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. 2018 Aug 5;15(6):958–965. doi: 10.1111/iwj.12955

Impact of Gram‐negative bacteria on the treatment of venous leg ulcers

Wibke L Engelberg 1,✉, Martin Dörler 1, Markus Stücker 1, Stefanie Reich‐Schupke 1,✉
PMCID: PMC7949991  PMID: 30079579

Abstract

Gram‐negative germs with and without multi‐resistance are garnering more and more importance. The aim of this study was to investigate the frequency and rate of resistance against antibiotics and to clarify the impact of Gram‐negative bacteria, especially with high rates of resistance, for the treatment of venous leg ulcers. This is a retrospective, monocentric, non‐randomised open study. Included were all data within 1 year of bacterial swabs of venous leg ulcers. We performed summarization, pooling, and descriptive analysis for frequencies and crossover. We analysed 679 swabs of 285 patients with venous leg ulcers. The mean patient age was 69.78 years. There were 76.1% Gram‐positive and 58.2% Gram‐negative germs detected; 56.5% of the swabs showed multi‐resistance. Gram‐negative bacteria were associated with more pain. Exacerbation and relevant aggravation of wounds that led to stationary treatment occurred more frequently. With polihexanid treatment, we saw less Gram‐negative flora. This study showed an immediate impact of Gram‐negative germs on the patient's pain, the risk for aggravation, and the choice of treatment. Further studies for prophylaxis and treatment of Gram‐negative germs in venous leg ulcer therapy are needed.

Keywords: bacterial swab, gram‐negative germs, multi‐resistance, pain, venous leg ulcer

1. INTRODUCTION

A chronic wound is defined as a wound that does not show any tendency of healing within 4 to 12 weeks despite professional and appropriate treatment according to the expert standard of the German Network for Quality Development in Care (Deutsches Netzwerk für Qualitätsentwicklung in der Pflege, DNQP).1 Leg ulcers, decubiti (pressure ulcers), and diabetic foot syndrome represent common causes for chronic wounds.2, 3 Current analysis based on data from a general health insurance demonstrate that the prevalence of chronic wounds in the year 2012 is estimated at 330 000 treated patients (standardised prevalence 0.4%).4 National data based on a register do not exist. Supposedly, the estimated number of unreported cases is high.

Chronic wounds are never sterile. As in healthy intact skin, they are always colonised by indigenous microorganisms. According to the amount and the state of reproduction of the detected germs, the phases can be differentiated into contamination (germs detectable but not replicative), colonisation (microorganisms present without immune reaction of host), or infection (high germ reproduction with local and/or systemic host reaction). The transitions between these conditions are fluent. Discussion is ongoing that the presence or absence of bacteria and their amount and species can have a significant impact on the healing tendency or therapy resistance of a chronic wound. Accordingly, bacterial swabs form a part of recommended basic methods for the treatment of chronic wounds. However, even by specialists, they are only performed in about 70% of the cases.5

In the past years, the detectable germ spectrum of chronic wounds has changed. While a few years ago, observations were focused on Gram‐positive germs, for example, Staphylococcus aureus, Gram‐negative germs appear to gain importance with regard to the frequency and clinical relevance detected worldwide.6, 7 Pseudomonas aeruginosa, Acinetobacter baumanii, and Proteus mirabilis are being detected more and more frequently, and they often show resistance against common antibiotics.8 Moreover, Gram‐negative germs are often characterised by a high therapy resistance against local treatment methods.

The amount of multi‐resistant Gram‐negative bacteria causing infections in intensive care units has seriously increased worldwide: from 39% in 1992 to 62.2% in 2007.9 Already in the year 2007, Gram‐negative germs reached a quota of 62% of all infections in intensive care units, and they represent two‐thirds of all deaths of nosocomial infections.10 Of particular interest are Pseudomonas and Acinetobacter species, as well as extended‐spectrum beta‐lactamases (ESBL)‐forming strains of Klebsiella, Escherichia coli, and other Gram‐negative bacteria.11

According to the literature and expert opinions, there are currently no promising newly developed antibiotics or alternative treatment strategies targeted against Gram‐negative germs.6 Therefore, these germs represent a danger, especially for multi‐morbid and/or immunocompromised patients in case of multi‐resistance.12 It can be assumed that the relevance of Gram‐negative germs will increase with their incidence and challenge future therapies and strategies.

