(Link to PubMed Abstract: http://www.ncbi.nlm.nih.gov/pubmed/20585070) 

This was a population based, nested control study of a population >66 year olds who were receiving Angiotensin Converting Enzyme Inhibitors and various antibiotics.  The numbers were impressive.  This was a 14 year study with 4148 identified admissions involving hyperkalemia.  To quote the Conclusions, it was found that “Compared with amoxicillin, the use of TMP/SMX was associated with a nearly 7 fold increased risk of hyperkalemia-associated hospitalization.  No such risk was found with the use of comparator antibiotics”.

I still believe that if you have a mild CA-MRSA infection or are considering a “step down” from either vancomycin or linezolid, then doxycycline or minocycline is frequently preferable over TMP/SMX for therapy. Sure, I have used TMP/SMX in some cases.  One of the more recent that comes to mind was a patient with CA-MRSA plus Stenotrophomonas maltophilia.  Using TMP/SMX gave me a single agent I could use to cover both bugs.  I don’t want to “trash” TMP/SMX but given all of the data out there on potential problems with it, I would encourage you to chose it with a full understanding of the issues surrounding it and not just because you see others prescribing it so freely and randomly.

McCarthy NL, et al.  Health care-associated and community associated MRSA infections: A comparison of Definitions.  American Journal of Infection Control, 2010:  This retrospective chart review attempts to determine risk factors for CA-MRSA and HA-MRSA based on two commonly used definitions; the epidemiology of the infection and the phenotypic antibiotic sensitivity without looking at the genotype (i.e. looking for the SCCmecIV gene to determine a USA300 strain).  Not surprisingly, to quote their Conclusion from the Abstract “We found few differences between CA- and HA-MRSA infections regardless of how health care association was found. We believe that the migration of CA-MRSA into health care settings and the recent increasing antibiotic resistance of CA-MRSA strains contribute to the lack of factors associated with HA (vs CA) MRSA.”  One finding I did think was particularly relevant was that CA-MRSA accounted for the overwhelming majority of skin and soft tissue infections (p <.0001).

For the past year or two I have been lecturing and writing that the use of classic “risk factors” to determine HA vs CA was a technique of the past. This was recently driven home to me when I saw 3 patients in the hospital with MSSA, 2 of whom were 80+ years old and lived in long term care facilities while I had a perfectly healthy 30 something with no pertinent medical history whatsoever present with a CA-MRSA.  I still continue to use the phenotypic method of looking at antibiotic susceptibilities, particularly toward Bactrim and tetracyclines since we have not seen much CA-MRSA resistance to these drugs at our facility.  It is becoming clearer that perhaps we will need to do the genetic typing, such as the TEM-PCR I discussed in a recent post to really know what we have.  Of course, it may be a moot point in skin and skin structure infections since, as validated by this report, I don’t remember seeing an HA-MRSA in over 2 years.

Nagoba BS et al. A Simple and effective approach for the treatment of diabetic foot ulcers with different Wagner grades.  International Wound Journal, April 23, 2010:  This is a retrospective case series from India that collected data from 1998 into 2009.  They looked at the application of a 3% citric acid gel preparation onto 115 diabetic foot ulcerations of various Wagner classification severities up to, and not including grades IV and V.  Of interest to me was that they took cultures of all of the wounds and performed broth dilution sensitivities of all the organisms against the citric acid.  They found that in grade I-II ulcerations they had 94%+ healing in 5-34 applications.  They also found that in deeper wounds there was marked decrease in slough and drainage with increases in healthy granulation.  They concluded that citric acid was safe and maybe even promoted granulation tissue while killing the bacteria found on the wounds.   

I find various problems with the design of this study and am not reporting it because I consider it an earth shattering breakthrough.  Rather, I bring it to your attention because, currently, one of the “Holy Grails” of wound healing is to find an safe, effective, affordable topical antimicrobial to, perhaps, assist in wound healing.  Heck, I am still not even convinced that bioburden reduction is all that many claim it is, as I have blogged before, however, we are all programmed to kill bacteria on a wound and maybe this is an option.  It should probably at least be looked at in more detail.

