Web Annex B. Evidence-to-decision tables

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For further information, contact:

Department of Global Infectious Hazard Preparedness World Health Organization

20 avenue Appia 1211 Geneva 27

for plague management:

revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission

guidelines

WHO

ISBN 978-92-4-001560-9

Web Annex B. Evidence-to-decision tables

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WHO guidelines

for plague management:

revised recommendations for the use of rapid diagnostic tests,

fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission

Web Annex B. Evidence-to-decision tables

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This publication forms part of the WHO guideline entitled WHO guidelines for plague management: revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post- mortem transmission. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014).

Design and layout by Sophie Guetaneh Aguettant

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1. F1RDT for plague 1 1.1 Question 1. Should F1RDT be used to detect pneumonic plague in

areas where plague is endemic? 1

1.1.1 Assessment 1

1.1.2 Summary of judgements 4

1.1.3 Type of recommendation 5

1.1.4 Conclusions 5

1.2 Question 2. Should F1RDT be used to diagnose pneumonic plague in

patients in areas where an outbreak is in progress? 6

1.2.1 Assessment 6

1.2.2 Summary of judgements 9

1.2.3 Type of recommendation 10

1.2.4 Conclusions 10

1.3 Question 3. Should F1RDT be used to detect bubonic plague in areas

where plague is endemic? 10

1.3.1 Assessment 10

1.3.2 Summary of judgements 13

1.3.3 Type of recommendation 14

1.3.4 Conclusions 14

1.4 Question 4. Should F1RDT be used to diagnose bubonic plague in

patients in areas where an outbreak is in progress? 14

1.4.1 Assessment 15

1.4.2 Summary of judgements 17

1.4.3 Type of recommendation 18

1.4.4 Conclusions 19

2. Antibiotics for treating plague 21 2.1 Question 1. How do fluoroquinolones compare with streptomycin

for the treatment of pneumonic and septicaemic plague? 21

2.1.1 Assessment 21

2.1.2 Summary of judgements 23

2.1.3 Type of recommendation 24

2.1.4 Conclusions 24

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2.2.4 Conclusions 28 2.3 Question 3. How do fluoroquinolones compare with

chloramphenicol for the treatment of plague meningitis? 28

2.3.1 Assessment 28

2.3.2 Summary of judgements 30

2.3.3 Type of recommendation 31

2.3.4 Conclusions 31

2.4 Question 4. How do fluoroquinolones compare with doxycycline for

the postexposure presumptive treatment of plague? 31

2.4.1 Assessment 32

2.4.2 Summary of judgements 34

2.4.3 Type of recommendation 34

2.4.4 Conclusions 34

3. Use of personal protective equipment 35 3.1 Question 1. Should full personal protective equipment be used

instead of no personal protective equipment for the handling of a

dead body of a person infected with plague? 35

3.1.1 Assessment 35

3.1.2 Summary of judgements 37

3.1.3 Type of recommendation 38

3.1.4 Conclusions 38

References 39

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1.1 Question 1. Should F1RDT be used to detect pneumonic plague in areas where plague is endemic?

■ Population: populations in which plague has previously occurred.

■ Intervention: F1RDT (a rapid diagnostic test [RDT] for plague).

1.1.1 Assessment

Judgement Research evidence Additional considerations

Problem. Is the problem a priority?

No Probably no Probably yes Yes Varies Don't know

Plague is a serious disease and has the potential to trigger large outbreaks with high mortality if control measures are not immediately implemented.

Pneumonic plague is rare, but has a high case-fatality rate, therefore it is important to detect the disease.

Test accuracy. How accurate is the test?

Very inaccurate Inaccurate Accurate Very accurate Varies Don't know

Where there is a high suspicion of pneumonic plague based on the presentation of symptoms, this test appears useful in terms of sensitivity.

This test appears to be of low specificity. However, this may in part be due to the inadequacy of the reference test (culture) and other factors.

Desirable effects. How substantial are the desirable anticipated effects?

Trivial Small Moderate Large Varies Don't know

The test allows for rapid generation of alerts that point to an outbreak.

The test is easy to perform and does not require advanced training of health staff.

The test is easy to access, including in remote areas and low- resource settings.

There is uncertainty around the true level of false positives with F1RDT because the reference standard for which data are available (culture) is imperfect, and may not detect the disease.

This can create apparent high levels of false positives with F1RDT.

continues ...

