The role of piperacillin/tazobactam in the treatment of Hidradenitis suppurativa

Abstract

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Most patients with moderate-to-severe disease require long-term antibiotic treatment, or biologic treatments to control their disease. Despite these interventions, relapses are common. This study evaluated the effectiveness of piperacillin/tazobactam treatment in patients with Hurley stage II and III HS who experienced disease flares and did not respond to conventional antibiotic and biologic treatment. Methods: Patients with HS hospitalized at the Department of Dermatology, Sheba Medical Center between August 2021 and January 2023 were retrospectively analyzed. Results: A cohort of ten such patients were treated with piperacillin/tazobactam for 6–21 days. Eight (80%) and two (20%) patients respectively demonstrated 2- and 1-grade improvements, from their baseline HS-Physician Global Assessment score. During the follow-up period, nine patients were monitored. HS Clinical Response (HiSCR) was achieved in six (66.7%) and five (55.6%) patients at the 3- and 6-month follow-up visits, respectively. Conclusions: In conclusion, Piperacillin/tazobactam emerges as a promising therapeutic option for disease flare-up in patients with Hurley stage II and III HS who do not respond to conventional treatment. Thus, piperacillin/tazobactam should be considered as crisis therapy for this patient subset.

Keywords:

• Hidradenitis suppurativa
• piperacillin/tazobactam
• HS-Physician Global Assessment score
• HS Clinical Response

Introduction

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects hair follicles in areas with apocrine sweat glands, such as the underarms, groin, gluteal, and perianal areas (1). It is characterized by painful, recurrent nodules and abscesses that can lead to scarring and sinus tract formation (1–3). Its pathophysiology is characterized by the occlusion of the folliculopilosebaceous unit, follicular rupture, and subsequent release of follicular contents into the surrounding tissue, leading as a consequence to tunnel formation. The obstruction creates a microenvironment that promotes bacterial growth and inflammation. Follicular rupture and release into the surrounding tissue trigger an immune response. Initially, the innate immune system is activated, leading to the recruitment of neutrophils and macrophages to the affected area. Adaptive immune system is also activated in HS, as evidenced by the presence of lymphocytes in the affected tissues. Although its exact role in HS pathophysiology is not fully understood, it is thought to play a role in perpetuating the chronic inflammation seen in the disease. The cellular infiltrate causes abscess formation and destruction of pilosebaceous and sweat gland units, leading to the development of clinical HS lesions (4). The exact mechanism behind this sequela is not fully understood but is thought to be related to a combination of genetic, environmental, and immune factors, including the involvement of cutaneous microbiota (4–7). HS is associated with various other pathological conditions (8) and has a significant impact on the quality of life of affected individuals (9).

HS is classified according to its severity, which can be assessed by few available methods (10); these include the Hurley staging system, HS-Physician Global Assessment (HS-PGA), and HS Clinical Response (HiSCR). The Hurley staging system is a widely used grading system to characterize the extent of disease in patients with HS. This categorizes patients into three groups based largely on the presence and extent of lesions, scarring, and sinus tracts. Hurley stage III is the most severe (5,11) and characterized by the diffuse or broad involvement of multiple abscesses, sinus tracts, and scarring, covering a wide area. Hurley stage II is less severe and involves single or multiple abscesses and tracts that are not as widespread or interconnected as those seen in stage III. Since the Hurley staging system has been used to inform HS management decisions, it does not accurately reflect the inflammatory activity present in HS patients. There are different scores to evaluate inflammatory activity, one of which is the HS-PGA. The HS-PGA is a 6-point scale that evaluates overall disease severity based on clinical examination by a physician, considering the number of HS lesions. The score ranges from 0 to 5, with higher scores indicating more severe disease. HiSCR is a scoring system that monitors HS disease activity and treatment response, based on a 50% or greater reduction in inflammatory lesion count and no increase in abscesses or draining fistulas compared to baseline.

Currently, there is no definitive cure for HS. Treatment options focus on symptom management and prevention of complications, often requiring multiple therapies tailored to the degree of clinical severity (1,12). The objective is to achieve an optimal balance between alleviating symptoms and reducing adverse effects. Lifestyle modifications are also useful because unhealthy lifestyle habits can exacerbate HS (13,14).

