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A Meta-analysis of Salvage Therapy for Pneumocystis carinii Pneumonia
Raymond A. Smego, Jr, MD, MPH, DTM& ;H;
Shashi Nagar, BSc;
Bonnie Maloba, MBBCh;
Mirjana Popara, MBBCh
Arch Intern Med. 2001;161:1529-1533.
ABSTRACT
| |
Objective To determine the relative efficacies of alternative antipneumocystis
agents in human immunodeficiency virus (HIV)–infected patients with Pneumocystis carinii pneumonia unresponsive to primary
drug treatment with a combination product of trimethoprim and sulfamethoxazole
or parenteral pentamidine.
Methods Meta-analysis of 27 published clinical drug trials, case series, and
case reports involving P carinii pneumonia. Data
extracted included underlying disease, primary antipneumocystis treatment,
days of failed primary treatment, salvage regimen, use of systemic corticosteroids
and antiretroviral drugs, and clinical outcome.
Results In 497 patients with microbiologically confirmed P carinii pneumonia (456 with HIV or acquired immunodeficiency syndrome),
initial antipneumocystis treatment failed and they therefore required alternative
drug therapy. Failed regimens included trimethoprim-sulfamethoxazole (160
patients), intravenous pentamidine (63 patients), trimethoprim-sulfamethoxazole
and/or pentamidine (258 patients), aerosolized pentamidine (6 patients), atovaquone
(3 patients), dapsone (3 patients), a combination product of trimethoprim
and dapsone (2 patients), and trimethoprim-sulfamethoxazole followed by a
combination of clindamycin and primaquine phosphate (2 patients). Efficacies
of salvage regimens were as follows: clindamycin-primaquine (42 to 44 [88%-92%]
of 48 patients; P<10-8), atovaquone
(4 [80%] of 5), eflornithine hydrochloride (40 [57%] of 70; P<.01), trimethoprim-sulfamethoxazole (27 [53%] of 51; P<.08), pentamidine (64 [39%] of 164), and trimetrexate (47 [30%]
of 159).
Conclusion The combination of clindamycin plus primaquine appears to be the most
effective alternative treatment for patients with P carinii pneumonia who are unresponsive to conventional antipneumocystis agents.
INTRODUCTION
FOR PATIENTS with Pneumocystis carinii pneumonia,
a combination product of trimethoprim and sulfamethoxazole and parenteral
pentamidine are first-line therapeutic agents and have been shown to have
comparable clinical efficacy.1-4
Trimethoprim-sulfamethoxazole is considered the drug of choice because of
its excellent tissue penetration and oral bioavailability, more rapid in vivo
activity, and relatively lower cost and wide availability. Intolerance to
both trimethoprim-sulfamethoxazole and pentamidine is not uncommon, especially
in patients with human immunodeficiency virus/acquired immunodeficiency syndrome
(HIV/AIDS), and may require a change in therapy in up to 50% to 60% of treated
patients.3, 5 For these individuals,
substitution of pentamidine for trimethoprim-sulfamethoxazole or vice versa
is generally effective.2, 6 However,
there is a paucity of published data on the efficacy of "salvage" therapy
for patients unresponsive to conventional treatment with trimethoprim-sulfamethoxazole
or pentamidine. Agents available for treating first-episode and unresponsive P carinii pneumonia include trimetrexate, atovaquone, and
a combination of clindamycin and primaquine phosphate, but no comparative
trials using these drugs as salvage regimens have been conducted. We conducted
a literature review and meta-analysis of drug treatment studies and case series
or reports to determine the relative efficacies of alternative antipneumocystis
agents in patients with unresponsive P carinii pneumonia.