Therefore, the aim of the current study was to investigate the relevance of Gram‐negative germs in the treatment of leg ulcers with a predominant venous cause. The following central questions should be answered:

  • How frequent are Gram‐negative germs present in venous leg ulcers?

  • What rates of resistance are present in detected germs?

  • What impact do Gram‐negative germs have on the clinical course of the wound?

2. MATERIAL AND METHODS

This is a retrospective, monocentric, non‐randomised open study. The study was approved by the ethical committee of the Medical Faculty of the Ruhr‐University Bochum (vote no. 3835). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Included were data of all patients who—within 1 year—presented with a leg ulcer at the university's wound outpatient department and who had received at least 1 bacterial swab of the ulcer. The data on swabs and patients were retrospectively acquired from the digital patient record by means of a standardised documentation sheet. The swabs themselves were not performed as a method of this study but according to routine procedures at consultation, using the “Essener Kreisel” technique13 at the beginning of wound treatment in our centre, in case of relevant changes of the wound's condition (eg, infection) and as a control after antiseptic and/or antibiotic measures. The microbiological investigation of the swabs was performed at the Institute of Microbiology of the city of Bochum, Department of Medical Microbiology of the Ruhr‐University Bochum (Head: Prof. Dr. S. Gatermann).

Data analysis was based on the swabs (every swab represented 1 event). The results were summarised and pooled with SPSS statistics. For unclear statements or documentation, the answer “not reported” was included in the finding sheet's variables. This information was not included in the analysis.

First, we performed a descriptive analysis of the frequencies of the given variables and, moreover, cross tables. The analysis was conducted with SPSS to investigate the variables with regard to the detection of various germs: Gram‐positive, Gram‐negative, mixed flora, and candida species. The patient collective was heterogeneous. As multiple swabs of identical patients were included, further statistical analyses of the data were not performed as such swabs are naturally more similar than swabs of different patients. Therefore, our results only describe descriptive frequencies and cannot show significant differences.

3. RESULTS

3.1. Complete collective

Altogether, we analysed 679 swabs of 285 patients (Table 1). Among these, 169 were female (59.3%), and 116 were male (40.7%). The mean patient age was 69.78 years (23‐98 years). Every patient received an average of 2.38 swabs (1‐21) within the 1‐year time frame of this investigation. Within the last 4 weeks prior to the bacterial swabs, 22.83% of the wounds were treated with systemic antibiotics. In 609 swabs, statements with regard to the use of antiseptics were available. Polihexanid‐containing antiseptics and octenidin‐containing antiseptics were used in 24.4% and 35.8%. respectively. In 39.7%, no antiseptics were used.

Table 1.

Bacterial swab results with regard to gender and age of the patients

Gram‐positive Gram‐negative Mixed flora Candida Total
Gender
Male 119 70 102 1 292
Female 157 92 137 1 387
Age
<30 0 0 2 0 2
30‐40 13 3 6 0 22
40‐50 11 9 23 0 43
50‐60 56 18 36 0 110
60‐70 33 41 39 0 113
70‐80 117 56 71 1 245
>80 46 35 62 1 144
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3.2. General spectrum of germs

Among the 679 collected swabs, Gram‐positive germs were detected in 76.1%, and Gram‐negative germs were detected in 58.2%. They were either present in a pure or mixed flora (Figure 1).

Figure 1.

Figure 1

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Frequency of the detected germ spectrum, n = 679 swabs

3.3. Detected Gram‐positive germs and resistance

In 35.8% of the swabs, further differentiation of the colonising Gram‐positive germs was not performed because of a polymicrobial mixture without dominant main germs. Among the remaining swabs, at least 1 Gram‐positive germ and a maximum of 2 Gram‐positive germs were differentiated and analysed with regard to resistance. Altogether, 12 different Gram‐positive germs were detected. The most frequently detected germ by far was S. aureus (Figure 2).

Figure 2.

