I guess it would be just wishful thinking that I have this figured out yet at all...

It certainly is confusing even now that some of the literature is willing to blame both L-forms and SCVs of causing persistent, recurrent infections, and I still get the feeling way too often that even the authors of these works that may be so important to many HS patients, may not have it very well sorted out themselves.

I keep trying to back to hopeful thoughts here, like how SCVs, L-forms, or biofilms have yet to keep them from saving my life from infections with antibiotics in emergencies, how even the worst statistics I've seen still suggest that 1 in 3 HS patients may NOT have biofilm issues, how antibiotics would never have gotten off the ground in the first place if they were really as useless as literature often seems to make it sound anymore...

Meanwhile, here is an interesting article - maybe one of the best I've run into so far. It's probably enough to make three doctors' heads explode, but I'm very grateful to find any articles that even bring up half of the points raised here. (Just don't let it talk you or your doctor into giving up hope!)

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics
David Lebeauxa,b, Jean-Marc Ghigoa and Christophe Beloina
http://mmbr.asm.org/content/78/3/510.full

Sigh... You know what? I'm afraid the relevance of any of these phenomena may depend on so many things that there may not be one that's a particular obstacle to HS treatment - all three of them (or none of them) could be going on at the same time or at different stages of HS therapy, depending.

I wish I didn't have to think about any of them, let alone all three, but they are becoming an issue, and now I'm having to get into more things I was wishing my specialist had a good grasp of, and might need to get a better grasp of myself to get help, or to help keep doctors on the right track if I can. I've no use for my next appointment to go like my last.

Recently, my doctor suggested Hibiclens for HS specifically to discourage biofilm infections from forming on the skin surface (actually using the B-word), which might not be a bad idea at all were it not that the new additions to my own HS symptoms seem to originate from relatively deep in the tissues rather appearing on the surface as if from a fresh skin microbe, and it might still be a good idea for anyone who does show a tendency toward fresh surface lesions or open or actively suppurating lesions.

However, I am concerned somewhat since biofilms may not be something that the medical community understands very well yet, that doctors' awareness of the possibility of biofilms being involved in HS might further add to their sense of futility of treatment that they seem to adopt all too easily already (a specialist recently talked himself out of even trying to help me and we hadn't even gotten to biofilms or variant forms of microbes yet, just anaerobes), even though research may have already given us a number of important leads about what to do about biofilms and so forth.

A little more background... Numerous authors have proposed that HS may involve biofilm infection as a way to explain both its reluctance to treatment and the frequent need for protracted (long) courses of antibiotics to resolve it

"We note that the characteristics of HS comport exactly with the features of bacterial biofilm-based infections, and examined a case where HS of the buttocks had progressed to an advanced stage. Physical examination of the sinus tracks at surgery revealed a mucinous accumulation consistent with biofilm formation.... The clinical characteristics of HS as an infectious disease are all highly suggestive of other bacterial biofilm-based disorders (although HS has never been recognized as such): a chronic course punctuated by acute exacerbations, localized to specific anatomic regions, and temporarily responsive, but ultimately refractory to conventional antibiotic therapy. We hypothesized that HS bacteria exist in biofilm configuration, which would explain the clinical features of HS and have implications for the development of adequate therapies... It seems paradoxical that these agents [TNF-a inhibitors], which are anti-inflammatory and known to predispose to infection in other circumstances, should be meliorative in HS. One possible explanation is that the tissue damage that leads to the symptoms of HS is due not to the biofilm bacteria themselves, but to an exaggerated inflammatory response engendered by the biofilm that in the process destroys bystander tissue." (Kathju et al 2012)

"Overall, 17 [HS] patients (63%) were found positive for bacterial colonization. Of these, 15 showed colonization in hair follicles and/or sinus tracts. The most commonly identified bacteria were DAPI labelled coccoids that were seen in 71% of the positive patients in the form of biofilms and microcolonies." (Jahns et al 2014)

Another study expresses similar sentiments about HS and biofilms, but may have achieved somewhat different findings? (Unfortunately the link provided by PubMed to a free copy of this paper does not seem to lead me to a free copy, so all that I've read of this paper is the abstract I'm quoting from here, which at least sounds like they found biofilm less of a problem than they expected in HS).

"The clinical course of HS is compatible with a biofilm-driven disease, and biofilm has been described in lesional HS skin. We therefore hypothesized that clinically unaffected HS skin would also have an increased presence of biofilm compared with that of healthy controls... Surprisingly, we detected fewer bacteria and less biofilm in patients with HS." (Ring et al 2016)

One of the reasons I haven't been that concerned about biofilms is that in some of the exemplary work treating HS with antibiotics (the Pasteur Institute and other studies), they are using what a lot of literature makes to sound like some very good choices to deal with the problem. Noah Scheinfeld has written a number of rewarding papers on HS, and has a recent one out that is particularly good on this subject and that touches on some of the strengths of the antibiotics in question (as well as some of their possible limitations - are they very good choices but just not good enough?)

"The reasons why rifampin is so effective against HS have not been fully defined and might involve rifampin's (1) antibacterial effects (2) effects on bacterial biofilms (3) anti-inflammatory effects (4) effects against granulomas (5) and immunomodulatory effects on neutrophils... Rifampin is effective alone or in combination with other antibiotics against some, but not all, of the bacteria that make up biofilms and mitigate the biofilms themselves [25,26]. Staphylococcus epidermidis biofilms often can be controlled with the use of a combination of N-acetylcysteine and rifampicin [27]. Research confirms that rifampicin at a concentration of 1.2 mg/mL immediately reduces established biofilms formed by S. epidermidis although it is not bactericidal despite very low MICs at planktonic conditions [28]. In another experiment, rifampin penetrated biofilms formed by S. epidermidis, but failed to effectively kill the bacteria [29]." (Scheinfeld 2016)

Indeed, rifampin and moxifloxacin both also sound like attractive choices in that their action is bactericidal (kills bacteria) suggesting greater finality than bacteriostatic antibiotics which inhibit growth or replication of bacteria.

The phenomenon of SVCs (small colony variants) in biofilms is pointed out by Lebeaux (and numerous others), along with what seems to be mixed praise for certain antibiotics or combinations such as rifampin with moxifloxacin [a fluoroquinolone]

"As SCV may be present in biofilms, they may be involved in the global recalcitrance of the bacterial community... Furthermore, in vivo models of foreign-body-related infections demonstrated that fluoroquinolones were the most efficient molecules when associated with rifampin (223)... many reports also suggested that reduction of antibiotic penetration cannot fully explain biofilm recalcitrance toward antibiotics. Indeed, antibiotics such as fluoroquinolones, rifampin, and ampicillin penetrate well through the matrix, even though they fail to eradicate 100% of biofilm bacteria (22, 42, 45, 46)... ...Moreover, even in the case of compounds slowly diffusing within biofilms, most antibiotics ultimately reach all biofilm bacteria."

An association between biofilm and SCVs seems to be favored by numerous sources, for example this one which also underscores that SCVs can have different antibiotic resistance patterns than their ordinary form (or their parent microbes)

"Bacteria persisting as SCVs within biofilms may explain the recurrent nature of biofilm infections. SCVs cause persistent and relapsing infections due to their increased resistance to antibiotics. The depressed electron transport activity seen in these auxotrophic SCVs may account for their in vitro resistance to a variety of antibiotics (Proctor and Peters 1998). In addition, SCVs have defective catalase activity, which may interfere with oxidative metabolism and aminoglycoside uptake (Rusthoven et al. 1979)... he minimum inhibitory concentrations of four aminoglycoside antibiotics were found to be 8- to over 16 times higher for SCVs than for the normal large colony type (Rusthoven et al. 1979). Moreover, the slow growth of SCVs and consequently cell-wall division reduces the effectiveness of antibiotics that act at the cell wall (Looney 2000)." (Neut et al 2007)

The same work goes on to discuss some of the sensitivities of SCVs of Staphylococcus aureus (there is likely a far greater wealth of literature on SCVs of S. aureus than on S. lugdensis, which may be the Staph of greatest importance to HS)

"However, SCVs are susceptible to a range of antibiotics with other modes of action, the hydrophilic antibiotics tetracycline and erythromycin for example, and to the hydrophobic antibiotics rifampicin and chloramphenicol (Langford et al. 1989). For optimal eradication of SCVs, treatment should consist of therapy with an antibiotic that has optimal bactericidal activity against slowly growing bacteria (Vaudaux et al. 2006). Rifampin may be the most efficient antibiotic because of its excellent efficacy against stationary and adherent bacteria (Widmer et al. 1990). Although rifampin has very good bactericidal activity against slow-growing bacteria, it should be given in combination with other antibiotics because of the rapid emergence of resistance when given alone (Vaudaux et al. 2006). The combination proposed by Sendi et al. (2006), rifampin with a fluoroquinolone, has been shown to be successful when dealing with hip replacements infected with S. aureus SCVs." (Neut et al 2007)

SCVs frequently encountered may be impaired in their ability to synthesize certain nutrients such as menadione, hemin, or thymidine (these SCVs can be induced in vitro by antibiotics such as aminoglycosides or trimethoprim-sulfamethoxazole, which may help account for their corresponding characteristics - also, when supplemented with the missing nutrients, they may revert to their normal forms.