PATIENTS AND METHODS
From January 1975 through August 1999, a comprehensive analysis of the
English-language literature was conducted on the basis of a MEDLINE computerized
search, perusal of Index Medicus and Current Contents,
and review of bibliographies of articles and major infectious diseases textbooks
to identify clinical trials or case series or reports in which alternative
agents were used for patients with P carinii pneumonia
and conventional treatment failure. Key words included P carinii, HIV/AIDS, salvage therapy, trimethoprim-sulfamethoxazole, pentamidine,
trimetrexate, atovaquone, and clindamycin-primaquine. Twenty-seven clinical studies were identified that reported sufficient
details of drug treatment failure and alternative therapy for P carinii pneumonia, including clinical outcome, and were included
in this review. Only cases of pneumonia that were microbiologically confirmed
by lung biopsy, bronchoalveolar lavage, or sputum smear to be due to P carinii infection were included in the analysis. Data
extracted included underlying disease, primary antipneumocystis treatment,
days of failed primary treatment, salvage regimen, use of systemic corticosteroids
and antiretroviral drugs, and clinical outcome.
Failure of primary antipneumocystis treatment was generally defined
as clinical deterioration occurring during the first 4 to 5 days of therapy
or lack of improvement in the patient's condition after 7 or more days of
treatment. We included patients from 3 studies in which patients were switched
to alternate drug therapy after only 3 or more days of treatment because of
the stringent criteria that were used: (1) progressive clinical deterioration
as demonstrated by the inability to maintain a stable arterial PaO2
despite an increase in the fraction of inspired oxygen (FIO2),
and (2) progressive deterioration of vital signs (pulse rate, blood pressure,
and respiratory rate) with a requirement for increased FIO2. Four
studies (with a total of 51 patients) were also included in the analysis even
though a precise duration of initial antipneumocystis treatment was not given;
these included a National Institutes of Health study (37 patients) and a Centers
for Disease Control multicenter trial (14 patients).
In the studies reviewed, a positive response to salvage treatment was
variably defined but included 1 of the following: (1) amelioration or resolution
of baseline signs and symptoms (eg, fever, cough, dyspnea, pulse, and respiratory
rate), chest radiograph, and arterial blood gases; (2) sustained clinical
improvement for at least 2 to 4 weeks after cessation of antipneumocystis
therapy with no alternate treatment given during that time; (3) patient discharged
alive from the hospital; or (4) patient alive 30 days after confirmation of
the diagnosis. Salvage therapy was considered a failure when the above criteria
for positive response were not met.
Systemic corticosteroids were not administered with salvage agents for
most study patients. Six studies indicated that steroids had been used for
some patients (a maximum of 38 patients, or 7.6% of the study cohort) with
moderately severe P carinii pneumonia, usually at
the discretion of the attending physician, but few details were given. There
were no statistically significant differences in the incidences of adjuvant
corticosteroid or antiretroviral drug use between the salvage regimens examined.
Statistical interpretation of data was performed using a computer software
package (Epi Info; Centers for Disease Control and Prevention, Atlanta, Ga)
and the  2 test with Yates correction factor or Fisher exact
test, as appropriate. For all tests, P<.05 was
considered statistically significant. Confidence intervals were determined
assuming a binomial distribution of values.
RESULTS
Clinical and treatment features for patients treated with salvage drug
regimens for P carinii pneumonia are shown in Table 1. Four hundred ninety-seven patients
were identified in our systematic literature review and included in the data
analysis. Most patients were adults (467 of 497 patients). In the study population,
HIV/AIDS was the major underlying disease, accounting for 92% of cases treated
with salvage therapy. Drugs used in failed treatment regimens included trimethoprim-sulfamethoxazole
(160 patients), parenteral pentamidine (63 patients), inhaled pentamidine
(6 patients), atovaquone (3 patients), dapsone (3 patients), a combination
product of trimethoprim and dapsone (2 patients), and trimethoprim-sulfamethoxazole
followed by clindamycin-primaquine (2 patients). For 258 patients, failure
was reported for conventional therapy (ie, trimethoprim-sulfamethoxazole and/or
pentamidine; when patients received both drugs, they were generally given
sequentially). Duration of failed primary therapy was 3 days or more (33 patients),
4 days or more (20 patients), 6 days (25 patients), or 5 to 7 days or more
(358 patients); the length of failed treatment was not stated for 61 patients.