F1RDT for plague

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... continued

Undesirable effects. How substantial are the undesirable anticipated effects?

Large Moderate Small Trivial Varies Don't know

False-positive results can have serious consequences. However, if a positive test is used as an alert of a potential outbreak, and capacity exists to further investigate the patients, then these serious consequences (false alarms) can be mitigated.

Ensure this is part of the recommendation.

Certainty of the evidence of test accuracy. What is the overall certainty of the evidence of test accuracy?

Very low Low Moderate High

No included studies

The certainty of the evidence for the sensitivity and the specificity of the test is very low (see GRADE tables (1)).

Certainty of the evidence of the test's effects. What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test?

Very low Low Moderate High

No included studies

The Guideline Development Group was certain that low sensitivity would have a critical impact on detection, but this is not the case because the test seems to be sensitive. However, increased certainty of the evidence is required because the confidence intervals are wide and the included studies have a high risk of bias.

The Guideline Development Group was also certain that false- positive tests could lead to false alarms of an outbreak. Thus, the panel was asked to consider the evidence around false positives, and the number of false positives that might be expected.

Certainty of the evidence of effects of management decisions. What is the overall certainty of the evidence of effects of management decisions that are guided by test results?

Very low Low Moderate High

No included studies

A positive test result is highly likely to lead to further investigation of a possible outbreak.

Early treatment prevents further transmission.

Certainty of the evidence of test results/management decisions. How certain is the link between test results and management decisions?

No included studies

A positive test result will lead to immediate treatment of the patient.

A positive test result will also lead to further investigation and, if confirmed, will lead to implementation of preventive measures, including the tracing of contacts for postexposure prophylaxis.

Certainty of effects. What is the overall certainty of the evidence of effects of the test?

Very low LowModerate High

No included studies

There remain problems with the certainty of the evidence in relation to false positives.

continues ...

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... continued

Values. Is there significant uncertainty about or variability in the extent to which people value the main outcomes?

Significant uncertainty or variability

Possibly significant uncertainty or variability

Probably no significant uncertainty or variability No significant uncertainty or variability

The main outcome is plague, which is associated with high mortality.

A highly accurate RDT is needed to ensure prompt diagnosis of the disease and decrease the case-fatality rate.

From a public health perspective, there is uncertainty concerning

"false positives". However, any positive test results would then lead to further investigation to confirm the presence of an outbreak.

From the perspective of the community, people want a rapid result, and want to have the result confirmed. Thus, the test, in combination with confirmatory actions, is valued; however, the delays in confirmation need to be carefully managed (risk communication approaches are needed).

Balance of effects. Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Favours the comparison Probably favours the comparison

Does not favour either the intervention or the comparison Probably favours the intervention

Favours the intervention Varies

Don't know

The balance between the desirable and undesirable effects favours using the test in these circumstances in the appropriate way.

Resources required. How large are the resource requirements (costs)?

Large costs Moderate costs

Negligible costs and savings Moderate savings Large savings Varies Don't know

RDTs are inexpensive.

The consequences of missing one case are potentially considerable, but if there are a large number of false-positive results, this has resource implications.

Certainty of evidence of required resources. What is the level of certainty for the evidence of resource requirements (costs)?

Very low Low Moderate High

No included studies

–

Cost–effectiveness. Does the cost–effectiveness of the intervention favour the intervention or the comparison?

Does not favour either the intervention or the comparison Probably favours the intervention Favours the intervention Varies

No included studies

The cost–effectiveness of the test is likely to be high: there are likely to be positive outcomes resulting from its use and the test is inexpensive.

continues ...

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... continued

Equity. What would be the impact on health equity?

Reduced Probably reduced Probably no impact Probably increased Increased

Varies Don't know

The ease of access to and affordability of RDT might benefit populations living in remote areas and/or resource-limited settings, including the poorest settings.

However, any positive test results need to be confirmed and this has implications for people in these regions.

Acceptability. Is the intervention acceptable to key stakeholders?

RDTs for the diagnosis of other diseases, such as malaria and HIV, are widely used and well accepted worldwide.

Feasibility. Is the intervention feasible to implement?

No Probably no Probably yes Yes

Varies Don't know

Implementation of RDT for diagnosing other diseases has been successful in many settings, including settings with limited resources.

The test requires organization of a supply chain as well as staff training.

GRADE: Grading of Recommendations, Assessment, Development and Evaluation; HIV: human immunodeficiency virus; RDT: rapid diagnostic test.