"The SCV phenotype is often unstable, with some strains reverting at a high frequency to a normal colony phenotype (4, 25)... supplementation of clinical SCVs with hemin or menadione completely reverses the SCV phenotype." (Lannergard 2008)

The question of whether or not these SCVs have access in human beings to such materials that promote their conversion back into ordinary forms, or what circumstances this access might depend on, is not one that I've seen addressed yet.

There is also room for concern whether SCVs are particularly well-suited for taking refuge in the host, such taking up residence in host cells and becoming an intracellular infection.

"In addition, SCVs make the infection difficult to eradicate. They often lead to recurrence since they respond poorly to standard antibiotic treatment and can sometimes survive intracellularly." (Neut et al 2007)

"An additional key property of SCVs is their increased ability to survive within nonprofessional phagocytes, such as epithelial cells, fibroblasts, osteoblasts, and endothelial cells [2]. S. aureus is not traditionally considered to be an intracellular pathogen; however, over the last decade, published evidence of SCVs' ability to survive intracellularly has increased, from a few sporadic reports to, at present, a myriad of model systems that report bacterial uptake and persistence within nonprofessional phagocytes. Most of these studies reported cytopathologica effects of intracellular S. aureus, but only a few of these studies specifically addressed the underlying mechanisms of intracellular survival. Notable advances include the report that intracellular S. aureus may persist in epithelial cells and may serve as reservoirs for recurrent infections in cases of chronic rhinosinusitis [4]. One explanation for the improved intracellular survival of SCVs is their decreased overall metabolism and dampened production of cytotoxins, which may downregulate the induction of cell lysis or apoptosis [2]. Their intracellular location, combined with the lack of efficient bactericidal mechanisms in nonprofessional phagocytes, are assumed to protect SCVs from professional phagocytes and from antimicrobial agents whose action is mainly extracellular." (Vaudaux et al 2006)

"Persistent and relapsing infections, despite organism susceptibility and apparently adequate antibiotic therapy, occur frequently with many pathogens, but it is an especially prominent problem with Staphylococcus aureus infections (Lowy, 1998). The basis for persistence has been slowly unraveled over the past two decades, and many of the pathways involve changes in metabolism. One phenotype of microorganisms has helped to pave the way to understand persistence, and this is represented by small colony variants (SCVs) (Proctor et al., 2006). The linkage between S. aureus SCVs and persistent infection was first reported in a small clinical series in 1995 (Proctor et al., 1995). Because S. aureus SCVs were able to establish an intracellular infection in cultured cells, it was hypothesized that this might form the basis for the development of persistent infections (Balwit et al., 1994). Moreover, the instability of these SCVs wherein they could revert to the parental normal phenotype would also provide a mechanism for relapsing, virulent infections. An important part of the ability to persist was associated with the quiescent metabolic state (Proctor et al., 1995). S. aureus SCVs were found to produce fewer lytic enzymes, thereby allowing them to persist within the host cells (Proctor et al., 2006)." (Proctor et al 2014)

Yet this possible obstacle might also be addressed in a number of ways, including by some of the antibiotic regimens that have shown the most promise in HS

"At an extracellular concentration corresponding to their Cmaxs (total drug) in humans, only oxacillin, levofloxacin, garenoxacin, moxifloxacin, and oritavancin had truly intracellular bactericidal effects." (Barcia-Macay et al 2006)

"The three types of SCV displayed contrasting behaviours, which rely, at least in part, on their respective capacity to grow inside the cells. Against the stable thymidine-dependent SCV isolated from a patient with cystic fibrosis, vancomycin, oxacillin, fusidic acid, clindamycin, linezolid and daptomycin were much less active than quinupristin/dalfopristin, moxifloxacin, rifampicin, and oritavancin. Yet, for all drugs, the maximal efficacy was markedly reduced against the thymidine-dependent SCV when compared with the normal-phenotype and revertant isogenic strains, probably due to its slower growth.23 Against the haemin-dependent SCV derived from the COL methicillin-resistant S. aureus (MRSA) strain, oritavancin and moxifloxacin were also much more effective than vancomycin, gentamicin, daptomycin or rifampicin, and their activity was indistinguishable from that observed against the parental strain, in line with the restored intracellular growth of this SCV.22 Against the menadione-dependent SCV also derived from the COL MRSA strain, the maximal efficacy of antibiotics remained unaffected, which is surprising in view of its slow intracellular growth. Yet the affected pharmacodynamic parameters were rather the amplitude of the dose–response curve (which was reduced) and the potency of antibiotics (which was increased)." (Garcia et al 2013)

"ii) Biofilms. The ability of rifampin to enter cells is its most important mechanism of intracellular killing of tuberculosis (220). This major ability of rifampin to penetrate into cells and biofilms to treat infections is supported by strong clinical data for prosthetic material infections." (Forrest & Tamura 2010)

So a lot of what we read makes it sound like these antibiotics should be working rather well to rid HS cases of our arch-enemy, Staphylococcus, and we can see why they were chosen - even though what is quoted here may also leave room for the ultimate failure of these antibiotics and the tendency of HS to return after their use, and they may ultimately be only as perfect as their kill rate of key HS pathogens. This has probably created considerable confusion, perhaps contributing to the suggestion expressed by several authors that the dramatic improvements in HS associated with these antibiotics owe not to the established antimicrobial activity of these antibiotics (and the known prevalence of pathogenic microbes in HS) but to other properties such as anti-inflammatory properties (perhaps also inspired by the efficacy of anti-inflammatory anti-TNFa therapies for HS), in spite of the Pasteur Institute researchers having emphasized that they used more than one antibiotic that is not known to have such properties.

Again, SCVs are associated with both a low growth rate and with decreased production of some noted toxins, which may help contribute to their intracellular survival, and even a purported reversion rate that may be too low for them to contribute to inflammatory symptoms

"As part of a general reduction in metabolic activity, SCV do not produce virulence ... factors such as alpha-toxin, coagulase, hemolysins or other products which are associated with stimulation of cytokine release and immune response... SCV of S. aureus, which normally kills endothelial cells using alpha-toxin, do not produce this toxin, are not lethal and therfore capable of intracellular survival. Supply of menadione and haem to these intracellular survivors in vitro restored alpha-toxin production and precipitated a significant reduction in intracellular survival of the bacteria as well as in survival of the endothelial cells." (Allison 2000 pg 302).

This may however be about where some semantics nearly come into play, and it concerns who the troublemakers are exactly, i.e., SCVs may not be qualified to assume responsibility for HS relapse upon suspension of antibiotics (as seems to be generally suggested by a number of researchers), but their offspring may be. If even a few SCVs manage to revert to their normal, rapidly reproducing forms, then these revertants to normal form and their more typical exponential growth with antibiotics absent might quickly give rise to a sizable population of normal microbes with the required virulence to produce inflammation and other pathogenic symptoms of infection.

(The same goes for how the question of whether it's L-forms or L-forms reverted to normal that are under suspicion of perpetuating disease symptoms following suspension of antibiotics. Even if L-forms are poor at causing diseases - which may remain a controversial matter - numerous generations of their normal offspring might conduct disease-producing business as usual when given the chance).

Moreover, these descriptions of intracellular infections might be accurately taken to imply a situation in which we can have cells infected with SCVs, which may reproduce in these infected cells and send offspring out into the extracellular environment, which then revert into normal microbial form. In essence, these cells may become literally factories for recurring infections if they are not successfully cleared of these variant microbes.

It may not be entirely clear exactly why these SCVs do not revert to normal form in these infected cells (any more than it may be entirely clear how they can persist in phagocytic cells equipped for their killing in the first place) but perhaps one might speculate that their intracellular environment may represent one that is deficient in the appropriate factors known to promote the reversion of SCVs to normal form whereas the extracellular enviroment might not, so that SCVs escaping the parent host cell might be expected to readily revert upon escape?), as stated by some of these authors, intracellular reversion might likely be evidenced by the death of, rather than the persistence of, the infected host cells.

In spite of the shortcomings of these otherwise fairly optimal antibiotics, it is encouraging to see that for example authors such as (Neut et al 2007) suggest possible recourse, in the form of antibiotics to which SCVs might still remain susceptible, which might be strategically applied in conjuction with antibiotics like rifampin and moxifloxacin to attempt to achieve true 100% killing of SCVs if it is actually lacking in efforts to treat HS thus far.