Despite advancements in medical knowledge, HS currently lacks a definitive cure. Therapeutic modalities, such as antibiotics, hormonal agents, and retinoids are mainly directed toward symptom alleviation and complication prevention, by decreasing sebum secretion, follicular occlusion and the subsequent inflammatory process (12,15,16). Among these treatment, antibiotics are primarily used for their anti-inflammatory properties, as HS is a chronic inflammatory disorder. When some or all these fail, biologic therapies are given, including adalimumab. However, not all patients respond well to this drug either alone or in combination with antibiotics, and many experience relapses that can have a substantial impact on their quality of life (17,18). Intravenous ertapenem is reserved as a third-line therapy and administered as a single 6-week course as rescue therapy for severe disease, bridge to surgery, or other long-term maintenance (12). An alternative option for managing severe HS is piperacillin/tazobactam.

Piperacillin/tazobactam is a parentally given antibiotic combination; piperacillin is a broad-spectrum penicillin-based antibiotic, and tazobactam is a beta-lactamase inhibitor. This antibiotic combination is effective against a wide spectrum of both gram-negative and gram-positive bacteria, encompassing both aerobic and anaerobic species (19–21). Its clinical applications extend to treating a diverse array of bacterial infections, including skin and soft tissue infections, as well as pneumonia (19,22). However, it may cause adverse effects such as headache, skin rash, and nausea, and severe complications, including Clostridium difficile infection (22). The current literature reports a limited number of isolated cases in which piperacillin/tazobactam was administered to patients with HS, exclusively (23) or as part of an antibiotic combination (24,25).

This study, therefore, describes a case series of ten patients with Hurley stage II-III HS who were treated with piperacillin/tazobactam, initiated as empirical therapy, both as an anti-inflammatory agent and to target secondary infections and influence the microbiome associated with HS. The aim was to evaluate the efficacy and safety of this therapeutic approach in this cohort and to report its potential benefit as a crisis therapy in cases of severe HS lesions with secondary infection.

Materials and methods

This retrospective case series analyzed the data of patients with HS who were treated with combined piperacillin/tazobactam during hospitalization at the Department of Dermatology of the Sheba Medical Center, Tel Hashomer (Israel), between August 2021 and January 2023. Data on epidemiological variables, personal medical history, clinical and laboratory characteristics of acute presentation, clinical response following treatment, and side effects of therapy, were collected during the follow-up period.

The clinical response was evaluated using the HS-PGA (26) before and after treatment, as well as in cases of exacerbations. The HiSCR criteria (26) were used to assess clinical response during follow-up at 3 and 6 months after hospitalization. Descriptive statistics were employed to summarize the demographic and clinical characteristics of the study participants. Continuous variables were presented as mean and standard deviation (SD).

The study was approved by the local IRB committee (no-SMC-8401-21).

Results

The case series included a cohort of ten patients (6 women and 4 men). The mean age at the time of treatment was 45.2 years (± 14.6 years) (Table 1). The cohort comprised individuals who fulfilled the diagnostic criteria for Hurley stage II and III HS with severe inflammatory lesions upon initial evaluation, exhibiting recurrent abscesses and nodules and involvement of at least two anatomical regions (Table 1). At presentation, their HS-PGA scores ranged from 3 to 5; specifically, two patients scored 5, four patients scored 4, and four patients scored 3. The number of inflammatory nodules and abscesses is also noted in Table 1. During the hospitalization period, all ten patients received piperacillin/tazobactam as an empirical therapeutic intervention after exhausting various antibiotic options. During piperacillin/tazobactam treatment, no additional therapies, including biological therapies, were administered. Seven patients were given piperacillin/tazobactam even after the administration of biological treatments (Table 1). At presentation, eight (80%) patients exhibited elevated levels of C-reactive protein (CRP) beyond the normal range (0 − 5 mg/L), while six (60%) patients displayed leukocytosis (normal range: 4.00 − 10.80 K/μL) (Table 1). Inflammatory lesions from seven patients were sampled and cultured, revealing a polymicrobial growth pattern in four swabs. The other three swabs showed Citrobacter koseri, a Gram-negative, facultative anaerobe; Corynebacterium amycolatum, a Gram-positive, aerobic, or facultatively anaerobic bacterium; and a mixture of Streptococcus anginosus (milleri) and Meticillin-sensitive Staphylococcus.

Table 1. Patient demographics and clinical characteristics at presentation and response following piperacillin/tazobactam treatment.

