Sustavni antibiotici u terapiji malignih rana
Appendices
Appendix 1. Central search strategy
Cochrane Wounds Specialised Register
1 MESH DESCRIPTOR Skin Ulcer EXPLODE ALL AND INREGISTER
2 MESH DESCRIPTOR Neoplasms EXPLODE ALL AND INREGISTER
3 #1 AND #2
4 MESH DESCRIPTOR Ulcer EXPLODE ALL AND INREGISTER
5 MESH DESCRIPTOR Skin Neoplasms EXPLODE ALL AND INREGISTER
6 #4 AND #5
7 (fungat* near3 (wound* or tumor* or tumour* or lesion* or ulcer*)) AND INREGISTER
8 (ulcera* near3 (tumor* or tumour*)) AND INREGISTER
9 (malodorous near3 (wound* or tumor* or tumour* or ulcer*)) AND INREGISTER
10 (smelly near3 (wound* or tumor* or tumour* or ulcer*)) AND INREGISTER
11 ((malignant or tumoral or neoplas* or cancer) near3 wound*) AND INREGISTER
12 ((melanoma or carcinoma or sarcoma or metasta*) near5 ulcer*) AND INREGISTER
13 #3 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12
14 MESH DESCRIPTOR Anti‐Infective Agents EXPLODE ALL AND INREGISTER
15 MESH DESCRIPTOR Antibiotic Prophylaxis EXPLODE ALL AND INREGISTER
16 MESH DESCRIPTOR Nitroimidazoles EXPLODE ALL AND INREGISTER
17 (Antibiotic* or Nitroimidazole* or Dimetridazole or Etanidazole or Ipronidazole or Metronidazole or Misonidazole or Nimorazole or Ornidazole or Ronidazole or Tinidazole) AND INREGISTER
18 MESH DESCRIPTOR Tetracyclines EXPLODE ALL AND INREGISTER
19 (Tetracycline* or Chlortetracycline or Demeclocycline or Doxycycline or Lymecycline or Methacycline or Minocycline or Oxytetracycline or Rolitetracycline) AND INREGISTER
20 (Erythromycin or Clindamycin or Ciprofloxacin) AND INREGISTER
21 (Spiramycin or Azithromycin or Roxithromicin or Roxithromycin) AND INREGISTER
22 MESH DESCRIPTOR Penicillins EXPLODE ALL AND INREGISTER
23 (Penicillin* or Phenoxymethylpenicillin or Amoxicillin or Ampicillin or Flucloxacillin or Amoxiclav) AND INREGISTER
24 #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23
25 #13 AND #24
The Cochrane Central Register of Controlled Clinical Trials (CENTRAL)
#1 MeSH descriptor: [Skin Ulcer] explode all trees
#2 MeSH descriptor: [Neoplasms] explode all trees
#3 #1 and #2
#4 MeSH descriptor: [Ulcer] explode all trees
#5 MeSH descriptor: [Skin Neoplasms] explode all trees
#6 #4 and #5
#7 (fungat* near/3 (wound* or tumor* or tumour* or lesion* or ulcer*)):ti,ab
#8 (ulcera* near/3 (tumor* or tumour*)):ti,ab
#9 (malodorous near/3 (wound* or tumor* or tumour* or ulcer*)):ti,ab
#10 (smelly near/3 (wound* or tumor* or tumour* or ulcer*)):ti,ab
#11 ((malignant or tumoral or neoplas* or cancer) near/3 wound*):ti,ab
#12 ((melanoma or carcinoma or sarcoma or metasta*) near/5 ulcer*) .ti,ab.