As I have often mentioned, another possible source of less than 100% killing of pathogenic microbes in HS might owe to actinomycosis. Actinomyces has turned up with what is most likely significant frequency in HS studies reasonably geared for its detection, and literature has suggested before that dense fungus-like colonies of Actinomyces might protect small populations of other microbes from antibiotics during their course of administration. The recourse for actinomycosis that I most often see in literature is penicillin, and perhaps a preparatory course of penicillin prior to other antibiotics as a prophylaxis against this effect could help improve the outcome of antibiotics in HS provided this rarely-mentioned sort of scenario is really a significant problem.

"The mycelial masses of Actinomyces reduce the rate of penetration of antibiotics and may physically protect the associated bacteria. In addition, associated organisms which produce -lactamases can complicate treatment. Therefore, the dense granules of Actinomyces and the presence of associated bacteria can enhance the virulence of the infection and influence the mode of use of antibiotics, thereby adding to the difficulty of treating the disease." (Bowden 1996)

I have not yet found explicit reference to whether not only the fungus-like microbe Actinomyces, but also genuine fungal infections, could also create this effect. Fungal pathologies like Candida may occur a in number of us along with our HS, which is probably very true for myself as well, even if there is probably little reference in literature to candidiasis in HS per se.

Still, even with this already sizable list of complications, the question of what more researchers would have to have done with antibiotics in HS to be consistently curing it instead of temporarily making great improvements, may well turn out to be just something simple like well-timed addition of tetracycline or erythromycin or penicillin (or perhaps difluconazole in the event of Candida ever being an actual obstacle). I firmly believe that the Staphylococcal part of my own HS was purged from my lesion years ago with one of the obvious common antibiotics being tried at the time - doxycycline, erythomycin, or perhaps clavamox, in contrast to the association of the use of some of these other antibiotics with Staph that refuses to stay away. Whatever it was seemed to have no trouble to penetrate even into sinus tracts (which are sometimes suggested to present a possible hard-to-reach target for some antibiotics) and put a stop to them.

Perhaps it might be more expeditious sometimes to specifically target various troublemakers in HS such as Staphylococcus individually? In truth, the broad-spectrum-cocktail approach to antibiotics might be better at revealing the nature of HS as a plausible product of microbes by showing just much an antibiotic can do about it, than at making it sufficiently simple to treat with lasting results?

Another possible ray of sunshine in all this awful mess is that there may be agents, including some natural products provided that any are actually powerful enough to work at safe and achievable doses, that might potentiate antibiotics by increasing the permeability of microbial cell walls, allowing higher and more effective doses into the cell, which might apply to SCVs as well as ordinary forms of microbes - just as there are natural products which can reduce biofilms in experiments, and one or more of these agents, or some combination of them, also could turn out to be powerful and safe enough to help overcome biofilm in vivo. (There are even pages out there giving lists of them, although they are usually not written by experts so they usually end up a mix of good and bad suggestions at best, buyer beware).

Impacting microbes by permeabilizing microbial membranes may also be a property of some of the body's natural antimicrobials like cathelicidins/LL-37, a benefit we might be already be enjoying were it not fairly plausible that we have may have multiple infections that are able to degrade LL-37 before it can get to work on them.

So, as always, even though it can obviously be very complicated, no matter how hopeless HS may TRY to sound, IT'S NOT HOPELESS. Don't EVER give up hope!!!

So while I'm on that subject... I can still count myself among HS patients not because it's really hopeless, but because my doctors are good at being convinced that it is by reading their usual sort of reference materials that make it out to be. The specialist I recently saw spoke as if it would be impossible to sort out who the troublemakers actually are are no matter how many tests were run - the familiar problem with normal skin bacteria (skin commensals) being so frequently found in HS lesions and abscesses - and was so devoted to that proposition that they really couldn't even see what I was trying to do, or already had done, to try to help them sort it out.

I know it isn't practical to test me for everything let alone to try to kill everything they find, but I actually walked in with VERY specific microbiological concerns after factoring in all the clues I could think of (including my life story going back 30 years), that ended up completely ignored.

Meanwhile, back at the Pasteur Institute, there are number of last names appearing on this next paper (like Join-Lambert, Guet-Revillet and Nassif) that we hopefully recognize on sight after all they have done to help understand and to help fight HS. It's a bacteriological review of HS, and Figure 1 is remarkable - with luck you can easily see, graphically, what I've been saying for some time after reading the same source literature, about who the most typical and who the highest value targets in HS are (they may be one in the same) - Staph, Strep, Bacteroidales (Bacteroides and Prevotella) and Actinomyces if it is genuinely acting as promoter of persistence by protecting small populations of other microbes from antibiotics or immune cells, across a set of different HS studies (this probably helps put Corynebacterium and Staph. aureus lower on the suspect list, which is likely right where they belong). (Nikolakis et al 2015)

I believe if one looks closely, it also says a lot for the perilesional swap technique employed by the Pasteur Institute in clarifying the likeliest suspects and highest value targets among microbes in HS. (Basically, lesional specimens are taken from lesions along with perilesional swabs from adjacent healthy skin, and anything found in a lesion but not on normal skin of the patient, may no longer so easily be dismissed as being simply "a normal bacteria of the skin" even when it could be causing disease symptoms).

Still, I fail to understand the reluctance of any of these fine researchers and many others to more firmly suggest the possibility of a purely microbial causal hypothesis for HS (with anything else that contributes to it including any genetic factors therefore considered as predisposing or exacerbating factors, or triggers). After all, you can have all the predisposing and exacerbating factors you want, but you will most likely still need microbes for it to turn into one of the troublesome infections characteristic of HS, complete with known signs of infection like inflammation, boils, abscesses, lesions, etc.

I understand they are practicing respectable professional caution here, but I often come to wonder just how much these champions of the fight against HS really know about the virulence of a number of the microbes they're battling. One of the saddest things I have ever seen in HS is when another HS study identifies well-known abscess-inducing bacteria carefully isolated from an HS abscess, and then actually cannot seem to figure out whether these bacteria had something to do with causing the abscess! (This also seems to set a REALLY bad example for my specialist). :-)

So far, its still only a theory that microbes deserve the bulk of the blame, but what more does HS actually require to produce its characteristic symptoms, and what else is so much the same from one patient to another as the more typical parts of our bacteriology? (The principle of Occam's Razor keeps trying to at least imply that microbes may be an adequate etiology to HS in themselves - that is, they may suffice for an causal explanation).

Anyway, if I can figure any of this out, obviously there's tons of hope for actual intelligent people to get to the bottom of it. In recently reviewing some of the HS papers published this year, I'm generally pleased with the progress in perspectives that is being made - important ideas are being tabled and seconded. I'm pleased to see evidence that some of the antibiotics that have proved so promising at the Pasteur Institute seem to have given good albeit brief results for other professional authors on the subject of HS also, and pleased to see corroboration of the Pasteur Institute's bacteriological findings by researchers also reporting Staphyloccus lugdunensis as prominent aerobic isolates (Katoulis et al 2015).

Admittedly, our choices of antibiotics may be subject to numerous limitations sometimes including availability, but there still many possibilities for combinations of available antibiotics for HS or even antibiotics and supplements that might hold considerable promise with a somewhat more premeditated approach than has been applied thus far.

There is more to this subject of course, including L-forms, which will hopefully follow. The occasion for thinking I had something new to say is the reluctant realization that numerous different various forms of microbes could try to present obstacles in some cases. Perhaps the most successful clinical work to date involved a regimen of rifampin-moxifloxacin-metronidazole, with the metronidazole replaced at six weeks with ertapenem (Join-Lambert et al 2011). In trying to apply these concepts of variant organisms to the results, there may have been opportunities for both the generation of SCVs and L-forms, both of which might have been exploited by troublemaking (virulent) microbes, so even in that shining example there might be multiple complications which might be corrected to yeild better clinical results.

And as always, I probably don't really know what I'm talking about here. Unfortunately that doesn't change the fact that someone needs to, so I am just trying to think of answers to HS that may not yet appear in these wonderful studies, for everyone's sake including my own. The sad truth is that if one of my doctors happened to be feeling especially cooperative and said, "Alright, I'm willing to consider any therapy you suggest - what do you, the patient, recommend?" I still wouldn't be quite sure what to say, and there's a fair part of that I had been hoping they could help me with if it came to that.