Figure 2

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Frequencies of Gram‐positive germs from leg ulcer swabs, n = 466 detected Gram‐positive germs

Penicillin was the antibiotic drug with the highest rate of resistance. Overall, resistance occurred in 8 of the 17 tested antibiotics in more than 50% of the cases (Figure 3). Even resistance against last‐resort antibiotics, like tigecylin or tobramycin, was detected.

Figure 3.

Figure 3

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Frequency of antibiotic resistance of Gram‐positive germs from leg ulcer swabs, n = 1988 resistance

3.4. Detected Gram‐negative germs and resistance

In 379 swabs, a further analysis of Gram‐negative germs was performed. A minimum of 1 and a maximum of 4 different Gram‐negative germs were differentiated and analysed with regard to resistance. Altogether, 35 different Gram‐negative germs were detected. The most frequently detected Gram‐negative germ by far was P. aeruginosa (50.5%), followed by E. coli, P. mirabilis, and Enterobacter cloacae, with approximately 15% each (Figure 4).

Figure 4.

Figure 4

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Frequencies of Gram‐negative germs from leg ulcer swabs, n = 503 detected Gram‐negative germs

Testing showed no resistance only in a minority of germs (10.9%), whereas in 0.53%, resistance against 28 antibiotics was found. On average, Gram‐negative germs showed resistance against 6.65 antibiotics. The highest rate of resistance was found for doxycycline (65.6%). Overall, 13 antibiotics showed rates of resistance higher than 35% (Figure 5).

Figure 5.

Figure 5

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Frequency of antibiotic resistance of Gram‐negative germs from leg ulcer swabs, n = 2465 resistance

3.5. Multi‐resistant germs

The term “multi‐resistant” was used for Gram‐positive germs in case of methicillin/oxacillin resistance of S. aureus as well as for other Gram‐positive germs if the microbiological laboratory stated that they were germs requiring specific hygiene measures. Gram‐negative germs were classified as multi‐resistant if the laboratory explicitly suspected an ESBL‐producing germ and recommended certain hygiene measures or if the germ was specifically labelled as “difficult to treat”. Moreover, Pseudomonas spp. was evaluated as multi‐resistant if resistance against more than 4 groups of antibiotics (4 of the following: beta‐lactam antibiotics, cephalosporins, carbapenems, aminoglycosides, tetracyclines, quinolones, monobactams, beta‐lactamase inhibitors) was indicated. Multi‐resistance was also concluded for swabs with only 1 germ fulfilling the criteria of multi‐resistance among other germs.

Based on these rules, in 295 of 679 swabs, no multi‐resistant germs (43.5%) were detected. However, in more than half of the cases (56.5%), multi‐resistant germs, Gram‐positive (23.3%), Gram‐negative (28.1%), or as part of a mixed flora (5.15%), were detected, of which both Gram‐positive and Gram‐negative germs were multi‐resistant.

3.6. More pain in case of Gram‐negative germs

For 593 swabs, a correlating visual analogue scale (VAS from 0 to 100) on pain was available. Patients reported pain in 72.2% of a Gram‐positive and in 80.3% of a Gram‐negative flora. In case (of the detection) of a mixed flora, 83.2% of the patients reported pain. The mean value on the VAS was 35.2 for Gram‐positive, 45.6 for mixed, and 52.3 for Gram‐negative germs. Thus, Gram‐negative germs appear to be associated with more severe wound pain.

3.7. No difference of frequency of clinical signs of infection

For 451 swabs, data with regard to the clinical assessment of the presence or absence of signs of infection were available. In 172 cases, signs of infection were documented. Among these, almost equal proportions of Gram‐positive (12.0%) and Gram‐negative germs (11.3%) were present. A mixed flora was detected in 14.9% of the cases.

3.8. Reduced Gram‐negative germs with polihexanid treatment

For 610 swabs, data on the use of antiseptics in wound care were available. In 367 swabs, antiseptics were used regularly. Among these, 159 (26.07%) swabs with a Gram‐positive, 90 (14.75%) with a Gram‐negative, and 118 (19.34%) with a mixed flora were detected. While the rate of Gram‐positive germs did not vary considerably based on the use of antiseptics, Gram‐negative germs and mixed flora showed significant differences (Table 2).

