HIV and Methicillin-resistant Staphylococcus Aureus (MRSA)

HIV-infected patients could increase the risk for Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection, including bloodstream infection. A study reported that the incidence of methicillin resistant Staphylococcus aureus (MRSA) bacteraemia increased significantly in HIV-infected patients from 2000 to 2004. Injection drug use (IDU), end-stage renal disease (ESRD) and CD4 count <200 cells/μL were independent predictors for incident MRSA bacteraemia, while ESRD was more common in patients with MRSA bacteraemia than methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. IDU, ESRD and CD4 count <200 cells/μL factors may serve as important clinical markers of MRSA likelihood in decisions regarding initial antimicrobial management.

Initial antimicrobial therapy for presumed sepsis in HIV-infected patients may require agents active against MRSA, including vancomycin, linezolid and, in nonpulmonary infections, daptomycin, particularly in patients with risk factors for MRSA bacteraemia.

(HIV Med. 2008;9(10):858-862)

Syphilis in Pregnancy

Syphilis in pregnancy could threatening the fetus. T. pallidum could crosses the placenta, resulting in fetal infection. Vertical transmission can occur at any time during pregnancy and at any stage of syphilis. Vertical transmission of syphilis is more common in primary (50%) and secondary syphilis (50%), compared with early latent (40%), late latent (10%), and tertiary syphilis (10%). Seventy to one hundred per cent of infants born to untreated infected mothers are infected. Pregnancies complicated by syphilis may result in intrauterine growth restriction, non-immune hydrops fetalis, stillbirth, preterm delivery, and spontaneous abortion in up to 50% of pregnancies. Women who had documented treatment for syphilis in the past do not need treatment during current or subsequent pregnancies.
Penicillin is the drug of choice for treating all stages of syphilis. Parenteral rather than oral treatment has been the route of choice as the therapy is supervised and bioavailability is guaranteed. Most women treated during pregnancy will deliver before their serological response to treatment can be assessed definitively. Neonates born to such women should be evaluated for congenital syphilis. For the treatment of early syphilis during pregnancy is procaine penicillin 750 mg daily for 10 days. If it is not possible to give daily procaine penicillin on the weekend, then either long-acting procaine penicillin in aluminium stearate, 2 million units (MU) or long-acting benethamine penicillin 1.2 MU should be given IM on the Friday. Patients with penicillin allergy: erythromycin 500 mg four times a day should be given for 14 days. Alternatively, azithromycin 500 mg should be given daily for 10 days. In addition to this, examination, tests, and treatment of all babies at birth should be carried out. Desensitization to penicillin may be considered, followed by the first-line treatment. Mothers treated with erythromycin or azithromycin may be considered for retreatment with doxycycline after delivery and when breast-feeding is stopped.
(Expert Rev Vaccines. 2008;7(10):1465-1473)

Inappropriate Antibiotic Prescribing Contributes To The Higher Bacterial Resistance

Inappropriate antibiotic prescribing contributes to the problem of higher bacterial resistance. Bacterial resistance to antibiotics is a major public health problem, increasing morbidity and mortality as well as healthcare costs.

Rates of antimicrobial resistance were higher in countries with the highest consumption of antibiotics. In countries with the highest use of antibiotics, prescription rates peaked during cold and flu seasons. The antibiotics were prescribed for sore throat during 73% of visits although the prevalence of sore throat caused by bacterial infection among adults is between 5% and 17%. Moreover, most of these patients received antibiotics that were not recommended for pharyngitis, with a high number of prescriptions being for extended-spectrum antibiotics. More than half of children with sore throats received antibiotics, a rate significantly higher than the regular prevalence of bacterial pharyngitis. Furthermore, more than one quarter of these children received an inappropriate antibiotic.
In a study it was found that the rates of resistance of S. pneumoniae to penicillin, amoxicillin-clavulanate, and cefdinir were 16%, 6.4%, and 19.2%, respectively. The least effective agents against S. pneumoniae were trimethoprim-sulfamethoxazole and azithromycin, with resistance rates of 23.5% and 34%, respectively. In a study of resistance in urinary tract infections in one health maintenance organization in the United States, the prevalence of resistance among isolates of Escherichia coli to ampicillin, cephalothin, and sulfamethoxazole exceeded 20% in each of the study years 1992 to 1996. The overall prevalence of resistance to trimethoprim-sulfamethoxazole doubled between 1992 and 1996.