1.1.2 Summary of judgements

Assessment Judgement

Problem No Probably no Probably yes Yes Varies Don't know

Test accuracy Very

inaccurate

Inaccurate Accurate Very accurate Varies Don't know

Desirable effects Trivial Small Moderate Large Varies Don't know

Undesirable effects Large Moderate Small Trivial Varies Don't know

Certainty of the evidence

of test accuracy Very low Low Moderate High No

included studies Certainty of the evidence

of the test's effects

Very low Low Moderate High No

included studies Certainty of the

evidence of effects of management decisions

Very low Low Moderate High No

evidence of test results/

management decisions

included studies

Certainty of effects Very low Low Moderate High No

included studies

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... continued

Values Significant

uncertainty or variability

Probably no significant uncertainty or variability

No significant uncertainty or variability Balance of effects Favours the

comparison

Probably favours the comparison

Does not favour either the intervention or the comparison

Probably favours the intervention

Favours the

intervention Varies Don't know

Resources required Large costs Moderate costs

Negligible costs and savings

Moderate

savings Large savings Varies Don't know Certainty of evidence of

required resources

Very low Low Moderate High No

included studies Cost–effectiveness Favours the

comparison

Probably favours the intervention

Favours the intervention

Varies No included studies

Equity Reduced Probably

reduced

Probably no

impact Probably

increased Increased Varies Don't know

Acceptability No Probably no Probably yes Yes Varies Don't know

Feasibility No Probably no Probably yes Yes Varies Don't know

1.1.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

1.1.4 Conclusions

Recommendation

F1RDT should be used as an alert tool for a potential outbreak when there is a suspicion of pneumonic plague based on clinical signs.

Justification

The conditional recommendation relates to the need:

■ to organize a confirmatory test;

■ to train staff to use the test properly and undertake proper sample collection; and

■ to assure supplies of the test.

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Implementation considerations

The quality of the RDTs should follow the principles of Good Laboratory Practice.

1.2 Question 2. Should F1RDT be used to diagnose pneumonic plague in patients in areas where an outbreak is in progress?

■ Population: patients in areas where an outbreak is in progress.

■ Intervention: F1RDT.

1.2.1 Assessment

Yes. Identifying cases with pneumonic plague in an outbreak is important.

Very inaccurate Inaccurate Accurate Very accurate Varies Don't know

The test is highly sensitive, but the confidence intervals are wide.

The test has low specificity compared with culture; no data are available about its specificity compared with PCR.

The high sensitivity of the test means that it can help to rule out the disease (unless there is a high clinical probability of the disease).

Large Moderate Small Trivial Varies Don't know

If the test gives a positive result that is in fact a false positive, this leads to overtreatment. The uncertainty about the number of false positives means that other diagnoses may be missed.

No included studies

The certainty of the evidence for sensitivity and specificity is very low (see GRADE tables (1)).

continues ...

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... continued

Very low Low Moderate High

No included studies

The test helps to exclude the diagnosis in people suspected of having the disease, but there is a problem with false positives.

Certainty of the evidence of effects of management decisions. What is the overall certainty of the evidence of effects of management decisions that are guided by the test results?

It is fairly certain that a positive test result leads to a management decision.

The panel discussed whether a negative test result leads to a decision not to treat a patient.

There is no research evidence on how the test is used and the outcomes with a diagnostic algorithm using confirmatory tests.

Possibly significant uncertainty or variability Probably no significant uncertainty or variability No significant uncertainty or variability

If the test is negative and this is used to rule out the disease, it is of benefit to the community. This does not include people who have a high clinical probability of the disease (as discussed above).

If the test is positive, further confirmatory tests are required.

Don't know

–

continues ...

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... continued

Negligible costs and savings Moderate savings Large savings Varies Don't know

The resource requirements depend on how the test is used. There are potential cost savings in ruling out plague, but possible costs associated with false-positive results.

Very low Low Moderate

HighNo included studies

–

Favours the intervention Varies

–

Varies Don't know

Plague occurs in remote areas in resource-limited settings. The test will help to improve the clinical detection and treatment of groups in these settings.

Varies Don't know

Implementation is feasible, although training in the collection of specimens and reading the results is required.

GRADE: Grading of Recommendations, Assessment, Development and Evaluation; HIV: human immunodeficiency virus; PCR: polymerase chain reaction;

RDT: rapid diagnostic test.