Table 2.

Frequency of detected germs in reference to the use of antiseptics

Number of swabs Gram‐positive (%) Gram‐negative (%) Mixed flora (%)
No antiseptics 242 14.8 8.5 16.1
Octenidin 218 13.8 10.8 11.2
Polihexanid 149 12.3 3.9 8.21
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3.9. Relevant aggravation of wounds occurred more frequently in case of a Gram‐negative flora

For 667 of the swabs, data were available on whether or not a patient had to be admitted to the hospital within the following 4 weeks because of an uncontrolled situation of the leg ulcer in an outpatient setting. Overall, hospitalisation of patients occurred in 27.3% based on the swabs. The rate of hospitalisation based on the bacterial spectrum was 17.0% for Gram‐positive germs, 35.2% for Gram‐negative germs, and 33.2% for mixed flora.

4. DISCUSSION

The presented data impressively show the enormous impact of Gram‐negative germs on the treatment of leg ulcers. The central questions asked in the beginning may be answered and discussed as follows:

4.1. How frequent are Gram‐negative germs present in leg ulcers?

In more than half of the swabs (58.2%), Gram‐negative germs were detected, either alone (23.6%) or as part of a mixed flora (34.6%). Thus, the rates are comparable with those of a wound centre in our neighbourhood. In this wound centre, Pseudomonas and Enterobacteriaceae were detected in more than half of the patients with chronic leg ulcers.14 Moreover, similar rates were detected in a Turkish study, which isolated Gram‐negative germs in 61.3% of swabs from diabetic foot ulcers.15 In studies from outside of Europe, Gram‐negative germs could even be detected in approximately 80% of chronic leg ulcers.16 The impact of Gram‐negative germs on the treatment of chronic wounds, and specifically of venous leg ulcers, is therefore undoubted.

The most commonly detected Gram‐negative germ by far in our and others studies is P. aeruginosa (50.5% of Gram‐negative isolates). With approximately 10% of all hospital infections, P. aeruginosa constitutes 1 of the most common hospital germs in Germany.17 It is a germ with high resistance and a low demand of nutrients, which is mainly found in a wet environment. As a “wet germ”, it contaminates many areas of the clinical and private environment, but it can also survive relatively long in a dry milieu.17 P. aeruginosa is already resistant to many antibiotics by nature.

4.2. What rates of resistance are present in detected germs?

In the investigated swabs, 35 different bacteria that were resistant against up to 18 antibiotics were detected; 90% of Gram‐negative germs were resistant to at least 1 antibiotic. For 13 of the 28 tested antibiotics, resistance rates of more than 35% were found. Only 11 of the tested antibiotics showed resistance rates of less than 10% for Gram‐negative germs. In 33.3% of the swabs, Gram‐negative germs evaluated as multi‐resistant, and therefore leading to stricter hygiene measures, were found. Thus, the rate of multi‐resistant germs was higher for Gram‐negative germs than for Gram‐positive germs.

Multi‐resistant germs often lead to treatment failure or a complicated course of the disease. In case of colonisation with multi‐resistant germs, the risk of an infection with these germs is elevated.18 Lethality is increased in infections with multi‐resistant germs compared with germs responding to antibiotics. Finally, they also cause immense costs. In national and international studies of the last years, the additional costs per case because of an methicillin‐resistant staphylococcus aureus (MRSA)‐infection were estimated to be 8000‐12 000 USD.19, 20 This includes costs for isolation, increased efforts of care, treatment of complications, eradication measures, and so on. So far, analyses on the impact of multi‐resistance were mainly focused on Gram‐positive germs, specifically MRSA. Data on Gram‐negative germs are rare.