Salvage treatment included trimetrexate (159 patients), pentamidine (164 patients),
eflornithine hydrochloride (70 patients), clindamycin-primaquine (48 patients),
trimethoprim-sulfamethoxazole (51 patients), and atovaquone (5 patients).
Comparable efficacies of these salvage regimens are shown in Table 2.
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Table 1. Clinical Drug Studies and Case Reports of Salvage Therapy
for Pneumocystis carinii Pneumonia*
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Table 2. Efficacies of Salvage Drug Regimens Used in 497 Patients With Pneumocystis carinii Pneumonia*
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COMMENT
For HIV-related P carinii pneumonia, treatment
with trimethoprim-sulfamethoxazole or parenteral pentamidine is effective
in about 75% to 95% of cases1-3,5-6,15;
improvement generally occurs within 4 to 8 days of treatment, and some patients
appear to respond within 24 hours. However, the optimal clinical approach
for patients whose condition does not improve or continues to deteriorate
despite 4 to 10 days of primary drug treatment is not certain. Switching therapy
from trimethoprim-sulfamethoxazole to pentamidine or vice versa or to agents
such as trimetrexate, atovaquone, or clindamycin-primaquine is typically the
recommended strategy,1, 3 but there
are few useful data available that detail the likelihood of success with these
substitutions.
In most settings, trimethoprim-sulfamethoxazole is the agent of first
choice for P carinii pneumonia, and when intolerance
or unresponsiveness to treatment occurs, pentamidine is usually the alternative
drug used. For many years it has been observed that patients with P carinii pneumonia who are switched to pentamidine because of adverse
effects due to trimethoprim-sulfamethoxazole, such as fever, rash, hepatitis,
leukopenia, or azotemia, respond much better than when pentamidine is used
because of clinical disease refractory to trimethoprim-sulfamethoxazole.2, 5-6 In a large prospective
comparative trial of trimethoprim-sulfamethoxazole vs pentamidine for P carinii pneumonia, Klein and colleagues2
showed that survival rates for persons requiring a change in therapy (to either
drug) because of failure to respond were 46% for the trimethoprim-sulfamethoxazole
group and 56% for the pentamidine group. When a change in therapy was made
because of toxic effects, survival rates were 97% and 94% for these 2 drugs,
respectively. In the present meta-analysis, pentamidine was successful in
only 37% of patients in whom trimethoprim-sulfamethoxazole treatment had failed,
and conversely trimethoprim-sulfamethoxazole appeared little more effective
(53%) when used because of unresponsiveness to pentamidine. Eflornithine,
an antiprotozoan drug that reduces polyamine synthesis via irreversible inhibition
of ornithine decarboxylase, has been investigated during the past 15 years
as a possible therapeutic option for primary P carinii
pneumonia and for treatment failures with first-line agents.12, 20-21,28, 30
The cumulative data summarized herein suggest that eflornithine has efficacy
(40 [57%] of 70 patients; P<.01) as a salvage
drug for unresponsive P carinii pneumonia.
Trimetrexate is a lipid-soluble analogue of methotrexate and a much
more potent inhibitor of protozoan dihydrofolate reductase than either trimethoprim
or pyrimethamine.19, 32-34
The drug is currently available only in intravenous form and is administered
in combination with leukovorin (folinic acid) to prevent adverse hematologic
effects. In comparison with trimethoprim-sulfamethoxazole as primary treatment
for moderately severe P carinii pneumonia, trimetrexate
was better tolerated than trimethoprim-sulfamethoxazole but was associated
with a lower response rate and a higher incidence of relapse than trimethoprim-sulfamethoxazole
therapy.32-34
In this review, trimetrexate was effective in only 30% of trimethoprim-sulfamethoxazole
and pentamidine treatment failures.19 Trimetrexate
does not appear to be a useful salvage agent for patients with HIV-related P carinii pneumonia that is clinically resistant to conventional
therapy.