SOURCE MATERIALS

Allison, DG (2000). Community Structure and Co-operation in Biofilms, Issue 59 isbn:0521793025 https://books.google.com/books?isbn=0521793025

Barcia-Macay et al (2006). Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1426441

Bowden, GHW (1996). Actinomyces, Propionibacterium propionicus, and Streptomyces. Chapter 34 in: Medical Microbiology. 4th edition. http://www.ncbi.nlm.nih.gov/books/NBK8385

Forrest, G & Tamura, K (2010). Rifampin Combination Therapy for Nonmycobacterial Infections http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806656

Garcia et al (2013). Antibiotic activity against small-colony variants of Staphylococcus aureus: review of in vitro, animal and clinical data. http://jac.oxfordjournals.org/content/68/7/1455.long

Jahns, AC et al (2014). Microbiology of hidradenitis suppurativa (acne inversa): a histological study of 27 patients. http://www.ncbi.nlm.nih.gov/pubmed/24475943 (abstract)

Join-Lambert et al (2011). Efficacy of rifampin-moxifloxacin-metronidazole combination therapy in hidradenitis suppurativa.
https://www.researchgate.net/publication/49637776_Efficacy_of_Rifampin-Moxifloxacin-Metronidazole_Combination_Therapy_in_Hidradenitis_Suppurativa

Kathju, S et al (2012). Considering hidradenitis suppurativa as a bacterial biofilm disease. http://femsim.oxfordjournals.org/content/65/2/385.long

Lannergard, J et al (2008). Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573106

Neut, D et al (2007). The role of small-colony variants in failure to diagnose and treat biofilm infections in orthopedics. http://www.tandfonline.com/doi/pdf/10.1080/17453670710013843

Nikolakis G et al (2015) Bacteriology of hidradenitis suppurativa/acne inversa: A review. http://www.eblue.org/article/S0190-9622(15)01989-1/pdf (see Figure 1).

Proctor, RA et al (2014). Staphylococcus aureus Small Colony Variants (SCVs): a road map for the metabolic pathways involved in persistent infections.
http://journal.frontiersin.org/article/10.3389/fcimb.2014.00099/full

Ring, HC et al (2016). Normal Skin Microbiota is Altered in Pre-clinical Hidradenitis Suppurativa. http://www.ncbi.nlm.nih.gov/pubmed/27377144 (abstract)

Scheinfeld, N (2016). Why rifampin (rifampicin) is a key component in the antibiotic treatment of hidradenitis suppurativa: a review of rifampin's effects on bacteria, bacterial biofilms, and the human immune system. https://escholarship.org/uc/item/85s8s1s8

Vaudaux, P (2006). Staphylococcus aureus small colony variants: difficult to diagnose and difficult to treat. http://cid.oxfordjournals.org/content/43/8/968.long

Left out an important reference...

Lebeaux, D (2014). Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187679

This might be a paper that is particularly relevant to HS?

Frank, et al (2007). In vitro effects of antimicrobial agents on planktonic and biofilm forms of Staphylococcus lugdunensis clinical isolates.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803120
http://pubmedcentralcanada.ca/articlerender.cgi?artid=538398

"An unexpected outcome of MBC testing was the observation that vancomycin was not bactericidal against 93% of S. lugdunensis isolates, suggesting widespread vancomycin tolerance in this species."

I'm curious whether this might be related to the likelihood of Staphylococcus ludgunensis being mistaken for MRSA if caregivers aren't more careful in distinguishing Staphylococci - just been reading some things that make it sound like it might not be quite as easy as most of them think, including where SCVs of S. aureus or S. lugdunensis can be lacking pigmentation. Just how common is misdiagnosis of MRSA, anyway?

You might expect that when that happens, the first thing they'll try is vancomycin, and the last thing they'll try is methicillin, on something presumed to be MRSA (Methicillin-Resistant Staphylococcus Aureus).

One paper I just read the other day shows successful culture of Staphylococcal l-forms, and the applicable suggestion may be that like other slow-growing microbes (including some of the gram-negatives that many HS patients may battle), the lab may need to give these variant forms extra time to establish a culture.

I've dug up A LOT of papers the last couple of days although I haven't read 1/4 of them yet, looking for corroboration of an important point - which is that maybe antibiotics that inhibit protein synthesis are better suited to some of these tasks BECAUSE THEY MAY BE ABLE TO MORE PROMPTLY INHIBIT MICROBIAL SYNTHESIS OF PROTEIN TOXINS THAT IMPEDE THE IMMUNE SYSTEM - ???? These toxins may mean that we cannot quite count on the combination of certain antibiotics and the immune system to achieve complete killing of microbes together. DNA and RNA synthesis inhibitors might act against FUTURE production of protein toxins eventually, while protein synthesis inhibitors might be able to work against them in the present?

Really not that much new happening here, a very obvious candidate for one of the protein toxins of Staphylococcus aureus that could present complications is the adenosine synthase AdsA (aka sasH), which has notable properties of being able to both degrade molecules that are vital to immune function against infections, and create by-products that can also interfere with proper immune function.

I remember making a big deal about this for our friend and (hopefully former) HS patient positivepris, on this forum maybe all of two years ago now, but I didn't quite realize before the roundabout way in which this sort of toxin might undermine the effectiveness of antibiotics even though it may not interact with them directly.

Two years later, what I still haven't been able to find, is clear and obvious evidence that Staphylococcus lugdunensis can produce a comparable toxin to AdsA, which is sort of a "broad-spectrum" nucleotidase compared to some others in its class. Maybe S. lugdunensis achieves comparable stubborness through a slightly different combination of immunosuppressive toxins?

Anyway, I wasn't fully aware of the relatively large target list of AdsA before

Firon, A et al (2014). Extracellular Nucleotide Catabolism by the Group B Streptococcus Ectonucleotidase NudP Increases Bacterial Survival in Blood. http://www.jbc.org/content/289/9/5479.full.pdf

"More recently, ecto-5-nucleotidases in bacterial pathogens
have been identified, including the S. aureus AdsA enzyme
(18–20). AdsA was first described as an adenosine synthase
because of its ability to hydrolyze AMP into adenosine (18), whereas further characterization demonstrated that AdsA is an eN enzyme that also hydrolyzes ADP, ATP, GTP, GDP, and GMP as well as 2-deoxyadenosine 3-monophosphate (19, 20).

Curiously a seldom-mentioned paper on HS (I rarely mention it because I still haven't found a free full text of it, for being way too busy hunting down others).

In it, they describe a case of HS featuring the same sort of "bactericidal defect" as we might expect to originate from a number of toxins including AdsA, and claim to have corrected it by boosting GTP levels with a "cholinergic agonists" - so I'm wondering again if essentially this treatment acted as an antidote to a GTP-attacking microbial toxin?

Ginder, PA et al (1982). Hidradenitis suppurativa: evidence for a bactericidal defect correctable by cholinergic agonist in vitro and in vivo. http://www.ncbi.nlm.nih.gov/pubmed/6126491

"We report a patient who had a defect in polymorphonuclear leukocyte killing of bacteria associated with low levels of intracellular cyclic GMP. This defect was corrected with a cholinergic agonist in vitro. Treatment of the patient with a cholinergic agonist, bethanechol chloride, resulted in prolonged clinical improvement, normal bactericidal function, and normal levels of intracellular cyclic GMP. The possible mechanisms responsible for the bactericidal defect and for the patient's improvement are discussed.."

All if only to hopefully reinforce my position that while HS may be challenging, it's far from unfathomable, or hopeless...

And that as a possible issue with variant microbial forms, it's not some rare "orphan disease" that no one should care about, it's part of a much broader community issue - namely, stubborn infections - that affects virtually everyone.
Perhaps it should come as good news that a great many more researchers might already be working on our "HS" that most of might realize?

Even if the research just shows us more and more that doctors may not really be entitled to the luxury of ignorance in these matters, or the luxury of panic...

Sorry, a correction - it's probably Staph SCVs I saw photographed (not L-forms) in the culture dish, and when I run into the article again I will post it. Also a clarification - as an example of something else that Staphylococcus lugdunensis might be doing to foul up human immunity might be arginine degradation, which could potentially result in further undermining of the immune system's defenses. Immune cells may rely on arginine as a substrate for nitric oxide synthase, which is involved in killing some microbes.

I'm not certain of which of a number of possible mechanisms it uses, but the fact that S. lugdunensis is ornithine-decarboxylase positive may certainly be suggestive that it indeed at least has ambitions of meddling in such areas in the host.

Again, I still don't have a good inventory of S. lugdunensis' equipment for compromising immunity and maybe not one for S. aureus either, even though AdsA is such an obvious toxin that it made it into the Virulence Factor Database (VFDB), which often doesn't even pay as much attention to microbes' abilities to immunosuppression as it does to microbes' abilities to stick to things...

BTW, if anyone wants to pursue of this any further - I'm tempted to issue yet another reminder for doctors that technically that's the doctor's job - I'm constantly finding this page invaluable in keeping my antibiotics sorted out at a glace, and others might too?

Antibiotic Classification & Mechanism - Author: Derek Moore
http://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism

Sorry, this stuff is confusing enough as it is, but one more correction (I honestly don't seem capable of writing something flawless no matter what)...

and claim to have corrected it by boosting GTP levels with a "cholinergic agonists" - so I'm wondering again if essentially this treatment acted as an antidote to a GTP-attacking microbial toxin?