				At presentation							Following treatment
Pat. No.	Age	Sex	Previous systemic treatment	Location	Leuco. (K/microL)	CRP (mg/L)	Swabs	Abscess (a) and inflammatory nodule (n)	HS-PGA	Days of administration	Leuco. (K/microL)	CRP (mg/L)	Abscess (a) and inflammatory nodule (n)	HS-PGA	Biology treatment following hospitalization	HiSCR50*
1	29	F	Clavulanic Acid/Amoxicillin, Adalimumab	Genitalia, Gluteal and perianal areas	8.24	1.14	---	a = 1, n = 8	3	9	9.55	0.96	a = 1, n = 0	2	Reinitiated Adalimumab right after hospitalization	Achieved at 3 and 6 months
2	40	F	Doxycycline, Clavulanic Acid/Amoxicillin, Clindamycin, Rifampicin, Trimethoprim-sulfamethoxazole, Adalimumab, Vedolizumab, Ustekinumab	Genitalia, Axilla, Breast, and sub mammary folds	8.52	9.46	Streptococcus anginosus (milleri) and MSSA	a = 0, n = 5	3	6	10.21	11.09	a = 0, n = 0	1	Reinitiated Ustekinumab right after hospitalization	Achieved at 3 and 6 months
3	33	M	Clavulanic Acid/Amoxicillin	Gluteal and perianal areas	10.96	76.04	---	a = 1, n = 1	3	8	5.98	11.82	a = 0, n = 0	1	Initiated Adalimumab 2 months following hospitalization	Achieved at 3 and 6 months
4	64	M	Clavulanic Acid/Amoxicillin, Clindamycin, Doxycycline, Rifampicin, Ciprofloxacin, Roxithromycin, Prednisone, Adalimumab	Genitalia, Gluteal and perianal areas	13.3	54.94	Polymicrobial growth	a = 2, n > 10	4	10	11.26	7.18	a = 0, n = 3	2	Initiated Infliximab 2 months following hospitalization	Achieved at 3 and 6 months
5	21	F	Minocycline, Rifampicin, Clindamycin, Doxycycline, Trimethoprim-sulfamethoxazole, Clavulanic Acid/Amoxicillin, Adalimumab	Genitalia, Axilla	9.56	8.75	---	a = 2, n = 11	4	7	9.12	8.09	a = 0, n = 4	2	Initiated Infliximab 1 month following hospitalization	Achieved at 3 and 6 months
6	58	M	Clindamycin, Rifampicin, Ciprofloxacin, Doxycycline, Adalimumab	Gluteal and perianal areas	10.95	104.6	Polymicrobial growth	a = 7, n > 8	5	21	8.92	76.53	a = 3, n = 4	4	Initiated Infliximab 2 months following hospitalization	Achieved at 3-month
7	60	M	Clavulanic Acid/Amoxicillin, Cephalexin, Ciprofloxacin	Genitalia, Axilla, Gluteal and perianal areas	13.95	198.6	Polymicrobial growth	a = 2, n > 11	4	7	8.92	7.74	a = 1, n = 0	2	---	Not achieved
8	57	F	Ciprofloxacin, Cephalexin, Clindamycin, Rifampin, Clavulanic Acid/Amoxicillin, Metronidazole, Moxifloxacin, Adalimumab, Infliximab, Ustekinumab, Cyclosporine, Acitretin, Secukinumab	Genitalia, Axilla, Gluteal and perianal areas, Breast and sub mammary folds	12.34	77.58	Polymicrobial growth	a = 6, n > 8	5	10	7.36	6.82	a = 0, n = 5	3	Initiated Guselkumab 1 week following hospitalization	Not achieved
9	48	F	Minocycline, Rifampicin, Clindamycin, Clavulanic Acid/Amoxicillin, Prednisone, Adalimumab	Genitalia, Gluteal and perianal areas	7.88	1.8	Citrobacter koseri (sensitive)	a = 0, n = 6	3	7	8.22	13.01	a = 0, n = 0	1	Initiated Infliximab 2 weeks following hospitaliztion	Not achieved
10	42	F	Clavulanic Acid/Amoxicillin, Clindamycin, Ciprofloxacin	Genitalia, Axilla, neck, anterior abdominal wall	15.22	141.7	Corynebacterium amycolatum	a = 2, n > 12	4	6	13.77	67.01	a = 0, n = 4	2	Lost to F/U	Lost to F/U

Pat. No.: patient number; Leuco: Leucocytes; HS-PGA: Hidradenitis Suppurativa Physician’s Global Assessment scale; HiSCR: Hidradenitis Suppurativa Clinical Response; MSSA: Meticillin-sensitive Staphylococcus Aureus; F/U time: follow-up time.

* Patients who achieved a response involving a ≥ 50% reduction in baseline abscess and inflammatory nodule count, with no increase in abscess and draining fistula counts relative to baseline (i.e. before Piperacillin/Tazobactam treatment).