Atovaquone is a 1,4-hydroxynaphthoquinone that has clinical activity
against P carinii, and it is a useful oral therapeutic
option for patients with mild to moderate P carinii
pneumonia. Like trimetrexate, atovaquone has been found to be less effective
than trimethoprim-sulfamethoxazole for the initial treatment of P carinii pneumonia, but it has fewer treatment-limiting adverse effects.35-37 The drug offers an
alternative for persons who cannot tolerate trimethoprim-sulfamethoxazole,
but there is insufficient experience with atovaquone as a salvage therapy
agent to allow practical comments about its use in cases of unresponsive P carinii pneumonia.
Of all the salvage agents examined, the combination of clindamycin-primaquine
was the most successful regimen for patients in whom conventional antipneumocystis
treatment failed. Approximately 90% (P<10-8) of patients with P carinii pneumonia
refractory to trimethoprim-sulfamethoxazole or pentamidine or both had a good
clinical response to clindamycin-primaquine. This dual combination is effective
as primary treatment of mild to moderately severe AIDS-related P carinii pneumonia and perhaps has fewer adverse effects compared
with trimethoprim-sulfamethoxazole.38-45
The reason(s) for the significantly better response rate for clindamycin-primaquine
compared with other salvage regimens is not clear; variables such as the duration
of failed primary treatment, severity of pneumonia or clinical presentation,
or type of underlying disease do not appear to account for these differences.
It is possible that combination treatment provides a synergistic antipneumocystis
effect not afforded by monotherapy, although the present difficulty in culturing
this organism in vitro precludes susceptibility testing and proof of such
a hypothesis. The most serious toxic effects of clindamycin-primaquine are
hematologic (eg, neutropenia, anemia, thrombocytopenia, and methemoglobinemia).44 The optimal role for clindamycin-primaquine may,
in fact, be as a salvage regimen for patients unresponsive to or unable to
tolerate trimethoprim-sulfamethoxazole or pentamidine.
It may be very difficult to determine whether a lack of response for
an individual patient with P carinii pneumonia to
conventional treatment is due to drug resistance, immunologic dysfunction,
concurrent pulmonary infection, or another factor. Sequencing of resistance
genes in P carinii can identify a molecular basis
for trimethoprim-sulfamethoxazole resistance, but this technology is not widely
available commercially and remains largely a research tool. Although there
are some patients who do better when taking one antipneumocystis agent compared
with another, it is much more common to recognize a second process (eg, concurrent
pulmonary infection, tumor, allergy, acute respiratory distress syndrome)
as a cause for unresponsiveness to treatment.14, 46-48
Bronchoscopic studies of unresolving HIV-related pneumonia have documented
a secondary pulmonary infection in 8.9% to 39% of cases.46, 49-50
Concurrent pathogens may include viruses (especially cytomegalovirus), mycobacteria,
fungi, and bacteria.46, 49-50
Noninfectious pathologic conditions such as Kaposi sarcoma or non-Hodgkin
lymphoma may also occur concurrently with P carinii
pneumonia. Accordingly, bronchoalveolar lavage with or without lung biopsy
should be strongly considered for any patient with presumptive or documented P carinii pneumonia who is not responding to antipneumocystis
treatment to detect alternative or coexisting lung pathologic conditions.46-50
When salvage therapy is indicated, clindamycin-primaquine appears to be the
most effective alternative form of drug therapy.
AUTHOR INFORMATION
Accepted for publication December 6, 2000.
Corresponding author: Raymond A. Smego, Jr, MD, MPH, DTM&H, Department
of Medicine, The Aga Khan University Medical College, Stadium Road, PO Box
3500, Karachi 74800, Pakistan.
From the Department of Clinical Microbiology and Infectious Diseases,
University of the Witwatersrand/South African Institute for Medical Research,
and the Sizwe Tropical Diseases Hospital, Johannesburg, South Africa.
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