#13 #3 or #6 or #7 or #8 or #9 or #10 or #11 or #12
#14 MeSH descriptor: [Anti‐Infective Agents] explode all trees
#15 MeSH descriptor: [Antibiotic Prophylaxis] explode all trees
#16 MeSH descriptor: [Nitroimidazoles] explode all trees
#17 (Antibiotic* or Nitroimidazole* or Dimetridazole or Etanidazole or Ipronidazole or Metronidazole or Misonidazole or Nimorazole or Ornidazole or Ronidazole or Tinidazole):ti,ab
#18 MeSH descriptor: [Tetracyclines] explode all trees
#19 (Tetracycline* or Chlortetracycline or Demeclocycline or Doxycycline or Lymecycline or Methacycline or Minocycline or Oxytetracycline or Rolitetracycline):ti,ab
#20 (Erythromycin or Clindamycin or Ciprofloxacin):ti,ab
#21 (Spiramycin or Azithromycin or Roxithromicin or Roxithromycin):ti,ab
#22 MeSH descriptor: [Penicillins] explode all trees
#23 (Penicillin* or Phenoxymethylpenicillin or Amoxicillin or Ampicillin or Flucloxacillin or Amoxiclav):ti,ab
#24 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23
#25 #13 and #24
Ovid MEDLINE
1 exp Skin Ulcer/ and exp Neoplasms/
2 Ulcer/ and exp Skin Neoplasms/
3 (fungat* adj3 (wound* or tumor* or tumour* or lesion* or ulcer*)).tw.
4 (ulcera* adj3 (tumor* or tumour*)).tw.
5 (smelly adj3 (wound* or tumor* or tumour* or ulcer*)).tw.
6 (malodorous adj3 (wound* or tumor* or tumour* or ulcer*)).tw.
7 ((malignant or tumoral or neoplas* or cancer) adj3 wound*).tw.
8 ((melanoma or carcinoma or sarcoma or metasta*) adj5 ulcer*).tw.
9 or/1‐8
10 exp Anti‐Infective Agents/
11 Antibiotic Prophylaxis/
12 exp Nitroimidazoles/
13 (Antibiotic* or Nitroimidazole* or Dimetridazole or Etanidazole or Ipronidazole or Metronidazole or Misonidazole or Nimorazole or Ornidazole or Ronidazole or Tinidazole).ti,ab,rn.
14 exp Tetracyclines/
15 (Tetracycline* or Chlortetracycline or Demeclocycline or Doxycycline or Lymecycline or Methacycline or Minocycline or Oxytetracycline or Rolitetracycline).ti,ab,rn.
16 (Erythromycin or Clindamycin or Ciprofloxacin).ti,ab,rn.
17 (Spiramycin or Azithromycin or Roxithromicin or Roxithromycin).ti,ab,rn.
18 exp Penicillins/
19 (Penicillin* or Phenoxymethylpenicillin or Amoxicillin or Ampicillin or Flucloxacillin or Amoxiclav).ti,ab,rn.
20 or/10‐19
21 and/9,20
22 randomized controlled trial.pt.
23 controlled clinical trial.pt.
24 randomi?ed.ab.
25 placebo.ab.
26 clinical trials as topic.sh.
27 randomly.ab.
28 trial.ti.
29 or/22‐28
30 exp animals/ not humans.sh.
31 29 not 30
32 21 and 31
Ovid Embase
1 exp skin ulcer/ and exp neoplasm/
2 (ulcer/ or exp nose ulcer/ or ulcer healing/ or exp urogenital ulcer/) and exp skin tumor/
3 (fungat* adj3 (wound* or tumor* or tumour* or lesion* or ulcer*)).tw.
4 (ulcera* adj3 (tumor* or tumour*)).tw.
5 (malodorous adj3 (wound* or tumor* or tumour* or ulcer*)).tw.
6 (smelly adj3 (wound* or tumor* or tumour* or ulcer*)).tw.
7 ((malignant or tumoral or neoplas* or cancer) adj3 wound*).tw.
8 ((melanoma or carcinoma or sarcoma or metasta*) adj5 ulcer*).tw.