Traunmuller F, et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections.  International Journal of Antimicrobial Agents, 2010:  This study assayed fluid from interstitial spaced, inflamed subcutaneous adipose tissue and metatarsal bone from patients with inflamed diabetic foot infections who were at steady state condition after 600 mg twice daily dosing of linezolid.  What they found was not particularly surprising; in all tissues linezolid penetrated to a level that was similar, if not slightly higher than what was found in plasma.  To quote their Abstract “We conclude that linezolid administered at 600 mg twice daily may be considered an effective treatment in diabetic patients suffering from bacterial foot infections complicated by osteomyelitis”. 

We all know that linezolid is not FDA indicated for the treatment of osteomyelitis.  In fact, NO antibiotic marketed in the past 10-12 years has been indicated for osteo, not because they don’t work but because the FDA has not developed “Guidance for Industry” on how to perform an osteomyelitis study.  I have also never been a believer in the concept of “bone penetration” as being an important indicator of osteo efficacy.  They techniques have never been standardized and really, to my mind, penetration numbers mean nothing. That all being said, at least this paper gives those of you who remain stuck on the concept of bone penetration evidence that linezolid does get into, not only bone but also frankly infected diabetic foot tissues.  This is not unlike data published by Gary Stein, PharmD and recently reviewed in the Jan/Feb 2010 issue of the Journal of the American Podiatric Medical Association (Nicolau DP, Stein GE. Therapeutic options for diabetic foot infections: A review with an emphasis on tissue penetration characteristics)

Prior to my session, I will be in the Exhibit Hall from 9:30 – 11:30 at the Data Trace Booth to sign copies of the Handbook, talk about this blog and just answer questions anyone might have about treating infections.

I hope to see folks there!

A Diabetic Foot Infection in Malatya, Turkey

In preparation for my talks I was asked to concentrate on the importance of a team approach to amputation prevention. Having just returned from DFCON I was up to date with the latest published data and reports from around the world about the successes that true amputation prevention teams have achieved in reducing the rates of “major” amputation. I have always found it amazing, if not a bit troubling, that smaller, less developed nations can codify a network of diabetic foot centers throughout their countries more than we have accomplished here in the United States. Even Pakistan and Kosovo, as discussed at this year’s DFCON, are able to reduce amputation rates by starting these centers. Turkey has made some progress towards the goal of developing amputation prevention teams.  Just last year Yesil, et al from Dokuz Eylul University Medical Center in Izmir (a facility, unfortunately, I did not have a chance to visit) reported a reduction of major amputations after starting such a team. (Yesil S. et.al. Exp Clin Endocrinol Diabetes, 2009).  In Istanbul I was honored to meet Dr. N. Saltoglu at Cerrahpasa Medical School, Istanbul University, when I gave one of my lectures to their Infectious Diseases faculty.  Dr. Saltoglu has just recently started a multidisciplinary diabetic foot team at this large institution of >1800 beds.  They are already beginning to see positive outcomes. 

During my trip I also lectured to the infectious disease faculties at Universities in the cities of Malatya and Kayseri both in the Eastern Provinces of the country.  They were very interested in the concept of starting comprehensive diabetic foot teams but were stymied by much the same turf battles and, dare I say, ego issues that we find here in the US.  Patients are treated by their local primary physicians for protracted periods before being sent to the hospital specialists.  Once admitted they are shuttled between various services including endocrinology, vascular surgery, orthopedic surgery and internal medicine with each passing the patient off to another service once their particular part of the job is completed with little coordination of effort.  The ID physicians, in particular, play a very primary role in the treatment of DFI and expressed frustration that, by the time they see the patient, it is often very late in the progression of the disease and they are dealing with infections that have received multiple, often inadequate antibiotics and now present with multi drug resistant pathogens.  The universal regret, oft expressed at DFCON, about the patient being seen too late in the progression of the disease was repeated time and time again.  It just goes to show that you can travel 5000 miles from home to a totally different culture, yet some issues are universal! 

A few other thoughts and interesting findings about lower extremity infections in Turkey:

1.  MRSA is not the problem we have here.  In fact, in most hospitals the rates have been decreasing the past 5 years.  Furthermore, they do not differentiate MRSA into HA- vs. CA- strains. The common thinking is that CA-MRSA is not a widespread problem and they just do not worry about it.  This is a huge difference from here where I need to treat everybody as if they have CA-MRSA until proven otherwise. 