That part should read,

and claim to have corrected it by boosting GMP levels with a "cholinergic agonists" - so I'm wondering again if essentially this treatment acted as an antidote to a GMP-attacking microbial toxin?

(That is oversimplifying it, but it does help to make the possible connection clearer).

Think I'll lay down for a bit now... Stay positive, hopefully we are actually witnessing this HS thing getting sorted out if it really hasn't been already.

I'm sure everyone remembers CoNS (Coagulase-negative staphylococci) in HS from this important Hidradenitis paper

Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery. Lapins J et al 1999. http://www.ncbi.nlm.nih.gov/pubmed/10215774 (Abstract only)

Still on the subject of Staphylococcal SCV forms in Hidradenitis, here are some passages about them and their affiliation with an intracellular environment from an article on CoNS (coagulate-negative Staphylococci) with an excellent collection of references (some 628 papers cited!)

Coagulase-Negative Staphylococci. Becker K et al 2014. http://cmr.asm.org/content/27/4/870.full

"Intracellular persistence—the SCV concept.The term “small-colony variant” (SCV) reflects a specific phenotype resulting from a switch from the normal (wild-type) phenotype (see Clinical Significance and Infections). SCVs have been described for several Gram-negative and Gram-positive species. While most work has been done on S. aureus SCVs (216), similar general characteristics may be assumed for SCVs of CoNS.

Irrespective of the species, the SCV phenotype is characterized by drastic changes in cellular metabolism, reflected by a reduced growth rate and substantial quantitative and qualitative modifications of the transcriptome, metabolome, and proteome (341–343). These changes determine the auxotrophism expressed by almost all SCV isolates (344–348). Metabolic changes also influence the colonial morphotype of SCVs, which are characterized by tiny colonies, reduced or lost pigmentation, and hemolysis compared to their wild-type counterpart (216).

Their intracellular location provides a survival niche in the host environment, shielding SCVs from host defenses and, additionally, from antimicrobial agents. The resulting habitation in an intracellular environment necessitates an adaptation to the anaerobic milieu. Moreover, virulence and pathogenic behaviors are modified; for instance, S. epidermidis mutants displaying the SCV phenotype demonstrated augmented expression of PIA."

(Note: PIA - Polysaccharide intercellular adhesin - is a Staphyloccal biofilm building material.
Polysaccharide intercellular adhesin in biofilm: structural and regulatory aspects. Arciola CR et al 2015. http://www.ncbi.nlm.nih.gov/pubmed/25713785)

Especially because this sounds so complicated, it helps me stay hopeful to remember that often when someone is talking about these same challenging microbes, they sound considerably more hopeful than when someone is talking about the very same thing in HS. It's also sort of a refreshing take on this with the insistance that there must be some significant genetic factor in HS, that outside the context of HS it seems fairly well known that to cause persistent troubles it's enough for the microbes to be mutants and we the patients don't actually have to be mutants too in order to experience similar troubles.

At least as far as the secretase genes go, the popular idea of them being "HS genes" still seems sort of silly to me, since the life story of the secretases and the proteins they process is a long and complicated one with many steps that might all present opportunities for interference by many factors including microbes and their toxins.

This article suggests that Bacteroidales (a possible staple of Stage 2 & 3 HS) might be able to manipulate or interfere with these functions

Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage. Wu S et al 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056613

And this article seems to go so far as to insinuate that some microbes might have come to possess such metalloproteases to us as toxins against us in the first place, by stealing them from us!

Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog. Goulas T et al 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033309

"Our findings support that fragilysins derived from a mammalian adamalysin/ADAM xenolog that was co-opted by B. fragilis through a rare case of horizontal gene transfer from a eukaryotic cell to a bacterial cell."

Toxins such as these metalloproteases may be one of a number of possible causes of microbially-induced inflammation in HS, even while adenosine produced by AdsA is often credited with being anti-inflammatory.

This article (besides what may amount to alluding to a possible ability of Staphylococcus to manipulate host metalloproteases to its own advantage), may be saying in essence that attacks on adherens junctions in tissue by metalloproteases like fragilysin, might make them more vulnerable to Staphylococcal toxins (possibly part of a basis for a partnership between Staphylococcus and Bacteriodales that may produce sinus tracts)?

The adherens junctions control susceptibility to Staphylococcus aureus a-toxin. Popov LM et al 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655540

BFT may also be able to encourage at least some cell types to devote enzymes to "cashing in" on the polyamine synthesis that may some of the microbes may be up to, as to come up with yet another weapon to use against the host

"Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) up-regulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N(1),N(4)-bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation."

This in addition to polyamine synthesis producing putrid smelling substances like putrescine and possibly involving piracy of host polyamine precursors originally intended for immune defense (NOS depends on arginine), and the possibility that polyamine synthesis by Staphylococcus lugdunensis may help explain why S. aureus doesn't seem that keen to share an abscess with it even though Bacteroidales might be). One article I read made it sound like perhaps the only S. aureus that might want to cohabitate with S. lugdunensis is the Staphylococcus aureus MRSA USA 300 strain.

The evolution of a superbug: how Staphylococcus aureus overcomes its unique susceptibility to polyamines. Anzaldi LL & Skaar EP 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2958.2011.07808.x/epdf

"Of these CA-MRSA strains, infections by USA300 lineage isolates are quickly becoming the most common (DeLeo et al., 2010). In addition to the antibiotic resistance of USA300, Joshi and colleagues found that these strains are less susceptible to spermine/spermidine toxicity. A significant difference between USA300 and other CA-MRSA strains (USA400 and USA500) is the presence of the arginine catabolic mobile element (ACME) (DeLeo et al., 2010). S. aureus is thought to have received ACME in two gene transfer events from both Staphylococcus haemolyticus and S. epidermidis (Bartels et al., 2011).

Arginine catabolic mobile element encoded speG abrogates the unique hypersensitivity of Staphylococcus aureus to exogenous polyamines. Joshi GS http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183340

"Polyamines, including spermine (Spm) and spermidine (Spd), are aliphatic cations that are reportedly synthesized by all living organisms. They exert pleiotropic effects on cells and are required for efficient nucleic acid and protein synthesis. Here, we report that the human pathogen Staphylococcus aureus lacks identifiable polyamine biosynthetic genes, and consequently produces no Spm/Spd or their precursor compounds putrescine and agmatine. Moreover, while supplementing defined medium with polyamines generally enhances bacterial growth, Spm and Spd exert bactericidal effects on S. aureus at physiological concentrations. Small colony variants specifically lacking menaquinone biosynthesis arose after prolonged Spm exposure and exhibited reduced polyamine sensitivity. However, other respiratory-defective mutants were no less susceptible to Spm implying menaquinone itself rather than general respiration is required for full Spm toxicity. Polyamine hypersensitivity distinguishes S. aureus from other bacteria and is exhibited by all tested strains save those belonging to the USA-300 group of community-associated methicillin-resistant S. aureus (CA-MRSA). We identified one gene within the USA-300-specific arginine catabolic mobile element (ACME) encoding a Spm/Spd N-acetyltransferase that is necessary and sufficient for polyamine resistance. S. aureus encounters significant polyamine levels during infection; however, the acquisition of ACME encoded speG allows USA-300 clones to circumvent polyamine hypersensitivity, a peculiar trait of S. aureus."

I have never seen it sorted out whether the resident Bacteroides in many HS cases (or some other pathologies) might be ETBF (enterotoxigenic Bacteroides fragilis), but it does tend to sound like it might be a particularly inflammatory variety. It's hard to blame the virulence of ETBF on toxins like BFT comfortably when corresponding genes seems widely distributed throughout the Bacteroidales, so perhaps researchers would be on the right track suggesting that what is actually different about them is that ETBF is a more accomplished producer of these toxins than other specimens, one that could be in possession of extra copies of BFT-producing genes?

However, given that influx of mast cells has been noted in HS lesions, histamine may also be part of that incessant burning sensation and almost irrestistable desire to scratch and at least one HS paper has suggested we might be candidates for antihistamines (or perhaps better yet, antibiotics to kill the bug that may be helping to causing the histamine production?) If the microbes wanted to join in with any mast cells that they may have manipulated into overproducing histamine, I presume it may not take them much more than, say, maybe a histidine decarboxylase enzyme to become little histamine factories themselves??