9 or/1‐8
10 exp antiinfective agent/
11 antibiotic prophylaxis/
12 exp nitroimidazole derivative/
13 (Antibiotic* or Nitroimidazole* or Dimetridazole or Etanidazole or Ipronidazole or Metronidazole or Misonidazole or Nimorazole or Ornidazole or Ronidazole or Tinidazole).ti,ab,rn.
14 exp tetracycline derivative/
15 (Tetracycline* or Chlortetracycline or Demeclocycline or Doxycycline or Lymecycline or Methacycline or Minocycline or Oxytetracycline or Rolitetracycline).ti,ab,rn.
16 (Erythromycin or Clindamycin or Ciprofloxacin).ti,ab,rn.
17 (Spiramycin or Azithromycin or Roxithromicin or Roxithromycin).ti,ab,rn.
18 exp Penicillins/
19 (Penicillin* or Phenoxymethylpenicillin or Amoxicillin or Ampicillin or Flucloxacillin or Amoxiclav).ti,ab,rn.
20 or/10‐19
21 and/9,20
22 Randomized controlled trials/
23 Single‐Blind Method/
24 Double‐Blind Method/
25 Crossover Procedure/
26 (random* or factorial* or crossover* or cross over* or cross‐over* or placebo* or assign* or allocat* or volunteer*).ti,ab.
27 (doubl* adj blind*).ti,ab.
28 (singl* adj blind*).ti,ab.
29 or/22‐28
30 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
31 human/ or human cell/
32 and/30‐31
33 30 not 32
34 29 not 33
35 21 and 34
EBSCO CINAHL Plus
S32 S18 AND S31
S31 S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30
S30 TI allocat* random* or AB allocat* random*
S29 MH "Quantitative Studies"
S28 TI placebo* or AB placebo*
S27 MH "Placebos"
S26 TI random* allocat* or AB random* allocat*
S25 MH "Random Assignment"
S24 TI randomi?ed control* trial* or AB randomi?ed control* trial*
S23 AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )
S22 TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )
S21 TI clinic* N1 trial* or AB clinic* N1 trial*
S20 PT Clinical trial
S19 MH "Clinical Trials+"
S18 S7 AND S17
S17 S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16
S16 TX (Penicillin* or Phenoxymethylpenicillin or Amoxicillin or Ampicillin or Flucloxacillin or Amoxiclav)
S15 (MH "Penicillins+")
S14 TX (Spiramycin or Azithromycin or Roxithromicin)
S13 TX (Erythromycin or Clindamycin or Ciprofloxacin)
S12 TX (Tetracycline* or Chlortetracycline or Demeclocycline or Doxycycline or Lymecycline or Methacycline or Minocycline or Oxytetracycline or Rolitetracycline or Tetracycline)
S11 (MH "Tetracyclines+")
S10 TX (Antibiotic* or Nitroimidazole* or Dimetridazole or Etanidazole or Ipronidazole or Metronidazole or Misonidazole or Nimorazole or Ornidazole or Ronidazole or Tinidazole)
S9 (MH "Antibiotic Prophylaxis")
S8 (MH "Antiinfective Agents+")
S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6
S6 TX ((melanoma or carcinoma or sarcoma or metasta*) N5 ulcer*)
S5 TX ((malignant or tumoral or neoplas* or cancer) N3 wound*)
S4 TX (ulcera* N3 (tumor* or tumour*))
S3 TX (fungat* N3 (wound* or tumor* or tumour* or lesion* or ulcer*)) OR TX (smelly N3 (wound* or tumor* or tumour* or lesion* or ulcer*)) OR TX (malodorous N3 (wound* or tumor* or tumour* or lesion* or ulcer*))
S2 (MH "Ulcer") AND (MH "Skin Neoplasms+")
S1 (MH "Skin Ulcer+") AND (MH "Neoplasms+")
US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov)
("malignant wound" OR "fungating wound") AND ("neoplasm" OR "cancer" OR "carcinoma" OR "tumor" OR "tumour")
World Health Organization International Clinical Trials Registry Platform
("malignant wound" OR "fungating wound") AND ("neoplasm" OR "cancer" OR "carcinoma" OR "tumor" OR "tumour")
Appendix 2. Risk of bias criteria
1. Was the allocation sequence randomly generated?
Low risk of bias
The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.