2.  There are different antibiotics.  Whereas we use so much vancomycin for our MRSA in-patient soft tissue infections, their drug of first choice is teicoplanin.  This is another glycopeptides that, although widely used in other parts of the world, never received its US approval.  Like vancomycin, teicoplanin presents its own set of problems with dosing including having to give adequate loading dose, measuring troughs and the potential for liver toxicity. There may also be “MIC Creep” issues with MRSA and teicoplanin.  Another unique antibiotics is cefoperazone/sulbactam a β-lactamase inhibitor combination I remember reading about 20 years ago when it was thought that it might be brought into the US.  Other drugs are the same including piperacillin/tazobactam, ertapenem and imipenem. 

3.  ESBLs are a major problem.  Whereas we are just now beginning to see extended spectrum β-lactamase (ESBL) producing gram negative rods here in our US diabetic foot infections, Turkey has had them for years.  In fact, there are enzymes found in Turkey that you would be hard pressed to find anywhere else in the world.   Surveillance surveys have found gram negative resistance rates to cephalosporins and even quinolones in the 50-60% range.  It is felt that some of this may be caused by the long term, inadequate antibiotic therapy that is often started by primary physicians or even pharmacists before the patient is seen by the ID specialists.  And, of course, the universal overuse of the flouroquinolones is thought to contribute.   

4.  Acinetobacter, especially multi-drug resistant strains, is a problem.  I found this particularly interesting given the well documented outbreak of Acinetobacter infections that has been reported in our troops returning from the current Middle Eastern conflict.  When in some of these Eastern sections of Turkey one is not far from Iraq and Syria.  Perhaps there is something in the environment or the locale that propagates this organism.

With Dr. Bayindir, Director of Infectious Diseases, University Hospital, Malatya, Turkey

TaiGen Announces Nemonoxacin (TG-873870) Once-A-Day Oral Dosing in Diabetic Foot Infection Met Primary Endpoints

According to its manufacturer TaiGen, nemonoxacin, a novel, non-fluorinated quinolone has shown promising results in a single armed, multinational, proof of concept Phase II clinical trial against diabetic foot infections (DFI). What is unique about this drug is that, unlike other currently available quinolones, nemonoxacin has activity against MRSA and vancomycin resistant gram positive organisms.  Those who have heard me lecture know that I have not been a huge fan of quinolones in the treatment of gram positive infections since, especially earlier generation drugs such as ciprofloxacin could, and often did, cause rapid development of resistance in these organisms.  In fact, a number of quinolones have been implicated in potentiating MRSA development.  Seeing a new agent in this class with this broadened gram positive coverage is really interesting and has potential to be an important therapeutic advance.

The use of quinolones in the treatment of DFI has an interesting history.  The first antibiotic ever officially labeled by the FDA for the treatment of “complicated skin and skin structure infections including diabetic foot infections” was a quinolone…trovafloxacin (Trovan®, Pfizer).  Unfortunately, the drug, having been granted the most indications of any new antibiotic at the time of release, 14, was heavily marketed and possibly over utilized.  A number of deaths resulted, although there has been question about the agent’s role in those deaths, and the drug was essentially pulled from the market (although it was technically still available it had extreme restrictions placed on its use by the FDA). Trovan was unique in that it was extremely broad spectrum including activity against many common gram-positives, gram-negatives, and even anaerobes. So, its spectrum of activity was extremely promising for use in DFI.  Few other quinolones that have been developed share the broad spectrum that Trovan possessed.   A number of other broad spectrum, anti-anaerobic quinolones looked to show promise in the treatment of DFI but were never pursued. Gemifloxacin received indications only for respiratory infections. Gatifloxacin was marketed for skin and skin structure infections but was pulled from the market when it was found to cause problems with glucose homeostasis.  Moxifloxacin has a spectrum of activity very similar to Trovan and should be useful in DFI.  It does have an indication for complicated skin and skin structure infections, is given orally and once daily.  However, it has not received a DFI indication.  A number of years ago a DFI trial was started but, from what I understand, was stopped mid stream.  I am not privy to the reasons the trial was halted and development for this indication stalled.  The drug has recently been acquired my Merck in its merger with Schering Plough.  Merck has a long history of DFI drug development so it will be interesting to see if anything comes of this.