Each patient received a total of 13.5 g daily intravenous piperacillin/tazobactam (12 g piperacillin/1.5 g tazobactam) divided into three doses. The mean duration of treatment was 9.1 days (range, 6 − 21 days). The patients were informed about the adverse effects of the medication, and informed consent was obtained prior to treatment. Piperacillin/tazobactam administration persisted as an empirical treatment despite isolating microorganisms in microbiological cultures, given the absence of an evident correlation between lesional swab results and treatment response (13). Following treatment, 8 out of 10 (80%) and 2 out of 10 (20%) patients respectively exhibited 2- and 1-grade improvements from their baseline HS-PGA score, as shown in Table 1.

The treatment not only led to clinical improvement but also reduced inflammatory markers in blood tests. Five out of eight patients with high CRP levels displayed reduced CRP levels by over 50%, and four of the six patients with leukocytosis exhibited normalized leukocyte levels after treatment (Table 1). Piperacillin/tazobactam was well-tolerated by all patients, as evidenced by the absence of any observed or reported adverse events or unexpected outcomes, including gastrointestinal symptoms, rash, infusion reactions, and laboratory abnormalities.

Nine patients with HS were monitored for 3–8 months, except for one patient who was lost to follow-up. Eight patients either started new biologic therapies, restarted previous biologic therapies, or switched to different biologic therapies (as shown in Table 1) after being hospitalized. Disease improvement was evaluated at the 3- and 6-month follow-up visit using the HiSCR criteria, relative to baseline evaluation. Among the nine patients included in the study, HiSCR was achieved in six patients (66.7%) following piperacillin/tazobactam treatment at the 3-month follow-up visits. At the 6-month follow-up visit, five patients (55.6%) achieved HiSCR. The remaining three patients did not achieve HiSCR at the 3-month follow-up.

Patients 1–5 exhibited sustained improvement, alongside ongoing biologic therapy, achieving HiSCR at both the 3- and 6-month follow-up visits. Despite undergoing deroofing of an inguinal tract after 5 months from the Piperacillin/tazobactam course, patient 1 still maintained HiSCR at the 6-month follow-up visit. However, patient 6, who had morbid obesity, type 2 diabetes, and poor treatment adherence, exhibited a 2-grade worsening in HS-PGA at the second visit and failed to achieve HiSCR. Patients 7 and 8 showed a 1-grade worsening in HS-PGA due to disease exacerbation and required systemic antibiotics, while patient 9 required increased infliximab frequency due to a 2-grade worsening in HS-PGA at the 3-month follow-up visit.

Discussion

HS is a chronic inflammatory disease that can significantly affect quality of life (17). Despite the availability of numerous treatment modalities (12), some patients still fail to achieve satisfactory clinical outcomes, and the optimal therapeutic approach remains elusive (5). Thus leaving the optimal therapeutic approach an ongoing challenge. A notable milestone in the pursuit of effective treatments for HS was the evaluation of a 6-week regimen of ertapenem as a crisis intervention in a cohort of 30 patients. The results showed a significant decrease in the number and severity of lesions, and further improvement was observed in patients who received continuous consolidation treatments (27). This success led to its inclusion in North American clinical management guidelines, suggesting the potential efficacy of broad-spectrum antibiotics in treating severe cases of HS. Parallelly, piperacillin/tazobactam, characterized by its own broad-spectrum antibiotic profile, could emerge as a promising alternative. Notably, piperacillin/tazobactam exhibits the potential to decrease the incidence of multi-drug resistant and fungal infections compered to carbapenems (28). However, the utilization of piperacillin/tazobactam raises ethical concerns regarding antibiotic resistance. This ethical dilemma necessitates a thoughtful assessment when devising combination therapies to prevent resistance, striking a balance between individual patient benefits and broader public health implications. It is crucial to address the challenge of antibiotic resistance while ensuring that eligible patients receive potentially efficacious treatment options, thereby mitigating the unwarranted overuse of antibiotics. Considering these ethical consequences, the current study focuses on evaluating the efficacy and safety of piperacillin/tazobactam as a crisis therapy, specifically for patients with severe HS (Hurley stage II and III) who have exhibited inadequate responses to prior treatment modalities.

The severity of HS lesions is positively correlated with the diversity of the skin microbiome, as indicated by studies employing 16S rRNA genome analysis and culture-based methods (29,30). Moreover, previous research has reported that almost all patients with HS have had a positive culture with up to five different bacterial species present, primarily consisting of Staphylococci, bacteria commonly found in the intestinal flora (including Enterococci and Enterobacteriaceae), and anaerobes (31).

