugs.
References:
- Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the
treatment of MAC-bacteremia in AIDS: rifabutin, ethambutol and clarithromycin versus
rifampin, ethambutol, clofazimine and ciprofloxacin. New England Journal of Medicine
1996;335(6):337-383.
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