Empirical antibiotics targeting gram‐positive bacteria for the treatment of febrile neutropenic patients with cancer

Ofrat Beyar‐Katz; Yaakov Dickstein; Sara Borok; Liat Vidal; Leonard Leibovici; Mical Paul

doi:10.1002/14651858.CD003914.pub4

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Failure.

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Figure 5

Mortality.

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Analysis 1.1

Comparison 1 Mortality, Outcome 1 Overall mortality.

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Analysis 1.2

Comparison 1 Mortality, Outcome 2 Overall mortality (adequate allocation concealment).

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Analysis 1.3

Comparison 1 Mortality, Outcome 3 Overall mortality (intention to treat).

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Analysis 1.4

Comparison 1 Mortality, Outcome 4 Mortality in Gram‐positive infections.

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Analysis 1.5

Comparison 1 Mortality, Outcome 5 Overall mortality (antiGP not covering Gram‐negatives).

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Analysis 1.6

Comparison 1 Mortality, Outcome 6 Infection‐related fatality.

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Analysis 2.1

Comparison 2 Treatment failure, Outcome 1 Overall failure (disregarding modifications).

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Analysis 2.2

Comparison 2 Treatment failure, Outcome 2 Failure, modifications included.

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Analysis 2.3

Comparison 2 Treatment failure, Outcome 3 Failure, modifications included (adequate allocation concealment).

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Analysis 2.4

Comparison 2 Treatment failure, Outcome 4 Failure, modifications included (intention to treat).

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Analysis 2.5

Comparison 2 Treatment failure, Outcome 5 Failure, modifications included (antiGP not covering Gram‐negatives).

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Analysis 2.6

Comparison 2 Treatment failure, Outcome 6 Failure in Gram‐positive infections.

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Analysis 2.7

Comparison 2 Treatment failure, Outcome 7 Febrile at 72 hrs. on empirical Tx.

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Analysis 2.8

Comparison 2 Treatment failure, Outcome 8 Addition of amphotericin.

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Analysis 3.1

Comparison 3 Superinfections, Outcome 1 Any superinfections.

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Analysis 3.2

Comparison 3 Superinfections, Outcome 2 Bacterial superinfections.

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Analysis 3.3

Comparison 3 Superinfections, Outcome 3 Gram‐positive superinfections.

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Analysis 3.4

Comparison 3 Superinfections, Outcome 4 Fungal superinfections.

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Analysis 4.1

Comparison 4 Adverse events, Outcome 1 Any adverse events.

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Analysis 4.2

Comparison 4 Adverse events, Outcome 2 Rash/ allergy.

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Analysis 4.3

Comparison 4 Adverse events, Outcome 3 Any nephrotoxicity.

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Summary of findings for the main comparison. Mortality with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

Mortality with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer
Patient or population: febrile neutropenic patients with cancer Setting: in‐hospital Intervention: anti‐gram‐positive antibiotics Comparison: placebo or added anti‐gram‐positive antibiotics
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with anti gram‐positive antibiotics
Overall mortality	Study population		RR 0.90 (0.64 to 1.25)	1242 (8 RCTs)	⊕⊕⊕⊝ MODERATE ^{1 2}
	104 per 1,000	94 per 1,000 (67 to 130)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Lack of blinding should not affect the objective outcome of mortality ² Wide CI ranging from a large benefit of anti‐gram‐positive antibiotics to possible harm

Summary of findings for the main comparison. Mortality with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

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Summary of findings 2. Treatment failure with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

Treatment failure with anti gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer
Patient or population: febrile neutropenic patients with cancer Setting: in‐hospital Intervention: anti‐gram‐positive antibiotics Comparison: placebo or added anti‐gram‐positive antibiotics
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with treatment failure
Overall failure (disregarding modifications)	Study population		RR 1.00 (0.79 to 1.27)	943 (7 RCTs)	⊕⊕⊝⊝ LOW ¹
	187 per 1,000	187 per 1,000 (148 to 238)
Failure, modifications included	Study population		RR 0.72 (0.65 to 0.79)	2169 (11 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	463 per 1,000	333 per 1,000 (301 to 366)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Lack of blinding in most studies, subjective outcome ² Indirectness: outcome driven by treatment modifications, an outcome not relevant to this patient population

Summary of findings 2. Treatment failure with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

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Summary of findings 3. Adverse events with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

Adverse events with anti gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer
Patient or population: febrile neutropenic patients with cancer Setting: in‐hospital Intervention: anti‐gram‐positive antibiotics Comparison: placebo or added anti‐gram‐positive antibiotics
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Adverse events
Any adverse events	Study population		RR 1.74 (1.50 to 2.01)	1936 (9 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	192 per 1,000	335 per 1,000 (289 to 387)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Lack of blinding ² Adverse events were not described in all studies and are interpreted differently in each study

Summary of findings 3. Adverse events with anti‐gram‐positive antibiotics compared to placebo for the treatment of febrile neutropenic patients with cancer

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Table 1. Study year and % gram positive (GP) out of single‐agent bacteraemias

Study ID	Study year	GP bacteraemia
Empirical
Menichetti 1986	1983	13%
Del Favero 1987	1984	19%
Karp 1986	1984	28%
Novakova 1991	1987	25%
Ramphal 1992	1988	25%
EORTC 1991	1988	18%
Molina 1993	1992	6%
Bucaneve 2014	2010	25%
Semi‐empirical
Cometta 2003	2000	11%