High risk of bias
The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.
Unclear
Insufficient information about the sequence generation process available to permit judgement of low or high risk of bias.
2. Was the treatment allocation adequately concealed?
Low risk of bias
Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.
High risk of bias
Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: use of an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. envelopes were unsealed, non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear
Insufficient information available to permit judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.
3. Blinding ‐ was knowledge of the allocated interventions adequately prevented during the study?
Low risk of bias
Any one of the following.
-
No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
-
Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
-
Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.
High risk of bias
Any one of the following.
-
No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.
-
Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.
-
Either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.
Unclear
Either of the following.
-
Insufficient information available to permit judgement of low or high risk of bias.
-
The study did not address this outcome.
4. Were incomplete outcome data adequately addressed?
Low risk of bias
Any one of the following.
-
No missing outcome data.
-
Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).
-
Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
-
For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is not enough to have a clinically relevant impact on the intervention effect estimate.
-
For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes is not enough to have a clinically relevant impact on observed effect size.
-
Missing data have been imputed using appropriate methods.
High risk of bias
Any one of the following:
-
Reason for missing outcome data is likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.
-
For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is enough to induce clinically relevant bias in intervention effect estimate.
-
For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes is enough to induce clinically relevant bias in observed effect size.
-
‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation.
-
Potentially inappropriate application of simple imputation.
Unclear
Either of the following:
-
Insufficient reporting of attrition/exclusions to permit judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).
-
The study did not address this outcome.
5. Are reports of the study free of suggestion of selective outcome reporting?
Low risk of bias
Either of the following.
-
The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.
-
The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
High risk of bias
Any one of the following.
-
Not all of the study’s pre‐specified primary outcomes have been reported.
-
One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified.
-
One or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).
-
One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.
-
The study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear
Insufficient information available to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category.
6. Other sources of potential bias
Low risk of bias
The study appears to be free of other sources of bias.
High risk of bias
There is at least one important risk of bias. For example, the study:
-
had a potential source of bias related to the specific study design used; or
-
has been claimed to have been fraudulent; or
-
had some other problem.
Unclear
There may be a risk of bias, but there is either:
-
insufficient information to assess whether an important risk of bias exists; or
-
insufficient rationale or evidence that an identified problem will introduce bias.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Metronidazole versus Placebo, outcome: 1.1 Malodour (Smell Score).
Comparison 1 Metronidazole versus Placebo, Outcome 1 Malodour (Smell Score).
| Metronidazole compared to Placebo for treating malignant wounds | ||||||
| Patient or population: treating malignant wounds | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with Placebo | Risk with Metronidazole | |||||
| Malodour (smell score measured on a scale of 0 to 3 with higher scores indicating a more offensive smell) | The mean malodour (smell score) was 3.33 (range 2.0 to 4.0) | MD 2.16 lower | ‐ | 6 | ⊕⊝⊝⊝ | It is uncertain whether metronidazole leads to a reduction in malodour because the quality of the evidence is very low |
| Adverse effects | Study population | not estimable | 6 | NA | ||
| 0 per 1000 | 0 per 1000 | |||||
| *The risk in the intervention group (and its 95% CI) 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; MD: mean difference. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 3 levels: serious limitation — insufficient details provided to make clear judgements on random sequence generation and allocation concealment. There was also a 33% loss to follow‐up; very serious imprecision; a small sample size of 6 participants. 2 Smell was independently assessed at each visit by the patient, doctor, and nurse, who graded the smell as "absent" (0), "not offensive" (1), "offensive but tolerable" (2), or "offensive and intolerable" (3), and an amalgamated score calculated. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Malodour (Smell Score) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