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1.2.2 Summary of judgements

Test accuracy Very

inaccurate Inaccurate Accurate Very accurate Varies Don't know

Undesirable effects Large Moderate Small Trivial Varies Don't know

Certainty of the evidence of test accuracy

Very low Low Moderate High No

Very low Low Moderate High No

of effects of management decisions

included studies Certainty of the

included studies

Certainty of effects Very low Low Moderate High No

Values Significant

Possibly significant uncertainty or variability

Probably no significant uncertainty or variability

comparison

Varies Don't know

Resources required Large costs Moderate costs Negligible costs and savings

Moderate savings

Large savings Varies Don't know

Certainty of evidence of required resources

comparison

Varies No included studies

reduced

Probably no impact

Probably

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1.2.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

1.2.4 Conclusions

Recommendation

F1RDT should be used in diagnosis when managing an epidemic.

The usefulness of the test is not to start treatment (given that treatment will be started anyway), but rather to consider other diagnoses if a negative result is obtained.

1.3 Question 3. Should F1RDT be used to detect bubonic plague in areas where plague is endemic?

■ Population: populations where plague has previously occurred.

■ Intervention: F1RDT.

1.3.1 Assessment

Plague is a health priority.

The sensitivity of the test is high.

The specificity of the test is low compared with culture and high compared with PCR.

See GRADE tables (1).

Confirming a disease outbreak is important, and such confirmation serves as an alert for rodent and flea control.

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... continued

Large Moderate Small Trivial Varies Don't know

If a case of bubonic plague is not detected owing to a false- negative result, the person concerned may develop pneumonic plague and/or die.

No included studies

The certainty of the evidence for sensitivity is low compared with culture and very low compared with PCR. The certainty of the evidence for specificity is very low compared with both culture and PCR.

No included studies

The test is easy to perform and enables rapid confirmation of cases.

It is useful for countries that share borders with plague-endemic areas.

No included studies

The consequences of missing an outbreak are considerable, and health professionals are highly aware of the significance of a positive result.

False positives are not helpful but the low number of false positives (high specificity) compared with PCR is reassuring.

No included studies

There are no studies that indicate a link between test results and management decisions. This “high” level of certainty was a consensus decision by the panel.

No included studies

–

Values. Is there important uncertainty about or variability in the extent to which people value the main outcomes?

Probably no significant uncertainty or variability No significant uncertainty or variability

Clinicians and communities value the ability of this test to provide an early alert of potential outbreaks.

In the absence of this test, there are delays in identifying an outbreak.

Any intervention that enables an outbreak to be detected rapidly is considered helpful.

continues ...

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... continued

Don't know

–

Negligible costs and savings Moderate savings

Large savings Varies Don't know

Low cost.

The resource requirements are unlikely to be significant, as per the panel discussion.

No included studies

No research studies were available; this judgement relates to the panel discussion.

Varies Don't know

The easy access and affordability of the test might benefit populations living in remote areas and/or resource-limited settings.

continues ...

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... continued

Varies Don't know

–

GRADE: Grading of Recommendations, Assessment, Development and Evaluation; HIV: human immunodeficiency virus; PCR: polymerase chain reaction;

RDT: rapid diagnostic test.

1.3.2 Summary of judgements

Test accuracy Very

inaccurate

Undesirable effects Large Moderate Small Trivial Varies Don't know

evidence of effects of management decisions

included studies

Certainty of effects Very low Low Moderate High No

included studies

Values Significant

Probably no significant uncertainty or variability

No significant uncertainty or variability Balance of effects Favours the

comparison

Favours the

intervention Varies Don't know

Resources required Large costs Moderate

costs Negligible

costs and savings

Moderate savings

included studies continues ...

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... continued

Cost–effectiveness Favours the comparison

Favours the

intervention Varies No included studies

reduced

Probably no

impact Probably

1.3.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

1.3.4 Conclusions

Recommendation

In areas where plague is endemic, F1RDT is recommended as an alert tool for a potential out- break when there is a suspicion of bubonic plague based on clinical signs.

Justification

The test enables treatment to be assured, development of the disease to be prevented, and public health control measures to be implemented.

1.4 Question 4. Should F1RDT be used to diagnose bubonic plague in patients in areas where an outbreak is in progress?

■ Population: patients in areas where an outbreak is in progress.

■ Intervention: F1RDT.

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1.4.1 Assessment

Bubonic plague is less common than pneumonic plague in outbreaks, but is still considered a health priority.