Risk factors for the occurrence of ESBL are recent use of antibiotics, accommodation in a long‐term care facility, recent hospitalisation, and the combination of an age > 65 years and male gender.21 However, the fact that, in a multinational analysis of 983 patients, 115 of 336 ESBL isolates were detected in patients without recent contact with health care facilities was alarming.21

With regard to increasing rates of resistance against antibiotics, alternative germ‐reducing measures gain importance. In this context, the observation that the rate of Gram‐negative germs was especially low with the use of polihexanid is interesting (Table 2). However, the right time for the use of antiseptics in wound treatment remains questionable. Does it make sense to use them prophylactically and continuously to prevent wounds from contamination with Gram‐negative germs and therefore from further complications? In eradication programmes on MRSA, antibiotics are being used successfully in outpatient and inpatient settings.22, 23, 24 So far, it remains unclear if this would also be a suitable option for Gram‐negative germs in clinical routine. In laboratory investigations, polihexanid proved to be non‐antagonistic and was not resisted when used against Gram‐negative bacteria and was evaluated as an adequate agent for the topical eradication of Gram‐negative germs by the authors.25 Furthermore, resistance and side effects are feared in the case of prophylactic use of antiseptics.26 Alternatively, there are wound dressings that allow the reduction of bacterial load of critically contaminated wounds through the use of silver or the potential to bind microorganisms.27 Ultimately, the use of systemic antibiotics should strictly be limited to cases showing clinical signs of infection.

4.3. What impact do Gram‐negative germs have on the clinical course of the wound?

In this study, patients with detected Gram‐negative germs, either isolated or in a mixed flora, suffered from significantly more pain than patients with a purely Gram‐positive flora. Moreover, these patients were at a higher risk of a clinical exacerbation of the wounds, leading to an uncontrolled situation in an outpatient setting and to hospitalisation. The data of this retrospective study, which show a few limitations with regard to the methods (see below), should be controlled in prospective investigations.

With regard to the spectrum of Gram‐negative germs and the frequency of resistance, therapy is overall difficult. In case of an infection, generally used antibiotics in an outpatient setting, such as doxycyline (65.6%), cotrimoxazol (48.9%), or ampicillin (47.4%), are not appropriate because of common resistance. Ultimately, the only thing that remains is the hospitalisation and the intravenous application of reserve antibiotics.

To prevent such situations, prophylactic measures against Gram‐negative germs are especially important. As discussed above, antiseptics and special wound dressings are potentially capable of reducing the burden of Gram‐negative germs in chronic wounds. In addition, optimised hygiene requirements must be discussed when handling chronic wounds. The most commonly isolated Gram‐negative germs are mainly transmitted by smear infections from persons or objects or contaminated water. Therefore, for patients with chronic wounds, only sterile solutions or water filters should be used for wound cleansing.28 In daily routine, and especially in a domestic setting, this is realised differently by the patients.

5. LIMITATIONS

This study shows some limitations, which should be mentioned.

  • The study was implemented in a university wound centre, which means that the patient collective is highly selected and generally experienced multiple pre‐treatments in other medical facilities, and therefore, it does not reflect basic care. On the other hand, approximately 70% of patients with leg ulcers are treated by a general practitioner in Germany.29

  • The 679 analysed swabs originate from 285 patients, corresponding to a mean of 2.4 swabs per patients, which were included in the analysis. Accordingly, the various swabs are not to be interpreted as completely independent events.

Therefore, the data of this current investigation are not to be generalised. However, they show interesting aspects, which need to be proven in prospective trials.

6. CONCLUSIONS

The data of this current study show the relevance of Gram‐negative germs in the treatment of leg ulcers. In many swabs, a Gram‐negative germ spectrum is detectable, which is of clinical significance with regard to the pain of the patients, the risk of a clinically relevant aggravation of the wound, the choice of antibiotics in case of infection, and the choice of antiseptics.

Considering the growing rate of Gram‐negative wound isolates and common resistance, alternative measures for the prophylaxis and therapy of Gram‐negative germs in wound treatment are urgently needed.

Conflict of interest

There are no conflicts of interests and no external funding.

Engelberg WL, Dörler M, Stücker M, Reich‐Schupke S. Impact of Gram‐negative bacteria on the treatment of venous leg ulcers. Int Wound J. 2018;15:958–965. 10.1111/iwj.12955

Contributor Information

Wibke L Engelberg, Email: wibkelena@web.de.

Stefanie Reich‐Schupke, Email: stefanie.reich-schupke@rub.de.

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