Another thing that still sounds somewhat silly to me is the idea of needing a genetic explanation for why our HS wounds won't heal, in the event that it were simply typical for wounds to tend not to heal while they're still infected with something that we're not fighting off effectively - particularly if adenosine were able to perform their phagocyte incapacitating trick at about step 2 of 4 in the healing process as it is described by Wikipedia https://en.wikipedia.org/wiki/Wound_healing

"This process is divided into predictable phases: blood clotting (hemostasis), inflammation, tissue growth (proliferation) and tissue remodeling (maturation). Blood clotting may be considered to be part of the inflammation stage instead of a separate stage.
Hemostasis (blood clotting): Within the first few minutes of injury, platelets in the blood begin to stick to the injured site. This activates the platelets, causing a few things to happen. They change into an amorphous shape, more suitable for clotting, and they release chemical signals to promote clotting. This results in the activation of fibrin, which forms a mesh and acts as "glue" to bind platelets to each other. This makes a clot that serves to plug the break in the blood vessel, slowing/preventing further bleeding.
Inflammation: During this phase, damaged and dead cells are cleared out, along with bacteria and other pathogens or debris. This happens through the process of phagocytosis, where white blood cells "eat" debris by engulfing it. Platelet-derived growth factors are released into the wound that cause the migration and division of cells during the proliferative phase..."

Which I suppose may be yet another way of saying that the inflammation may tend to continue until the infection is killed?

I suppose that's a good opportunity to put something else on the table - I have no idea how much this might apply to us or how seriously to take it, but I found several papers that hint at yet another thing that might prevent complete effectiveness of antibiotics. While this may not be a match for successful eradication of abscess by antibiotics since it seems to describe abscess formation IN SPITE OF antibiotic use, I'm curious if this could make a contribution to the persistence or recurring nature of some infections

Antibiotics fail to prevent abscess formation secondary to bacteria trapped in fibrin clots. Hau T et al 1988. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279316

"Escherichia coli entrapped in fibrin did not cause mortality but did result in abscess formation in all animals. Bacteroides fragilis incorporated into fibrin clots resulted in abscess formation in the majority of animals. Treatment with gentamicin sulfate, ampicillin sulfate, and cefoxitin sodium completely abolished the mortality secondary to E coli suspended in normal saline solution but did not influence the rate of abscess formation secondary to E coli incorporated into fibrin clots. Similarly, cefoxitin and clindamycin phosphate did not significantly change abscess formation secondary to B fragilis incorporated into fibrin clots. We conclude that systemic antibiotics are ineffective in the prevention of abscesses secondary to bacteria trapped in fibrin, either because they do not reach bactericidal levels in the fibrin clot, as in the case of gentamicin, ampicillin, and clindamycin, or, as in the case of cefoxitin, because of the inoculum effect caused by the high number of bacteria. Fibrinogen or fibrin itself do not afford any protection of bacteria against the action of antibiotics."

The effect of bacterial trapping by fibrin on the efficacy of systemic antibiotics in experimental peritonitis. Hau T et al 1983. http://www.ncbi.nlm.nih.gov/pubmed/6351305 (Abstract only).

"We conclude that entrapment of bacteria by fibrin abolishes systemic sepsis but also protects bacteria against the action of systemic antibiotics and favors abscess formation."

Regarding AdsA and its related toxins, sometimes it's hard to get excited over the possible importance of this, when there's probably a rather long list of things that pathogenic microbes do to subvert immunity. (In a way, we might be somewhat fortunate if the battle to arrest HS comes down to a few infected immune cells since just getting them into those immune cells in the first place might normally be a big part of the battle).

All the same, literature does continually suggest that this one Staphylococcal toxin may be critical

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA-Mediated Host Killing in the Airways. Pernet E et al. 2015 http://www.jimmunol.org/content/194/11/5312.full

"The present studies showed that the S. aureus mutant lacking adenosine production (-adsA strain) increased sPLA2-IIA expression in guinea pig airways and was cleared more efficiently, compared with the wild-type strain."

And this one presents the importance of AdsA even more dramatically, and also offers it some possible credit for the frequency of associated abscesses

How staph thwarts attack. Maxmen A 2009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768856

"Bacteria with intact adsA survived longer in whole blood from rodents and humans than did adsA-deficient bacteria. And mice infected with adsA-deficient strains cleared infection quickly and rarely developed the abscesses characteristic of progressive staph infections. The virulence of adsA-deficient staph could be regained by genetically restoring the enzyme."

And reminds us that some of the other most frequently encountered HS microbes might be up to similar tricks as we were already advised by Firon et al.

"Manipulating the adenosine pathway may turn out to be a widespread phenomenon, as the authors also identified putative 5'-nucleotidase–encoding genes in a variety of gram-positive bacteria."

And this one seems to some credit to AdsA and other possible adenosine souces for kicking immune cells out of abscesses

Staphylococcal Protein A Promotes Colonization and Immune Evasion of the Epidemic Healthcare-Associated MRSA ST239. Hong X et al 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922140

"Taken together, these results indicate that macrophages are excluded from S. aureus-induced abscesses by mechanisms requiring staphylococcal secretion of nuclease and AdsA."

So we may not actually be able to count on the luxury in treating HS with antibiotics, of expecting to kill most of the microbes or to slow their growth (bacteriostatics) and have the immune system take it from there, if every time the immune system tries to get near a few stubborn stragglers of Staphylococcus it gets clobbered over the head by an immunosuppressive?

Again, immunosuppressive toxins seem to be frequently overlooked as virulence factors, and this may allow that when SCV forms of Staphylococci are described as typically LESS virulent than their normal counterparts, to overlook whether in terms of immunsuppression, they may prove to be MORE virulent than their normal counterparts.

SCVs are sometimes suggested to be ideally adapted to survival in infected cells (see Becker K et al 2014 in previous post), and if we are talking about infected phagocytes as a possible last refuge for them, it would make sense if these surviving bacteria were particularly good at the art of immunosuppression since the number one requirement for them to persist in host cells designed to digest them, is to give those cells indigestion with immunosuppressive toxins.

(This may also raise the question of whether, even when medical professionals are careful not to select for more virulent or more antibiotic-resist strains, whether they may still be able to unknowningly select for the survival of the most IMMUNOSUPPRESSIVE strains with less that optimal antibiotic treatment).

Now, perhaps this is a long shot and it is still an ENTIRELY unfounded speculation on my part, but I am wondering just how much of this immunosuppressive adenosine might accumulate in or even near to infected cells or abscesses or boils or sinus tracts, and keep them off-limits to arriving immune cells recruited to assist, and get this - perhaps doing so even after all the bugs have been killed? At least on a cellular level, some of that might make a fair amount of sense.

We have a curious problem in treating HS that we seem to rarely if ever hear of it being a quick process (I was just describing in another thread about how metronidazole typically has to be
removed from HS antibiotic regimens after six weeks), even while we are reading all this stuff
posted here about how good rifampin is at dealing with Staph SCVs and biofilms, getting into infected cells, killing even non-reproducing bacteria and etc. - some of the things I've read make it to sound like rifampicin is accomplishing some of this in a matter of HOURS.

I have said before that maybe they just don't know when to quit with antibiotics, and I wasn't saying it to denigrate any of the fine professionals involved in these remarkable and helpful studies of HS and related antibiotic trails, but remember this is still in many ways experimental treatment, so how DO they know when to stop?

They give you antibiotics for x length of time, then when they suspend one or more of them, things get worse again so they decide to keep you on antibiotics some more, then eventually they stop them and things get worse again, etc etc until one just about wants to give up on antibiotics because there can be some troubling risks involved along with a lack of lasting benefits.

WHAT IF - because of variants, you're going to see the "it comes right back as soon as the antibiotics run out" effect whether you pull the antibiotics after 12 days, or 12 months?

WHAT IF - immune recovery is typically going to take weeks because the proposed adenosine stockpiles may tend to remain untouched by the phagocytes they incapacitate and are just going to have to keep trickling it out until they're depleted, and the phagocytes just have to wait until it is depleted before resuming business as usual?

WHAT IF - whether or not is has been suggested in literature, one of the most adventageous things about surgery for HS were the efficient and rapid removal of possible stockpiles of adenosine and/or other immunosuppressives?

WHAT IF - if it weren't for what may be relatively few stubborn persistant variants that's were talking about here, treating HS infection would be more like they give you antibiotics for two weeks and kill all the bugs, then you wait four more weeks as your immune system recovers and gets back to cleaning up messes?

WHAT IF - they used typical targeting of normal forms of our microbes, killed 99.9% of them as they might typically do, and went right back in directly and deliberately targeting persisters of whatever sort (real or hypothetical ones) to bring the eradication of the microbes to 100% to prevent recurrence?

(That's a lot of "What If"s right there, but WHAT IF they actually amounted to something?)

...For example, what about rifampicin followed by clindamycin, rather than given simultaneously, particularly if clindamycin is eventually called upon to serve as an antitoxin by way of inhibiting toxin synthesis? One might think otherwise, since it sounds like a good idea to get a possible antitoxin in there as soon as possible hence the suggestion of a simultaneous approach sounds appealing even when thinking about things more the way I'm trying to

Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients. Scheinfeld N.
http://escholarship.org/uc/item/5vw402nf

"For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline."