The sensitivity of the test is high.

The specificity of the test is low compared with culture and high compared with PCR.

Trivial Small Moderate Large Varies Don't know

Prompt detection and treatment is important; however, the clinical presentation is typical.

Large Moderate Small Trivial Varies Don't know

If a case is not detected owing to a false-negative result, there is a small risk of a fatal outcome, and a risk of progression to secondary pneumonic plague and further transmission of the disease.

Sometimes the test is negative, but this should be taken into account by the clinician.

No included studies

The sensitivity of the test is low compared with culture and very low compared with PCR.

The specificity is very low compared with both culture and PCR.

–

Early detection of the disease will reduce the likelihood of secondary pneumonic plague and human-to-human transmission.

continues ...

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... continued

– If the test is positive, this is

helpful confirmation of the diagnosis.

If the test is negative, it is important that the clinician interprets the result in light of the clinical presentation.

–

There is no disagreement about treating people with the condition.

Don't know

Patients with high clinical suspicion of bubonic plague during an outbreak are likely to be treated even if the test is negative.

A negative test result can help with seeking other diagnoses.

Negligible costs and savings Moderate savings

–

Unlikely to be important.

continues ...

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... continued

–

Varies Don't know

The test is easy to access and affordable.

Varies Don't know

Implementation is feasible, although it requires frequent training of health personnel to conduct RDTs.

HIV: human immunodeficiency virus; PCR: polymerase chain reaction; RDT: rapid diagnostic test.

1.4.2 Summary of judgements

Test accuracy Very

inaccurate

Desirable effects Trivial Small Moderate Large Varies Don't know

Undesirable effects Large Moderate Small Trivial Varies Don't know

included studies continues ...

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... continued

Certainty of the evidence of the test's effects

included studies Certainty of the evidence

of effects of management decisions

included studies Certainty of the

Certainty of effects Very low Low Moderate High No

Values Significant

Probably no significant uncertainty or variability

comparison

Varies Don't know

Resources required Large costs Moderate costs

Negligible costs and savings

Moderate savings

comparison

reduced

Probably no impact

Probably

1.4.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

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1.4.4 Conclusions

Recommendation

In areas where plague is endemic, it is recommended that F1RDT be used in the diagnosis of bubonic plague.

Justification

The test has strong evidence related to specificity.

The Guideline Development Group debated extensively whether the test made a difference

to whether treatment is initiated in an outbreak setting. The Group recognized difficulties in

obtaining samples, and that the interpretation of a negative test had to be made in the clinical

context. On balance, however, the administration of the test was felt to be useful for informing

both the clinician and the patient.

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2.1 Question 1. How do fluoroquinolones compare with streptomycin for the treatment of pneumonic and septicaemic plague?

■ Population: adults and children with clinical suspicion of pneumonic or septicaemic plague.

■ Intervention: fluoroquinolones.

■ Comparison: streptomycin.

■ Main outcome: mortality.

■ Setting: areas endemic for plague.

2.1.1 Assessment

Pneumonic and septicaemic plague are serious diseases with high mortality.

Trivial Small Moderate Large Varies Don't know

The data on fluoroquinolones from animal models,

pharmacological studies and case series indicate that these drugs are effective for treating pneumonic plague.

The data on the comparative effectiveness of fluoroquinolones and streptomycin are insufficient.

There are few adverse effects.

Fluoroquinolones have considerable advantages in terms of administration (oral), adverse effects and the lack of need for biological monitoring.

Fluoroquinolones are now being used as one of the options in first-line treatment in a few countries, with successful outcomes.

Fluoroquinolones are useful in other kinds of pneumonia, with indirect evidence of effectiveness in lung disease.

continues ...

Antibiotics for treating plague

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... continued

– The comparative efficacy

between fluoroquinolones and streptomycin is unknown.

Certainty of evidence. What is the overall certainty of the evidence of effects?

No included studies

The certainty of the evidence for mortality is very low (see evidence summary (2)).

The main outcome is mortality.

Don't know

There is a lack of research evidence on desirable and undesirable effects.

Panel consensus on indirect data, country experience, etc.

The costs of fluoroquinolones vary greatly.

–

continues ...

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... continued

– A planned and funded RCT

in Madagascar will examine the cost–effectiveness of fluoroquinolones for treating bubonic plague.

Varies Don't know

These are oral drugs.