Table 1. Study year and % gram positive (GP) out of single‐agent bacteraemias

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Comparison 1. Mortality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall mortality Show forest plot	8	1242	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.64, 1.25]

1.1 Glycopeptide empirical	2	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.47, 1.84]
1.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.36, 1.80]
1.3 Other antiGP empirical	4	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.60, 1.40]
2 Overall mortality (adequate allocation concealment) Show forest plot	7	1118	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.66, 1.40]

2.1 Glycopeptide empirical	2	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.47, 1.84]
2.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.36, 1.80]
2.3 Other antiGP empirical	3	592	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.61, 1.85]
3 Overall mortality (intention to treat) Show forest plot	6	1001	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.57, 1.19]

3.1 Glycopeptide empirical	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.31, 1.95]
3.2 Glycopeptide first modification	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.14, 1.47]
3.3 Other antiGP empirical	4	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.60, 1.40]
4 Mortality in Gram‐positive infections Show forest plot	5	195	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [0.58, 5.12]

5 Overall mortality (antiGP not covering Gram‐negatives) Show forest plot	6	728	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.55, 1.39]

5.1 Glycopeptide empirical	2	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.47, 1.84]
5.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.36, 1.80]
5.3 Other antiGP empirical	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.34, 2.36]
6 Infection‐related fatality Show forest plot	8	1810	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.76, 1.75]

6.1 Glycopeptide empirical	4	1030	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.62, 2.17]
6.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.51, 7.59]
6.3 Other antiGP	2	501	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.54, 1.87]

Comparison 1. Mortality

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Comparison 2. Treatment failure

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall failure (disregarding modifications) Show forest plot	7	943	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.79, 1.27]

1.1 Glycopeptide empirical	3	293	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.28, 4.20]
1.2 Glycopeptide first modification	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.18, 2.09]
1.3 Other antiGP empirical	3	485	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.81, 1.32]
2 Failure, modifications included Show forest plot	11	2169	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.65, 0.79]

2.1 Glycopeptide empirical	5	1178	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.61, 0.80]
2.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.79, 1.22]
2.3 Other antiGP empirical	4	712	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.51, 0.77]
3 Failure, modifications included (adequate allocation concealment) Show forest plot	7	1101	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.68, 0.89]

3.1 Glycopeptide empirical	2	230	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.59, 1.08]
3.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.79, 1.22]
3.3 Other antiGP empirical	3	592	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.53, 0.81]
4 Failure, modifications included (intention to treat) Show forest plot	7	1068	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.69, 0.90]

4.1 Glycopeptide empirical	2	186	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.61, 1.08]
4.2 Glycopeptide first modification	2	290	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.81, 1.23]
4.3 Other antiGP empirical	3	592	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.53, 0.81]
5 Failure, modifications included (antiGP not covering Gram‐negatives) Show forest plot	9	1659	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.69, 0.87]

5.1 Glycopeptide empirical	5	1178	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.61, 0.80]
5.2 Glycopeptide first modification	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.79, 1.22]
5.3 Other antiGP empirical	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.62, 1.67]
6 Failure in Gram‐positive infections Show forest plot	5	175	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.38, 0.84]

7 Febrile at 72 hrs. on empirical Tx Show forest plot	3	312	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.44, 1.17]

7.1 Glycopeptide empirical	3	312	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.44, 1.17]
8 Addition of amphotericin Show forest plot	5	1201	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.84, 1.80]

8.1 Non‐blinded	3	976	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.80, 2.83]
8.2 Double blind	2	225	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.75, 1.33]

Comparison 2. Treatment failure

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Comparison 3. Superinfections

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any superinfections Show forest plot	10	1896	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.66, 1.08]

1.1 Glycopeptide	6	1281	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.67, 1.13]
1.2 Other antiGP	4	615	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.38, 1.40]
2 Bacterial superinfections Show forest plot	9	1992	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.27, 0.60]

2.1 Glycopeptide	5	1296	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.24, 0.59]
2.2 Other antiGP	4	696	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.23, 1.15]
3 Gram‐positive superinfections Show forest plot	9	1688	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.14, 0.40]

3.1 Glycopeptide	6	1356	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.11, 0.37]
3.2 Other antiGP	3	332	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.15, 1.45]
4 Fungal superinfections Show forest plot	9	1637	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.69, 1.77]

4.1 Glycopeptide	6	1305	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.70, 1.99]
4.2 Other antiGP	3	332	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.27, 2.48]

Comparison 3. Superinfections

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Comparison 4. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any adverse events Show forest plot	9	1936	Risk Ratio (M‐H, Fixed, 95% CI)	1.74 [1.50, 2.01]

1.1 Glycopeptide	5	1195	Risk Ratio (M‐H, Fixed, 95% CI)	1.78 [1.53, 2.07]
1.2 Other antiGP	4	741	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.99, 2.34]
2 Rash/ allergy Show forest plot	7	1526	Risk Ratio (M‐H, Fixed, 95% CI)	2.31 [1.47, 3.63]

2.1 Glycopeptide	5	1336	Risk Ratio (M‐H, Fixed, 95% CI)	2.33 [1.43, 3.80]
2.2 Other antiGP	2	190	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [0.65, 7.30]
3 Any nephrotoxicity Show forest plot	10	1916	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.96, 1.70]

3.1 Glycopeptide	6	1282	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [1.06, 1.94]
3.2 Other antiGP	4	634	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.40, 1.75]

Comparison 4. Adverse events

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