Maraviroc, The CCR5 antagonists

Maraviroc (Celsentri or Selzentry; Pfizer Ltd., Sandwich, UK) belongs to a new class of anti-HIV drugs named CCR5 antagonists, which block HIV entry into cells. Viral entry is an attractive step for the development of new agents against HIV variants resistant to current antiretroviral drugs. HIV gains entry into CD4-expressing cells through a series of sequential interactions between the envelope glycoprotein gp120 and the CD4 receptor and one of two coreceptor molecules, chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4), which are expressed on the surface of target cells. Maraviroc specifically inhibits the replication of R5-tropic HIV variants by an allosteric mechanism after binding to the transmembrane CCR5 coreceptor cavity. Because of its exclusive activity against CCR5 tropic strains, viral tropism testing is mandatory before using CCR5 antagonists in the clinic.

Maraviroc is a substrate for the P-glycoprotein and the cytochrome P450 (3A4), both of which are involved in the metabolism of multiple other agents, including several antiretroviral drugs. Therefore, drug interactions using maraviroc should be kept in mind. Briefly, the standard 300 mg twice daily dose of maraviroc does not require changes when the drug is given concomitantly with methadone, statins, nevirapine, cotrimoxazole, etinilestradiol nor pegylated interferon and ribavirin. However, dose adjustments have to be made when maraviroc is used along with some potent inhibitors or inducers of CYP3A4.
(AIDS. 2008;22(17):2231-2240).

Beware for Prolonged Initial Antibiotic Therapy for Extremely-Low-Birth-Weight Infants

In extremely-low-birth-weight (ELBW, birth weight of <1000 g) infants, prolonged initial empiric antibiotic therapy should be used with caution. It could cause an increased risk for necrotizing enterocolitis (NEC) or death. Although cultures from normally sterile sites usually do not yield any bacterial agents and the incidence of culture-proven bacterial sepsis is low in this population, ELBW infants admitted to intensive care nurseries usually receive empirical antibiotic treatment in the first postnatal days. A study suggested that cefotaxime for the first 3 postnatal days is associated with higher mortality risk, even for the most preterm infants.
(Pediatrics. 2009;123;58-66).

Acquired Vancomycin Resistance Pathogens

Acquired vancomycin resistance appears to be a serious and growing therapeutic challenge among various Gram-positive pathogens worldwide. In Enterococcus, different types of gene clusters encoding vancomycin (and teicoplanin) resistance have been identified; the vanA and, to a lesser extent, the vanB types are the most prevalent. Occasionally, the vanA cluster spread to S. aureus, constituting the first seven cases of VRSA (vancomycin-resistant S. aureus) that all emerged independently. Vancomycin treatment failure can be associated with van-independent mechanisms of (intermediate) resistance to vancomycin and seems to be an increasing problem in S. aureus and the CNS (coagulase-negative staphylococci).
(Future Microbiol. 2008;3(5):547-562)

Drug-drug Interactions (DDI)

It is a difficult task to find the most appropriate medication regimen for our patients. Patients sometime require multiple medications placing them at risk for drug-drug interactions (DDIs). DDI is a situation that occurs when 1 of a combination of drugs alters the effect of another drug. Drug-drug interactions may result in decreased therapeutic benefit, adverse effects, or patient harm. Non-prescription medications, herbal preparations, and complementary medications also contribute to patient polypharmacy and the potential for DDIs.

DDIs contribute to patient morbidity and may cause emergency department visits, hospitalizations, and re-admissions. Examples of patient morbidity caused by DDIs include gastrointestinal (GI) bleeding, renal dysfunction, electrolyte imbalance, hypertension, hypotension, bradycardia, arrhythmia, drug toxicity, and decreased drug effect.