Quinolone have been perhaps the most abused class of antibiotic.  They have been massively overused because of their perceived broad spectrum and safety.  However, a significant number of these drugs have been pulled from the market for toxicities.  I mentioned 2 above, trovafloxacin and gatifloxacin.  There have been others.  Be aware of problems ranging from liver and renal toxicity to neurotoxicity and photosensitivity.  Last but not least, in the past few years they have received the dreaded FDA “Black Box” warning for the role they can play in tendon ruptures, particularly of the Achilles tendon.  Please use these antibiotics prudently when indicated.

The second study, out of the Netherlands, explored the issue of decolonization in nasal carriers of S. aureus.  http://content.nejm.org/cgi/content/short/362/1/9.  A total of 6771 patients were screened on admission using PCR for rapid identification of the Staph.  1270 swabs were positive, 808 underwent a surgical procedure.  The patients were all treated with mupirocin nasal ointment and chlorhexidine soap vs. a placebo.  The rate of S. aureus infection was 3.4% in the treated group vs. 7.7% in the placebo group.    Interestingly, ALL were methicillin susceptible (MSSA) so the study may, or may not be able to be extrapolated to MRSA carriage.

Hospital acquired infections, particularly surgical site infections cause a tremendous amount of morbidity and mortality not to mention costing billions of dollars to treat.  The monetary situation is complicated by CMS guidelines that may not pay a hospital for treatment of any nosocomial infection.  Therefore, new and improved techniques for minimizing these infections are being studied.  Some of what is done today for infection prevention in the surgical suite has not changed much in decades i.e. the use of the povidone iodine prep.  I remember doing those back when I was a surgical resident in the early 1980s!  Chlorhexidine is by no means a new product.  In fact, it may be older than povidone iodine.  A quick PubMed search finds papers going back to the 1960s.  More recently, the combination of chlorhexidine with alcohol has shown to be a better antiseptic with longer activity than chlorhexidine alone.  This is true not only for prepping the patient but also as a hand prep for the physician.  This recent study just shows us that as new high level evidence becomes available, we may have to change some very ingrained thoughts and practices.

As for the nasal carriage paper, I find that interesting and not unexpected.  What needs to be looked at is carriage of MRSA and surgical site infections.  There are some papers out there and I do discuss them in the book.  This is a more involved topic for another post. 

Without going into too much detail (which may infringe on copyright?), I would like to point out a few important take home messages that I got out of this paper and from my review of other literature on the subject. First some of the positives:

1.  The usual dose is 10mg/kg q24h.  Thus, we have the ease of a once daily dosing

2.  The drug is consistently bactericidal against most S. aureus.   Various reviews have shown that this probably has little impact in the treatment of cSSSI and may be more important in blood stream infections for which this drug is not approved.

3.  It is effective against MSSA, MRSA, VISA and hVISA.  It is also effective against daptomycin and linezolid resistant strains.  It does not have activity against the most common strains of VRE.

4.  Unlike vancomycin, there is no call to monitor serum trough levels

5.  In two pivotal cSSSI clinical trials it was found to be “non inferior” (FDA speak) to vancomycin. 63% of the S. aureus strains were MRSA making it the largest number of MRSA patients in a cSSSI study to date.

Now some downsides:

 1.  It is primarily excreted through the kidneys so significant dosage modification must be made in cases of renal insufficiency. The recommendations are the full 10 mg/kg q24h if the creatinine clearance is >50 mL/min, 7.5 mg/kg if 30-50 and 10 mg/kg q48h if the clearance is <30.

2.  Chronic, infected diabetic foot ulcerations were specifically excluded from the two pivotal trials!  I don’t see this drug receiving the coveted “…including diabetic foot infections” approval anytime soon.