Deciphering the microbiology of hidradenitis suppurativa: a step forward towards understanding an enigmatic inflammatory skin disease. Delage M et al 2015.
http://onlinelibrary.wiley.com/doi/10.1111/exd.12830/pdf

"As standard antimicrobial treatments usually do not work in HS, the disease was considered as predominantly inflammatory. Recently, however, improvement or clinical remission of HS, including disappearance of inflammation in chronic lesions referred to as ‘hypertrophic scars’, was obtained using prolonged wide spectrum antibiotics such as the rifampin–clindamycin combination, the rifampin–moxifloxacin–metronidazole combination or ceftriaxone"

Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Gener G et al 2009.
http://www.karger.com/Article/FullText/228334

"RESULTS: The Sartorius score dramatically improved at the end of treatment (median = 29, interquartile range = 14.5, vs. median = 14.5, interquartile range = 11; p < 0.001), as did other parameters of severity as well as the quality of life score... CONCLUSION: The combination of clindamycin and rifampicin is effective in the treatment of severe HS."

But in fact if we want another example of how certain antibiotics might get in each other's way, we perhaps need look no further than the usual sources (i.e., the Pasteur Institute affiliates Olivier Join-Lambert and colleagues):

Dramatic reduction of clindamycin plasma concentration in hidradenitis suppurativa patients treated with the rifampin-clindamycin combination. Join-Lambert O at al 2015.
https://www.researchgate.net/publication/259826631_Dramatic_reduction_of_clindamycin_plasma_concentration_in_hidradenitis_suppurativa_patients_treated_with_the_rifampin-clindamycin_combination

"The most probable explanation for these low clindamycin concentrations is a pharmacokinetic interaction between rifampin and clindamycin. Indeed, although it has not been clearly established to date, this interaction is very likely, since rifampin is a major inducer of cytochrome P450 3A4, the main metabolic pathway of clindamycin."

Could this be why (or part of why) what sounds at first like a brilliant combination might usually deliver what may be less than brilliant results?

(I have yet to be able to explore my concerns about whether metronidazole aka flagyl might be able to likewise find some underhanded way to undermine the effectiveness of any other antibiotics it might be combined with in attempting to treat HS).

Now it may be the case that although both rifampin and clindamycin have been accused of inducing persisters (which may give rise to drug-resistant populations), clindamycin may facilitate the killing of persisters via immune cell rehabilitation though antitoxin effects, something that rifampin may not be as accomplished at

This may not be entirely a matter of just my own speculation, if these are facts they should probably be known "out there somewhere"

Increased neutrophil extracellular trap-mediated Staphylococcus aureus clearance through inhibition of nuclease activity by clindamycin and immunoglobulin. Schilcher K et al 2014.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091580/

"The micrococcal nuclease Nuc1 is one of the major S. aureus virulence factors and allows the bacterium to avoid neutrophil extracellular trap (NET)-mediated killing. We found that addition of the protein synthesis inhibitor clindamycin to S. aureus LAC cultures decreased nuc1 transcription and subsequently blunted nuclease activity in a molecular beacon-based fluorescence assay. We also observed reduced NET degradation through Nuc1 inhibition translating into increased NET-mediated clearance."

There's a very clear credit to clindamycin for stopping one of AdsA's partners in crime

Protein synthesis inhibiting clindamycin improves outcome in a mouse model of Staphylococcus aureus sepsis compared with the cell wall active ceftriaxone. Azeh I et al 2002.
http://www.ncbi.nlm.nih.gov/pubmed/12130979 (Abstract only)

"CONCLUSIONS: Antibiotic treatment of Gram-positive sepsis with a protein synthesis inhibitor decreases morbidity and mortality compared with a bacteriolytic compound. This may be caused by a reduction of the concentrations of proinflammatory/toxic bacterial components and cytokines."

I've had a recent experience which is very curious, I have recent specimens of the same sort of cyst that ruptured under the skin a year or so ago with the resulting abscess requiring urgent care. This time I got a pair of these hard, pea-sized cysts side-by-side. Both of them seem to have started in the tissues underneath the skin rather than being associated with any surface lesions, only this time one of them was near enough to the surface to be able to rupture and drain outward instead of into the surrounding tissue. I've seen before where this sort of thing might easily call for surgical removal, yet the one that drained seems to have disappeared including the cyst wall while the deeper one that can't drain outward is unaffected.

This makes me very curious whether the one that vanished was rapidly drained of a stockpile of immunosuppressive material (the very kind mentioned here for being able to exclude immune cells from abscesses), presumably allowing the immune system to quickly move in and clean it up
the remains of it even when it was directly adjacent to another likely source of immunosuppressive seepage. It also makes me very curious what else would get cleaned up in the absence of immunosuppressive toxins made by microbes.

I can't be very sure of this, I don't know where exactly this toxin is hiding - if there are many cells where immunosuppressives like adenosine are stockpiled, maybe there was extensive and possibly recent intracellular invasion at some point and I'm not entirely sure how plausible that is as I'm currently trying to work with a specialized model of a handful of infected immune cells rather than more conventional models of infection, but if this part were to be corroborated by research we might have something?

Just me, trying to have a little more HOPE with this so-called hopeless disease. As I often say, perhaps if we could aim just a LITTLE more carefully with the antibiotics...???

So once again,

Q: when did simple Staph infections become so hard to treat and how did antibiotics ever get off the ground and attain their status as wonder drugs if they were always so undependable that the bugs always come right back?

A: Wouldn't happen to have anything to do with some of these "newfangled" antibiotics, would it???

Something I don't know yet know about clindamycin is the way it distributes if applied topically. I was offered topical clindamycin but have so far declined until I understand this. IF it's absorbed through the skin and distributed evenly through the body so it kills infection wherever it may be hiding, that's one thing - IF the microbes in the lesions that I'd be slopping the stuff onto are getting a whopping point blank dose of say, 10000mg/l while some HS bacteria in a far away facial lesion are getting a sublethal trickle of .01mg/l and becoming superbugs because of it, that would be another thing.

I'm not sure I was offered the topical clindamycin by something who was giving a lot of thought to why it might be recommended for HS or whether or not it really should be, and haven't gotten back to the question yet. Clindamycin might still offer me some HS hope in spite of my being presumably Staph-free, provided my remaining bugs don't manage to develop a resistance first, so I'm hoping to proceed with caution here concerning topical antibiotics until this gets figured out. Also as I've said before, some of our problem bugs appear to be gut bugs, so leaving a gut full of possible nasty mutant bugs in the patient - as perhaps some topical or IV antibiotics might? - may not be a good idea if these bugs could find their find their way right back into problem areas such as lesions that are trying to heal.

But again, as a possible antitoxin and immune rehabilitator, clindamycin or antibiotics with similar action might help to clear out a reservoir of microbes in infected immune cells, perhaps whether or not the microbes are actually susceptible to the same antibiotics???

This is a remarkable thought, as is the idea of a bacteriostatic antibiotic (inhibits bacterial growth) having the potential to be superior to a bactericidal antibiotic even in a situation where one would swear that killing microbes outright with a bactericide might be mandatory when we cannot have complete faith in the immune system to pick up where the antibiotics left off. I don't seem to be the only one to notice this

Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram-Positive Bacterial Infections. Pankey GA & Sabath LD 2004. http://cid.oxfordjournals.org/content/38/6/864.full
"The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity... The ultimate guide to treatment of any infection must be clinical outcome."

This article corroborates the ability of protein synthesis inhibitors to also reduce toxin production by Group A Streptococcus, although hinting that perhaps timing could prove to be important

Streptococcus Clindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome. Andreoni F et al 2016.
http://jid.oxfordjournals.org/content/early/2016/07/18/infdis.jiw229.abstract
"Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential."

And another suggesting that some antibiotics may inhibit bacterial toxin production or release in Group A Strep

Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin a release. Coyle EA et al 2003. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC153301
"Linezolid and clindamycin, alone or in combination with penicillin, may optimize the treatment of GAS infections by reducing bacterial burden and exotoxin release."

This article suggests possible high overall resistance to clindamycin in HS

Microbial Profile and Antimicrobial Susceptibility of Bacteria Found in Inflammatory Hidradenitis Suppurativa Lesions. Hessam S et al 2016.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/27351708
"Analyses of 113 bacterial samples from 113 HS patients revealed bacterial growth in 95 samples (84.1%). Polymicrobial growth was found in 51 samples (45.1%). Coagulase-negative staphylococci and Staphylococcus aureus were the most commonly isolated bacteria, followed by Proteus mirabilis and Escherichia coli. Data on susceptibility testing were available for 68 samples, which yielded 129 isolates. The isolated strains were primarily resistant to penicillin G, followed by erythromycin, clindamycin and ampicillin. The highest effectiveness against isolates was observed for fosfomycin, imipenem, fluoroquinolones (moxifloxacin, ciprofloxacin, levofloxacin), and cotrimoxazole."