Well known examples of mortality associated with DDIs include fatal outcome from a warwarin and nonsteroidal anti-inflammatory drug (NSAID) interaction, ciprofloxacin in fatal seizures, and moclobemide-clomipramine overdose in fatal serotonin syndrome. Other examples are fatal interactions between tranylcypromine and imipramine and also between methotrexate and trimethoprim.
Polypharmacy, narrow therapeutic range of the medication (eg, digoxin, cyclosporine, warfarin), decreased renal and or hepatic function of the patient each may increase the risk for DDIs and should be identified prior to coadministration. One should consider the potential for DDIs at all steps of the drug-delivery process. Furthermore, an increasing number of medications administered further increased the risk for adverse effects. Literatures said patients taking 2, 5, and 7 medications had a 13%, 38%, and 82%, respectively, for developing adverse drug interactions.
Advanced age is an additional risk factor for DDIs. The need for multiple medications often arises with advancing age that may further the risk for DDIs. Other patient-related risks for DDIs include very young age, female sex, genetics, decreased organ function, major organ impairment, metabolic or endocrine risk conditions (eg, hypothyroidism, hypoproteinemia), and acute medical issues (eg, dehydration).

Amlodipine Plus Benazepril Combination For Hypertension Therapy

Although the optimal pharmacotherapy regimen for hypertension is not yet determined, current guidelines recommend inclusion of a diuretic. The guidelines prefer to use diuretics as monotherapy or to use diuretics and an ACE inhibitor in combination therapy. However, recommendation of thiazide-type diuretics as initial therapy for most patients with hypertension needs to be reexamined. Combination therapy is probably a good initial strategy for high-risk patients, rather than starting with one drug and going slow.

Treatment with antihypertensive combination therapy (the angiotensin-converting enzyme (ACE) inhibitor benazepril plus the calcium-channel blocker amlodipine) is more effective than treatment with the ACE inhibitor and diuretic. Studies suggest that the calcium-channel blocker amlodipine effectively increases the availability of vascular endothelial nitric oxide and that the combined effects of amlodipine and an ACE inhibitor on nitric oxide are greater vs the effect with either drug alone.

In patients with hypertension who were at high risk for cardiovascular events, the benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing the primary composite outcome of cardiovascular events and death. The single-tablet benazepril-amlodipine combination reduced the risk of morbidity and mortality by 20% compared with conventional therapy. Putting patients on either combination doubled their control rate, so combination therapy is something clinicians need to think about, even if they want to keep the diuretic. But the drug that gives superior cardiovascular outcomes is the calcium-channel blocker and ACE inhibitor.

The cardiovascular benefits of specific classes of antihypertensive drugs may go beyond their effect on blood pressure. The combination of amlodipine and benazepril appears to synergistically reduce left ventricular hypertrophy and arterial stiffness, suggesting that they may protect target organs independently of the drugs' antihypertensive effects.

References:

Jamerson K, Weber MA, Bakris GL, et al. 2008. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 359: 2417-2428.

Chobanian AV. 2008. Does it matter how hypertension is controlled? N Engl J Med. 359:2485-2488.

New Guidelines for HIV Treatment

In AIDS 2008-XVII International AIDS Conference, the International AIDS Society–USA recommends new guidelines for HIV treatment. This recommendation is simplified and strengthened. One change in the recommendations is a greater emphasis on full virologic suppression. In this recommendation, deciding whether to start treatment in patients with a CD4 cell count of 350 cells/μL or more should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient willingness to begin treatment. Individuals with incomplete virologic suppression have greater morbidity and mortality than those who more completely suppress it.
The guidelines move aggressively toward earlier initiation of antiretroviral therapy. Treatment should be started before CD4 cell count decreases to less than 350/μL if there are correlates of faster HIV disease progression such as high plasma viral load (>100,000 copies/mL), rapidly decreasing CD4 cell count (>100/μL per year), active hepatitis B or C virus coinfection (resulting in faster progression of liver disease), cardiovascular disease risk, and HIV-associated nephropathy. Initiation of therapy in patients within the 200 to 350/μL CD4 cell count range should be strongly considered and individualized. The recommendations to start therapy in any patient with symptomatic HIV disease, regardless of CD4 count or viral load, and asymptomatic patients with less than 200/μL CD4 cell count.
Clinicians are encouraged to evaluate the whole patient, not just the status of HIV disease, but all coexisting conditions. Resistance testing should be conducted in all patients as part of their baseline workup. There is a little change in recommendations for an initial regimen in patients who are not infected with resistant virus. The first-line choice is a backbone of either an NNRTI or a ritonavir-boosted protease inhibitor (PI), combined with a dual nucleoside reverse transcriptase inhibitor (NRTI) component. The initial treatment regimen for HIV infection must be individualized, particularly in patients with comorbid conditions, but typically includes efavirenz or a ritonavir-boosted PI plus 2 NRTIs (tenofovir or emtricitabine or abacavir or lamivudine). Better not using darunavir as part of an initial regimen but holding it in reserve to use with patients who develop resistance to other PIs. Current first-line regimens are good and simple to use, and there is still concern about holding some drugs in reserve for patients who develop resistance to existing drugs. Even in heavily pretreated patients, the goal of treatment is an HIV-1 RNA level below assay detection limits. Treatment failure should be promptly identified and managed.