3.  Although the overall safety looked comparable to vancomycin there were higher rates of some significant adverse events including altered taste, nausea and vomiting along with an increase in renal events.  On the other hand, vancomycin had higher rates of infusion reactions

4.  The drug has received a black box warning for fetal risk.

So what is the bottom line?  I agree with the authors of this review that we need new novel antibiotics to combat MRSA especially given all of the increasing reports of vancomycin MIC creep and treatment failures.  Many of the drugs that looked promising earlier in their development have either been slowed considerably (ceftobiprole) or stopped totally (oritavancin, iclaprim) so the once fertile pipeline is looking a bit thin.  Telavancin gives us one more drug to add to that relatively short list of alternatives to vanco especially with organisms that have developed resistance (although extremely rare) to those other antibiotics.  At this early point in its history, I am somewhat concerned about its lack of diabetic foot infection data and its increase in adverse events compared to vanco.  The black box may also impact some potential patients.  Given that we have other vanco alternatives with years of clinical experience, including diabetic foot data, and well known safety profiles I may feel more comfortable seeing more clinical data and published AE experiences before jumping in with both feet.

http://money.cnn.com/news/newsfeeds/articles/marketwire/0572888.htm

Many of us had pretty high hopes for this antibiotic as it was to be the first cephalosporin active against MRSA.  Although it is IV only, the idea of having a new MRSA agent that was in a class of drugs well liked and trusted by most, was appealing.  It is also broad spectrum against a wide range of other Gram positive and Gram negative organisms. J&J even performed a clinical trial specifically looking at diabetic foot infections with promising results thus hoping to become only the 4^th antibiotic (after linezolid, ertapenem and piperacillin/tazobactam) with that specific FDA indication.  The drug was initially submitted for approval way back in 2007.  The FDA sent an Approvable Letter questioning conduct at some of the study sites.  The action taken yesterday by the Agency now seems to totally question the viability of the two pivotal trials.  This may mean that entirely new studies would have to be completed thus delaying this drug for years more.  It will be interesting to continue to watch this.

In the meantime, all is not lost for anti-MRSA cephalosporins.  The drug most thought would be the late-comer to this party, ceftaroline, seems to be moving ahead.  I will keep you all informed as I hear anything new.

I wish all of my readers a healthy, happy and prosperous, New Year

Clinical Infectious Diseases (CID) – put out by the Infectious Diseases Society of America www.idsociety.org and my favorite clinical ID journal.

Journal of Infectious Diseases (JID) – also an IDSA journal.  Mostly HIV and intense basic research but does occasionally publish in interesting review or bacteriology manuscript.

Antimicrobial Agents and Chemotherapy (AAC)  - this journal, published by the American Society for Microbiology asm.org is the best source for new antibiotic research and clinical microbiology

I periodically also receive manuscript files sent to me by a network of ID friends and colleagues. 

Although I try to review each as they are received I admit that, occasionally, they get lost in a pile on my desk. Because of prior commitments, I admit that this is what has happened over the past 3 months and I have been remiss in my reviewing of these back issues.  So, to bring folks up to speed, here are a few papers of relatively recent vintage that I find interesting.

 Thomas Lodise, et. al. Relationship between initial vancomycin concentration – Time profile and nephrotoxicity among hospitalized patients.  CID, August 15, 2009.  Tom Lodise’s pharmacology group from Albany has been doing some terrific work looking at nephrotoxicity of vancomycin given recent recommendations to increase trough levels to between 15-20mg/L.  Just last year in AAC they published their findings that bumping vanco doses to 4 grams/day (sometimes necessary to achieve these higher peaks) was associated with a significantly higher rate of nephrotoxicity.  In this study they concluded that “The results indicate that a vancomycin exposure – toxicity response relationship exists.  The vancomycin trough value is the pharmacodynamic index that best describes this association.”  I have blogged about this vancomycin dosing issue in the past.  Maybe I am being selective about what I read and share but I still have issues with this concept of bumping vanco trough levels especially given the total lack of data in diabetic foot infections where the patients may already have compromised kidneys. 

 Micheal Ryback, et. al. Vancomycin Therapeutic Guidelines: A summary of consensus recommendations from the IDSA, the American Society of Health System Pharmacists and the Society of Infectious Diseases Pharmacists.  CID, August 1, 2009.  Perhaps I should have listed this article before the one above since this summarizes the guidelines that promote this new dosing regimen and the concept of achieving an AUC/MIC ratio of >400 by using weight based dosing and bumping troughs.  Considering the attention given to these new guidelines my readership should become very familiar with them.  The full, original document can be accessed at http://www.ashp.org/DocLibrary/BestPractices/TPSVanco.aspx

 Shveta Rani Singh, et. al. In vitro 24-hour time-kill studies of vancomycin and linezolid in combination versus methicillin resistant Staphylococcus aureus.  AAC Oct. 2009.  This title is a perfect example of what one can expect reading AAC.  Once you get past the wordy titles there is some great information.  I found this interesting because, apparently, there are clinicians trying all different antibiotic combinations to fight MRSA. The authors found that there was no synergy at all, and, in fact, frank antagonism occurred in 3 out of 5 strains when linezolid was added to vancomycin.  The bottom line…try other combinations if you must, just not this one.