While this article seems to suggest lower clindamycin resistance rates (13%) in Staphylococci themselves in the specimens studied

Inducible clindamycin resistance among clinical isolates of Staphylococci.
Ciraj AM et al 2009.
Abstract with free full text link: http://www.ncbi.nlm.nih.gov/pubmed/19136780

"Clinical failure of clindamycin therapy has been reported due to multiple mechanisms that conferresistance to macrolide, lincosamide and streptogramin antibiotics. This study was undertaken to detect the presence of inducible clindamycin resistance among clinical isolates of staphylococci... RESULTS: Among the 244 clinical isolates of staphylococci studied, 32 (13.1%) showed inducible clindamycin resistance and belonged to the MLSBi phenotype... CONCLUSION: The test for inducible resistance to clindamycin should be included in the routine antibiotic susceptibility testing, as it will help in guiding therapy."

And of course a number of additional studies have nonetheless indicated some degree of effectiveness of clindamycin in HS:

Clindamycin and rifampicin dosing in hidradenitis suppurativa. Lamb R 2015.
Abstract: http://www.jaad.org/article/S0190-9622(15)00298-4/abstract
"Over a 14-month period 70 patients received rifampicin and clindamycin. Mean severity was Hurley stage II (2.4). 4% (3/70) received 150 mg BD, 66% (46/70) received 300 mg BD, 30% (21/70) received[300 mg BD (19: 450 mg BD, 2: 600 mg BD). Of those receiving 450 mg BD, 12 completed 3 months treatment: 42% (5/12) reported no improvement with subjective scores and 58% (7/12) reported a good/excellent response. "

Antibiotic treatment of hidradenitis suppurativa. Revuz J 2012.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22963962
"Treatment is usually long-term, with a frequent need for maintenance therapy. It has to be tailored to various clinical situations: intermittent development, in which "abortive" emergency treatment is used; major or major continuous forms, where combined antibiotics are used, most frequently rifampicin and clindamycin. The global treatment strategy involves a surgical approach, which can be aided but not replaced by antibiotics. While the risks of long-term antibiotic use are reduced in this specific population of "healthy" young adults, they are not absent."

Rifampicin and clindamycin for hidradenitis. Wall D & Kirby B 2011.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21414503

Clindamycin and rifampicin combination therapy for hidradenitis suppurativa. Mendonca CO, Griffiths CE 2006. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16634904
"RESULTS: Fourteen patients with HS had received treatment with combination therapy. Eight of these patients achieved remission and a further two achieved remission when minocycline was substituted for clindamycin. Four patients were unable to tolerate therapy.
CONCLUSIONS: This small retrospective study indicates that combination therapy with clindamycin and rifampicin may be effective for HS."

A systematic review of treatments for hidradenitis suppurativa. Rambhatla PV et al 2012. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22184715
"CONCLUSIONS: Shown to be effective treatments for HS were a clindamycin-rifampin combination regimen, a course of infliximab, monthly Nd:YAG laser sessions, and surgical excision and primary closure with a gentamicin sulfate-collagen sponge. Most therapies used to treat HS were supported by limited or weak scientific evidence."

Anyway, just some more literature, in case anyone else finds it interesting, useful, or encouraging.

Zhang 2014: "For example, Streptococcus pneumoniae seems to have poor ability to form persisters such that its cure by a single antibiotic can be achieved readily in a week or two. In addition, immune clearance of a small number of residual S. pneumonia seems effective, so there is usually no relapse after antibiotic treatment."

That at least TRIES to sound rather encouraging...

Sorry, I got very tired and rather silly myself about 2/3 of the way through that long piece (and probably still am). I'm sure I need to go back and sort the articles more carefully as to which antibiotics "stop toxin production" by acting in the proscribed manner and which "stop toxin production" because they (usually) kill the bugs making the toxins...

This article is interesting and admirable for trying to sort out some of the different types of variant microbes that may try to complicate HS as well as other pathologies

Persisters, persistent infections and the Yin–Yang model. Zhang, Y 2014.
http://www.nature.com/emi/journal/v3/n1/full/emi20143a.html

One of the things I found particularly interesting was comparing the material on Streptococcus pneumoniae in two different texts. While it's probably not a common concern in HS, it is supposed to be without an AdsA-type toxin, and is also supposed to be simpler to kill by both antibiotics and immune cells according to Zhang, which may be another suggestion that AdsA type toxins might be managing to interfere with antibiotics, and that offsetting this one toxin might just make considerable difference.

Firon 2014: "Homologues of ecto-5-nucleotidases are present in several Gram-positive pathogens, including Enterococcus faecalis, Bacillus anthracis, Listeria monocytogenes, Streptococcus pyogenes, and Streptococcus sanguinis but absent in the related human pathogen Streptococcus pneumoniae."

Zhang 2014: "For example, Streptococcus pneumoniae seems to have poor ability to form persisters such that its cure by a single antibiotic can be achieved readily in a week or two. In addition, immune clearance of a small number of residual S. pneumonia seems effective, so there is usually no relapse after antibiotic treatment."

That at least TRIES to sound rather encouraging...

I really need to catch up with my reading again but I'll try to fight the good fight just a little more today.

It probably begs for explanation whether production of nucleotidase is simply one of the characteristics of microbial persistence, or whether it could be an actual facilitator of microbial persistence.

I don't know the answer to that yet, but I guess that's what questions are for.

Since AdsA is ripping phosphate groups off of numerous purine nucleotides (its targets are AMP, ADP, ATP, GMP, GDP, GTP, where the P stands for phosphate)... Where does all this phosphate go?

Questions for researchers / medical professionals (I hope I'm phrasing them right)

1. Could the by-products of microbial nucleotidases be FEEDING microbial dormancy?
2. Could the by-products of nucleotidases be utilized by microbes as precursors in (dormancy- or persistence-inducing) (p)ppGpp catabolism?
3. Are phosphate transporters upregulated in persistance-related variants along with nucleotidase production? (Are there any transporters qualified for guanosine uptake, and might they also be upregulated in conjuction with nucleotidase upregulation?)
3. How many persistence phenomena (dormancy, persistence, resistance, colony phenotype, biofilm production) might be regulated via (p)ppGpp catabolism?
4. Could this occur across a gradiated scale so that the severity of microbial persistence / resistance may therefore be proportional to its production of nucleotidase toxin?
5. Are drug- or multi-drug resistant subpopulations of microbes also subpopulations featuring particularly elevated expression of nucleotidases and related proteins?
6. Could multidrug resistance in persisters be compromised by interference with these putative (p)ppGpp precursor systems, including nucleotides like AdsA?

(Also I'm not sure if it really means anything but somehow I'm very curious what may happen RIGHT BEFORE clindamycin may be managing to accomplish the killing of an intracellular microbe that technically it might not have been supposed to be able to kill. Are we still even now underestimating this type of antibiotic?)

Meanwhile, try to keep cozy and don't let this thing get you down. It's not as mysterious as it wishes it was, I'm pretty sure.

Oddly enough, I've been gathering papers related to my questions for another month now and while I can't any of them to come out and verify what I was thinking here, nothing so far has really discouraged me from what I was thinking here.

Just stumbled over this article about Staph and thought it was something I should share, since it sounds like another reason that Staphylococcus aureus may be scare in many HS patients?

(It's also interesting, with some doctors becoming more hesitant to use antibiotics for fear of creating superbugs, that some microbes don't seem to necessarily have the same reluctance to dose each other with antibiotics. Do microbes know something about using antibiotics that doctors don't?)

"...Meanwhile, a team of German bacteriologists has found that the human nostril is home to a bacterium producing a compound capable of killing several variants of the disease-causing Staphylococcus aureus. Among the staph infections the newly discovered agent can vanquish: methicillin-resistant Staphylococcus aureus (MRSA), the hospital acquired infection that kills more than 11,000 U.S. patients a year and sickens another 80,500.

The nasal resident with such superpowers is called Staphylococcus lugdunensis. In a study published in the journal Nature on Wednesday, researchers said S. lugdunensis produces lugdunin, a new class of antibiotic that not only drives down the replication of S. aureus, but does not send S. aureus into a frenzy of effort aimed at resisting lugdunin’s antibiotic action...

Many questions remain, the authors acknowledged. Not least among them is whether lugdunin, or the Staphylococcus bacterium that produces it, could itself cause disease."

http://www.latimes.com/science/la-sci-sn-antibiotic-discovery-nose-20160727-snap-story.html

PS: Don't let them fool you - the answer is YES, Staphylococcus lugdunensis which produces lugdunin and which dominates an increasing number of bacteriological studies of HS is already a known cause of infections, some of them serious. There's no need for them to be mystified over THAT question.