Depending on the NRTI mutations present, one might want to consider use of etravirine. Failure of a PI-based regimen can be more complicated, depending upon the genetic barriers. If caught early, changing the NRTI component to 2 active drugs might be sufficient to save the regimen. But as resistance points accumulate, one should consider use of darunavir or tipranavir.

The 3 drugs approved since the last version of the guidelines in 2006 are maraviroc, the first drug to target the CCR5 co-receptor on the surface of the cell; raltegravir, the first drug in the integrase inhibitor class; and etravirine, a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with clear activity against some NNRTI-resistant viruses. Enfurvitide remains an important option for the heavily treatment experienced population, but problems associated with daily injections and the emergence of other therapeutic alternatives such as raltegravir or maraviroc have reduced its use.

(AIDS 2008: XVII International AIDS Conference. Antiretroviral Treatment of Adult HIV Infection, 2008 Recommendations of the International AIDS Society–USA Panel. Presented August 3, 2008. JAMA. 2008;300:555-570)

Clostridium difficile-associated disease (CDAD)

Clostridium difficile-associated disease (CDAD) is an important nosocomial infection associated with healthcare, and it may recur in 15% to 30% of patients. The agent, Clostridium difficile, is a Gram-positive, anaerobic spore-forming bacillus. C. difficile was first identified as an aetiological agent of antibiotic-associated pseudomembranous colitis in the late 1970s. Approximately 15% to 20% of antibiotic-associated cases of diarrhea and nearly all cases of pseudomembranous colitis have been attributed to this bacteri. The incidence of CDAD has steadily climbed in the past decade, and it is an important cause of morbidity both in North America and in Europe.

Rapid diagnosis of CDAD further allows implementation of infection control measures and timely treatment. Stool assays is not a good strategy for rapid diagnostic since the false-negative rates is very significant. The best methods for rapid identification of C. difficile–associated pseudomembranous colitis is sigmoidoscopy.
Control of C difficile infection requires prudent use of antimicrobial agents, prevention of cross-infection, and ongoing surveillance. For patients with mild CDAD, discontinuation of the causative antibiotics without further treatment may be sufficient. Many guidelines recommend the use of metronidazole, an imidazole derivative, in patients thought to need antibiotic treatment, however it has a high failure rates and and resistance to metronidazole has been reported. Controlled clinical trials have shown efficacy for CDAD treatment with vancomycin, a glycopeptide. The mean duration of symptoms was also significantly shorter with vancomycin comparing with that of metronidazole. For patients with severe CDAD, intensive care unit (ICU) admission may be needed. A combined medical and surgical approach is recommended, with surgical resection of the inflamed colon as a therapeutic option.

The Tendon Rupture in Fluoroquinolone-treated Patients

Fluoroquinolone products (ciprofloxacin [Cipro, Bayer; and generics] extended-release ciprofloxacin [Cipro XR, Bayer; Proquin XR, Depomed], gemifloxacin [Factive, Oscient) levofloxacin [Levaquin, Ortho McNeil], moxifloxacin [Avelox, Bayer], norfloxacin [Noroxin, Merck], and ofloxacin [Floxin, Ortho McNeil; and generic]), increase the risk for tendon rupture.