Communities prefer to receive oral treatment as soon as the clinical situation allows.

Varies Don't know

– Health workers may need to be

trained to administer the drug intravenously if patients cannot take the drug orally because of the severity of the disease in the first few days of treatment.

RCT: randomized controlled trial.

2.1.2 Summary of judgements

Desirable effects Trivial Small Moderate Large Varies Don't know

Undesirable effects

Certainty of evidence

Very low Low Moderate High No included

studies

Values Significant

Probably no significant uncertainty or variability

No significant uncertainty or variability

continues ...

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... continued

Balance of effects Favours the comparison

Varies Don't know

Resources required

Large costs Moderate costs Negligible costs and savings

Moderate savings Large savings Varies Don't know Certainty

of evidence of required resources

included studies Cost–

effectiveness

Favours the comparison

reduced

Probably no

impact Probably

2.1.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

2.1.4 Conclusions

Recommendation

Fluoroquinolones can be used as an option for the treatment of pneumonic or septicaemic plague.

Subgroup considerations

There is no documented resistance to fluoroquinolones.

Implementation considerations

Some changes in practice will be needed to implement this drug because health care workers

have used streptomycin for decades.

(31)

Monitoring and evaluation

Monitoring of Y. pestis resistance to fluoroquinolones is important because resistance to this class of drugs develops quickly in a range of organisms when fluoroquinolones are used to treat other conditions.

Research priorities

There is a need for direct evidence from randomized controlled trials; a planned trial is important.

2.2 Question 2. How do fluoroquinolones compare with doxycycline for the treatment of bubonic plague?

■ Population: adults and children with clinical suspicion of bubonic plague.

■ Intervention: fluoroquinolones.

■ Comparison: doxycycline.

■ Main outcome: mortality.

■ Setting: areas where plague is endemic.

2.2.1 Assessment

Bubonic plague is a serious health problem. If left untreated, it can progress to secondary pneumonic plague or death.

The data on fluoroquinolones from animal models, pharmacological studies and case series indicate that these drugs are effective for treating plague. We have insufficient data on their effectiveness compared with doxycycline. There are few adverse effects.

–

No included studies

continues ...

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... continued

Don't know

The Guideline Development Group reached consensus based on indirect data, country experience, etc.

The cost of fluoroquinolones varies greatly.

–

– A planned and funded RCT

in Madagascar will examine the cost–effectiveness of fluoroquinolones for treating bubonic plague.

Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

– Both are oral drugs.

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... continued

Varies Don't know

– Both are oral drugs.

Varies Don't know

–

RCT: randomized controlled trial.

2.2.2 Summary of judgements

Undesirable effects

Certainty of

evidence Very low Low Moderate High No included

studies

Values Significant

comparison

Varies Don't know

Resources required

Large costs Moderate costs Negligible costs and savings

Moderate savings Large savings Varies Don't know Certainty

of evidence of required resources

included studies Cost–

effectiveness

Favours the comparison

reduced Probably no

impact Probably increased

Increased Varies Don't know

Acceptability No Probably no Probably yes Yes Varies Don't know

(34)

2.2.3 Type of recommendation

Strong recommendation against the intervention Conditional recommendation against the intervention

Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention

Strong recommendation for the intervention

2.2.4 Conclusions

Recommendation

Fluoroquinolones can be used as an option for treating bubonic plague.

2.3 Question 3. How do fluoroquinolones compare with chloramphenicol for the treatment of plague meningitis?

■ Population: adults and children with clinical suspicion of plague meningitis.

■ Intervention: fluoroquinolones.

■ Comparison: chloramphenicol.

■ Main outcome: mortality.

■ Setting: areas where plague is endemic.

2.3.1 Assessment

Plague meningitis is a severe form of plague associated with a high mortality rate.

The safety profile of fluoroquinolones is better than that of chloramphenicol.

Fluoroquinolones have good CSF penetration.

Fluoroquinolones are available worldwide; there are no plans to restrict their availability.

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... continued

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No included studies

Don't know

The Guideline Development Group reached a consensus based on a review of indirect data and experience of using fluoroquinolones for treating meningitis caused by other bacteria.

The costs of fluoroquinolones vary greatly.

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Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

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Varies Don't know

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Varies Don't know

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CSF: cerebrospinal fluid.

2.3.2 Summary of judgements

Undesirable effects

Certainty of evidence

Very low Low Moderate High No included

studies

Values Significant

No significant uncertainty or variability