Piperacillin is effective against both gram-positive and gram-negative bacteria by inhibiting cell wall synthesis through binding to penicillin-binding proteins, leading to cell lysis mediated by bacterial cell wall autolytic enzymes (20,32). Tazobactam exerts its effect by inhibiting bacterial beta-lactamase-producing organisms, which are typically resistant to beta-lactam antibiotics (33). Thus, the inclusion of tazobactam broadens the spectrum of piperacillin, rendering it effective against organisms that express beta-lactamase and would otherwise degrade it (22). Therefore, this combination covers a range of gram-positive and gram-negative aerobic and anaerobic bacteria (34), making it useful for treating infections caused by aerobic or anaerobic beta-lactamase-producing bacteria and potentially reducing the bacterial load of HS lesions.

A few case reports described the use of piperacillin/tazobactam for HS. One case involved administering piperacillin/tazobactam during hospitalization to manage HS exacerbations that emerged during treatment with IFX-1 – a monoclonal antibody that inhibits the activity of complement factor C5a (23). Another case used piperacillin/tazobactam in combination with imipenem and amikacin to treat a patient with HS and a secondary infection caused by Pseudomonas oryzihabitans (24). The third case involved administering piperacillin/tazobactam and vancomycin together as part of the initial antibiotic management for a patient who underwent wide resection of affected regions in the perineal area due to persistent lesions associated with suppuration, hemorrhage, and pain (25).

The present study found that treatment with piperacillin/tazobactam significantly improved the clinical symptoms of HS. In this cohort, eight out of ten (80%) patients demonstrated a 2-grade improvement from their baseline HS-PGA score, while the other two patients (20%) showed a 1-grade improvement. The treatment also resulted in reduced inflammatory markers in blood tests, with five out of eight patients displaying reduced CRP levels by over 50% and four out of six patients with leukocytosis showing normalized leukocyte levels.

The observed clinical response to piperacillin/tazobactam was notable, given that the patients had previously failed other treatments. Treatment resulted in significant clinical and laboratory improvements, suggesting the potential of piperacillin/tazobactam in managing HS. The specific gram-positive and gram-negative aerobic and anaerobic bacteria isolated and polymicrobial growth observed in the sampled inflammatory lesions of patients support the use of broad-spectrum antibiotics, such as piperacillin/tazobactam, to manage HS. Additionally, the absence of adverse events or unexpected outcomes suggests that the treatment was well-tolerated by patients.

During the follow-up period, six of the nine patients who were followed up (66.7%) exhibited improved clinical conditions, characterized by reduced skin lesions by at least 50% 3 months after piperacillin/tazobactam treatment. At the 6-month follow-up visit, five of the six responders continued to maintain a favorable clinical outcome, while one patient did not meet the criteria for a positive response at this time point. Three of the patients could not achieve a reduction of at least 50% in skin lesions at the 3-month follow-up visit. Some patients either maintained their pre-hospitalization biologic treatment or switch to an alternative biologic treatment following piperacillin/tazobactam therapy (Table 1), underscoring the complexity of HS management. Most of our patients consistently received biological therapy, yet experienced disease exacerbation during its course. Treatment with piperacillin/tazobactam resulted in a significant improvement, effectively restoring disease management. The sustained positive response in some of these patients may be attributed to the strategic use of biologic therapies. The clinical practice of initiating antibiotics concurrently with biologic treatments aligns with the aim of providing rapid relief and increasing the likelihood of a favorable response to biologic therapy (35).

This study had some limitations, including its retrospective design, small sample size, lack of a control group or blinding, and a relatively short follow-up period. Moreover, the clinical response during the follow-up period was based on HiSCR, which may not fully capture disease severity (36). Furthermore, during this period, treatment regimen varied among patients. Finally, patient comorbidities, such as those associated with tobacco consumption, could have influenced the treatment response.

In conclusion, piperacillin/tazobactam seems to be an effective third-line therapy for HS flares with potential long-term effects. The combination can also serve as a crisis therapy option for patients with HS, particularly those with Hurley stage II and III for whom previous treatments have failed. Treatment has shown significant improvements in both clinical symptoms and inflammatory markers with good tolerability. Further studies, including randomized controlled trials with larger sample sizes and longer follow-up periods, are warranted to confirm the current findings. Future studies should explore the underlying mechanisms of the observed clinical response, including the potential role of the antibacterial and immunomodulatory effects of piperacillin/tazobactam and its impact on the microbiome and resistance patterns (37), thus providing insight into the optimal therapeutic approach for HS.

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