 Stan Deresinski. Vancomycin in combination with other antibiotics for the treatment of serious MRSA infections.  CID Oct 1, 2009.  Stan Deresinski out of Stanford University has become a bit of a “go to guy” when it comes to MRSA and the ID community.  I urge all of my readers to find his 2005 CID review paper  Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic,and Therapeutic Odyssey which remains one of the most easily digestible treatises on the topic.  In this more recent review he scans the literature to find support of the commonly employed practice of combining vancomycin with a second antibiotic usually rifampin or gentamicin and finds to supportive evidence for these combinations but known potential toxicities.   

 Jose L. Del Pozo, et al. The electricidal effect is active in an experimental model of Staphylococcus epidermidis chronic foreign body osteomyelitis.  AAC Oct. 2009. This interesting rabbit study compared low amperage (200 µA) electrical current to IV doxycycline treatment to no treatment for foreign body osteomyelitis in the rabbit tibia.  As expected, both treatment groups were significantly better than the no treatment group.  Interestingly, the electrical current group was significantly more efficacious than the doxycycline group.  They feel that this might be related to the activity of the current against the bacterial biofilms.  This entire area of bioflims as determining factors in the treatment of chronic infections is fascinating and bears watching. 

Let me know what you think of the concept of writing up these reviews, and please suggest other papers you would like to hear my opinion about

Traditional approaches to empiric antibiotic selection suggests that you should chose the narrowest spectrum antibiotic against the organisms you suspect are causing the infection.  This, of course, would then be modified based on definitive culture results (if obtained) and the patient’s clinical response. Until relatively recently I would NOT have included MRSA coverage in my empiric selection for most patients.  I believed that beginning therapy against MSSA would be, for most cases except the most severe life and limb threatening infections, sufficient and then, if MRSA was cultured I could always ESCALATE therapy to include MRSA coverage.  My thinking on this approach starting changing about a year or so ago when I was called in to see a patient in our Emergency Department.  This 36 y/o healthy male had no history of any hospitalizations and related not remembering ever taking any antibiotics.  He had dropped a trash can on his foot at work and thought nothing of it until the 1^st MTP joint started becoming hot, red and painful.  During the History, I even specifically asked him “Have you or any of your family members ever had MRSA”.  Now, you pretty much have to be living under a rock not to have heard about MRSA given all of the press coverage.  His answer to me was a simple “What’s that”.  With this History and that response I turned to the Resident and basically stated that I would “eat my hat” if this guy has MRSA.  We started him on non-MRSA coverage.  Well, I think you can imagine what happened.  48 hours later the C&S was returned as CA-MRSA (Picture below is from after initial I&D by my podiatric surgical colleague).  From this point on I have started to practice DE-ESCALATION therapy.  I start the vast majority of my patients, particularly those being hospitalized, as if they have MRSA and will de-escalate to remove the MRSA therapy if MSSA or no staph is found.  Frankly, I don’t remember the last time I was even ABLE to de-escalate.  That is how prevalent MRSA is in our local hospital.

Now, this is NOT to say that my approach is appropriate in every clinical setting and every community.  In the outpatient setting in a locale with a relatively low MRSA rate, you can still begin coverage as if there is only MSSA and switch if the patient does not respond.  Notice I said, “NOT RESPOND” and not, “what the culture report says”!  I continue to believe that patients should be treated, not lab results.  Many studies have shown that, for most uncomplicated skin and skin structure infections, I&D without antibiotic therapy is still an appropriate approach to an abscess caused by MRSA.  If you want to escalate to anti-MRSA therapy then I do believe that doxycycline or minocycline is preferred over trimethoprim/sulfamethoxazole (TMP/SMX).  The reason for this is the significant rate of adverse events found in TMP/SMX and the lack of clinical evidence supporting it.  (I will try to cover this in a future post.  I do cover it in the 3^rd Edition of the Handbook)